Abstract

Background

Sugammadex shows a dose–response relationship for reversal of neuromuscular block (NMB) during propofol anaesthesia. Sevoflurane, unlike propofol, can prolong the effect of neuromuscular blocking agents (NMBAs), increasing recovery time. This open-label, randomized, dose-finding trial explored sugammadex dose–response relationships, safety, and pharmacokinetics when administered for reversal of moderate rocuronium- or vecuronium-induced NMB during sevoflurane maintenance anaesthesia.

Methods

After anaesthesia induction with propofol, adult patients were randomized to receive single-dose rocuronium 0.9 mg kg−1 or vecuronium 0.1 mg kg−1, with maintenance doses as needed. Anaesthesia was maintained with sevoflurane. NMB was monitored using acceleromyography. After the last dose of NMBA, at reappearance of T2, single-dose sugammadex 0.5, 1.0, 2.0, or 4.0 mg kg−1 or placebo was administered. The primary efficacy variable was time from the start of sugammadex administration to recovery of T4/T1 ratio to 0.9. Safety assessments were performed throughout.

Results

The per-protocol population comprised 93 patients (rocuronium, n=46; vecuronium, n=47). A statistically significant dose–response relationship was demonstrated for mean recovery times of T4/T1 ratio to 0.9 with increasing sugammadex dose with both NMBAs: rocuronium, 96.3 min (placebo) to 1.5 min (sugammadex 4.0 mg kg−1); vecuronium, 79.0 min (placebo) to 3.0 min (sugammadex 4.0 mg kg−1). Plasma sugammadex concentrations indicated linear pharmacokinetics, independent of NMBA administered. No study drug-related serious adverse events occurred. Evidence of reoccurrence of block was reported in seven patients [sugammadex 0.5 mg kg−1 (suboptimal dose), n=6; 2.0 mg kg−1, n=1].

Conclusions

During sevoflurane maintenance anaesthesia, sugammadex provides well-tolerated, effective, dose-dependent reversal of moderate rocuronium- and vecuronium-induced NMB.

Key points

  • Sevoflurane anaesthesia has the potential to prolong NMB.

  • The effect of sevoflurane on sugammadex reversal of rocuronium and vecuronium is explored.

  • Sugammadex 0.5, 1.0, 2.0, or 4.0 mg was given on recovery of T2.

  • A clear dose–response relationship was found for both NMB drugs.

  • This was similar to the doses described for total i.v. anaesthesia with propofol.

Sugammadex (Bridion®, MSD, Oss, The Netherlands) is a modified γ-cyclodextrin developed specifically for the rapid reversal of neuromuscular block (NMB) induced by the steroidal neuromuscular blocking agents (NMBAs) rocuronium and vecuronium.1–4 Preclinical and clinical data indicate a favourable efficacy and safety profile of sugammadex1,5 when compared with current frequently used acetylcholinesterase inhibitor–anticholinergic drug combinations.

Studies of sugammadex have consistently shown that sugammadex rapidly and effectively reverses moderate and profound rocuronium-induced NMB in patients under propofol maintenance anaesthesia.6–12 A dose-finding study in patients receiving propofol maintenance anaesthesia has shown a dose-dependent decrease in time to recovery from moderate vecuronium-induced NMB.4

Sevoflurane is also widely used for the maintenance of anaesthesia11 but, unlike propofol, sevoflurane has the potential to prolong the effect of NMBAs13,14 and significantly increase time to recovery.15 This randomized, controlled study explored the relationship between sugammadex dose and neuromuscular recovery under sevoflurane maintenance anaesthesia, when administered during moderate NMB [i.e. at reappearance of the second twitch (T2)] after the administration of rocuronium or vecuronium. The pharmacokinetic and safety profiles of sugammadex were also evaluated.

Methods

This open-label, randomized, placebo-controlled, safety-assessor blinded, multicentre, Phase II, parallel group, dose-finding trial investigated 0.5, 1.0, 2.0, and 4.0 mg kg−1 sugammadex and placebo in combination with rocuronium or vecuronium. The study was conducted from September 2005 until March 2006, was approved by the Independent Ethics Committee of each trial centre, and was conducted in compliance with the current revision of the Declaration of Helsinki, the International Conference on Harmonization guidelines, and Good Clinical Practice and current regulatory requirements. All patients provided written, informed consent.

Patients were eligible for inclusion if they were Caucasian, aged ≥20 and <65 yr, categorized as ASA class I–III, and undergoing elective surgery requiring muscle relaxation in the supine position, under sevoflurane anaesthesia, with an anticipated duration of ∼1.5–3 h. Patients were excluded from the study if difficult intubation was anticipated; if they had a neuromuscular disorder that could impair NMB or significant renal or hepatic dysfunction; a (family) history of malignant hyperthermia; allergy to narcotics, NMBAs, or other medication used during general anaesthesia; or were receiving medication expected to interfere with the NMBA. Female patients who were pregnant, breastfeeding, or of childbearing potential not using an adequate method of contraception were also excluded, as were those who had participated in another trial within the previous 6 months.

Patients were allocated a subject number in sequential order of their enrolment into the trial. Randomization was performed by the study sponsor in blocks of five according to Good Clinical Practice guidelines. Each patient received a treatment code using a central randomization system that was part of a secured trial website. For the first block at each trial site, patients were randomly assigned to rocuronium or vecuronium and then to one of the sugammadex 0.5, 1.0, 2.0, or 4.0 mg kg−1 or placebo groups. In subsequent blocks, the NMBA was alternated and patients were randomized to a sugammadex dose or placebo.

An i.v. cannula was inserted into a forearm vein for administration of anaesthetic drugs, rocuronium or vecuronium, and sugammadex. A second i.v. cannula was inserted into the opposite arm for collection of blood samples for safety and pharmacokinetic analyses. Anaesthesia was induced with i.v. propofol plus an opioid (fentanyl, remifentanil, piritramide, or sufentanil) and optional nitrous oxide, and maintained using sevoflurane and an opioid (with optional nitrous oxide). Other anaesthetic practices were consistent with routine practices at the trial sites. Drugs and doses used for anaesthesia were adjusted to provide optimal patient care.

After anaesthesia induction but before NMBA administration, monitoring of neuromuscular activity was started using acceleromyography (TOF-Watch® SX, Organon Ireland Ltd, a division of Merck and Co., Inc., Swords, Co. Dublin, Ireland). Stabilization and calibration of the TOF-Watch® SX were performed according to good clinical research practice.16 Repetitive train-of-four (TOF) stimulation was applied at the wrist ulnar nerve every 15 s until the end of anaesthesia, or at least until recovery of the T4/T1 ratio to 0.9. Neuromuscular data were collected via a transducer affixed to the thumb using the TOF-Watch® SX Monitoring Program (Organon Ireland Ltd, a division of Merck and Co., Inc.).

Rocuronium 0.9 mg kg−1 (three times ED95, dose selected based on regulatory requirements) or vecuronium 0.1 mg kg−1 (two times ED95) was administered as an i.v. bolus within 10 s into a fast-running venous infusion. Tracheal intubation was performed after NMBA administration. Maintenance doses of rocuronium 0.1–0.2 mg kg−1 (rocuronium group) or vecuronium 0.02–0.03 mg kg−1 (vecuronium group) were given as necessary to maintain the NMB depth at 25% of first twitch (T1) or deeper.

After the last dose of NMBA and at reappearance of T2, sugammadex (dose according to randomization) or placebo were administered as an i.v. bolus (within 10 s) into a fast-running saline infusion. Patients did not receive any other reversal agent or an NMBA other than rocuronium or vecuronium before recovery of the T4/T1 ratio to 0.9. Clinical assessments of recovery (5 s head lift, diplopia, tongue depressor test, and general muscle weakness) were performed in fully awake, orientated patients on admission to the recovery room.

For the pharmacokinetic assessment, nine blood samples (each 5 ml) were collected from each patient for the determination of plasma rocuronium, vecuronium, and sugammadex concentrations. Samples were collected before and 2, 5, and 15 min after administration of NMBA, and before and 2, 5, 15, and 60 min (or at the end of surgery) after administration of sugammadex or placebo. Drug plasma concentrations were determined by the Department of Bioanalytics, MSD, Oss, The Netherlands, using validated liquid chromatographic assay methods with mass spectrometric detection.17 Assay methods for sugammadex, rocuronium, and vecuronium plasma concentrations could not distinguish between complexed and non-complexed sugammadex/NMBA.

Patients were monitored or questioned for adverse events (AEs) and serious AEs (SAEs) from the time of NMBA administration until the seventh postoperative day. All AEs and SAEs were coded using Medical Dictionary for Regulatory Activities (MedDRA; version 9.0). At the second and seventh postoperative days, contact was made by phone or visit (if still hospitalized) to enquire after each patient's well-being.

Safety assessments also included regular monitoring of medical device (near) incidents, laboratory variables, physical examinations, vital signs, and ventilatory frequency. Continuous cardiac monitoring of the QT interval was performed intra-operatively and after operation and any clinically significant cardiovascular event was recorded as an AE. Central body temperature was monitored and maintained at ≥35°C.

Patients were monitored for signs of recurrence of NMB for ≥120 min after recovery to a T4/T1 ratio of 0.9. Monitoring included decline in the T4/T1 ratio from ≥0.9 to <0.8 for ≥3 consecutive TOF values, and clinical evidence of respiratory problems (post-anaesthetic oxygen saturation and breath frequency). Clinical signs of possible interaction of sugammadex with endogenous or exogenous compounds (such as a change in neuromuscular recovery or a difference in the expected activity of a co-administered drug other than NMBA) were recorded.

For biochemistry and haematology analysis, three 10 ml blood samples were collected from each patient just before NMBA administration, 60 min after sugammadex or placebo (or at the end of surgery) and at the post-anaesthetic visit. Urine samples were collected for chemistry and sediment analyses before leaving for the operating theatre and at the post-anaesthetic visit.

The primary efficacy variable was time from the start of sugammadex or placebo administration to recovery of the T4/T1 ratio to 0.9. Times to recovery of the T4/T1 ratio to 0.7 and 0.8 were also determined (secondary efficacy variables). Efficacy analyses were performed using data from the per-protocol (PP) population and confirmed with data from the intention-to-treat (ITT) population.

The ITT population comprised all randomized patients who received a dose of sugammadex or placebo and had a post-baseline efficacy assessment. The PP population comprised all patients from the ITT population who had no major protocol violation, nor multiple minor protocol violations leading to exclusion of all efficacy data. The safety population comprised all randomized patients who received a dose of sugammadex or placebo. Pharmacokinetic data were analysed from the all-subjects-pharmacokinetically evaluable group, which included patients with ≥1 measurable and documented sugammadex and rocuronium or vecuronium plasma concentration and no protocol violations that may interfere with pharmacokinetics. All analyses, including pharmacokinetic analyses, were performed using Statistical Analysis Software (SAS®) version 8.2 (Cary, NC, USA).

The sample size calculation was determined based on the time to recovery of the TOF ratio to 0.9 in previous sugammadex studies.4,6,7 Assuming that ∼10% of patients would have ≥1 major protocol violation or missing data, it was calculated that 10 patients would need to be enrolled in each sugammadex and placebo group for both NMBAs, that is, 50 patients would need to be randomized to each NMBA group, to achieve a 90% success rate.

To determine the relationship between dose of sugammadex and time from the start of administration of sugammadex to recovery of the T4/T1 ratio to 0.9, the following exponential model was used: estimated time to recovery of the T4/T1 ratio to 0.9 (dose)=a+b·exp{−c·dose}, where ‘a’ represents the fastest achievable recovery time for the average subject, ‘b’ the difference in time between mean spontaneous recovery and mean recovery after an infinitely large dose of sugammadex, and ‘c’ the extent of reduction in recovery time with sugammadex.8

Weighted non-linear regression was used to fit parameters of the exponential model to the recovery times. Weighting factors used were: (1/vari)/Σ(1/vari), where vari is the variance of the recovery times at dose i. When parameters in the exponential part of the model (‘b’ and ‘c’) are statistically significantly different from zero, a dose–response effect is demonstrated.

Other data are presented using descriptive statistics.

Results

The study was conducted in six centres in Europe (two in Sweden and one each in Belgium, Germany, Poland, and Austria). One hundred patients were randomized. Forty-nine patients in each NMBA group were treated with sugammadex or placebo; 48 and 45 patients in the rocuronium and vecuronium groups, respectively, completed the full 7-day follow-up (Fig. 1). All treated patients had at least one efficacy assessment, thus the ITT population comprised 49 patients for each NMBA group. For three patients in the rocuronium group and two in the vecuronium group, sugammadex was administered more than 2 min from reappearance of T2; these patients were therefore considered to have a major protocol violation and were excluded from the PP group, which thus comprised 46 and 47 patients for rocuronium and vecuronium, respectively.

Fig 1

Patient flow diagram. ASPE, all-subjects-pharmacokinetically evaluable; AST, all-subjects-treated; ITT, intention-to-treat; PP, per-protocol.

Fig 1

Patient flow diagram. ASPE, all-subjects-pharmacokinetically evaluable; AST, all-subjects-treated; ITT, intention-to-treat; PP, per-protocol.

There were no relevant differences in baseline characteristics between sugammadex and placebo groups both within and between the NMBA groups (Table 1). Patients underwent surgical procedures of the following categories: female genital organs [33% (open surgery, n=31; laparoscopic, n=2)], digestive system and spleen [31% (open, n=24; laparoscopic, n=7)], endocrine (16%), mammary gland (10%), urinary system, male genital organs and retroperitoneal space (4%), peripheral vessels and lymphatic system (3%), teeth, jaws, mouth and pharynx (1%), and ear, nose and larynx (1%).

Table 1

Baseline characteristics for the placebo and sugammadex dose groups (all treated subjects). ASA, American Society of Anesthesiologists; sd, Standard deviation

 Placebo Sugammadex dose (mg kg−1)
 
Total 
  0.5 1.0 2.0 4.0  
Rocuronium (n10 10 10 10 49 
 Age (yr) [mean (sd)] 50 (7) 52 (7) 50 (9) 49 (8) 49 (13) 50 (9) 
 Weight (kg) [mean (sd)] 73 (21) 70 (13) 67 (10) 77 (19) 69 (11) 71 (16) 
 Height (cm) [mean (sd)] 167 (11) 165 (6) 166 (7) 173 (9) 169 (8) 168 (9) 
 Female/male [n (%)] 8/2 (80/20) 8/2 (80/20) 7/2 (78/22) 5/5 (50/50) 6/4 (60/40) 34/15 (69/31) 
 ASA class [n (%)] 
  I 4 (40) 5 (50) 3 (33) 4 (40) 5 (50) 21 (43) 
  II 6 (60) 4 (40) 5 (56) 5 (50) 5 (50) 25 (51) 
  III 0 (0) 1 (10) 1 (11) 1 (10) 0 (0) 3 (6) 
Vecuronium (n10 10 10 10 49 
 Age (yr) [mean (sd)] 48 (10) 47 (9) 46 (9) 45 (10) 47 (10) 47 (9) 
 Weight (kg) [mean (sd)] 73 (15) 73 (13) 76 (21) 75 (11) 68 (13) 73 (15) 
 Height (cm) [mean (sd)] 170 (8) 170 (9) 169 (6) 169 (8) 167 (9) 169 (8) 
 Female/male [n (%)] 8/2 (80/20) 7/3 (70/30) 7/3 (70/30) 7/3 (70/30) 7/2 (78/22) 36/13 (73/27) 
 ASA class [n (%)] 
  I 4 (40) 3 (30) 6 (60) 6 (60) 4 (44) 23 (47) 
  II 5 (50) 7 (70) 4 (40) 4 (40) 5 (56) 25 (51) 
  III 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) 
 Placebo Sugammadex dose (mg kg−1)
 
Total 
  0.5 1.0 2.0 4.0  
Rocuronium (n10 10 10 10 49 
 Age (yr) [mean (sd)] 50 (7) 52 (7) 50 (9) 49 (8) 49 (13) 50 (9) 
 Weight (kg) [mean (sd)] 73 (21) 70 (13) 67 (10) 77 (19) 69 (11) 71 (16) 
 Height (cm) [mean (sd)] 167 (11) 165 (6) 166 (7) 173 (9) 169 (8) 168 (9) 
 Female/male [n (%)] 8/2 (80/20) 8/2 (80/20) 7/2 (78/22) 5/5 (50/50) 6/4 (60/40) 34/15 (69/31) 
 ASA class [n (%)] 
  I 4 (40) 5 (50) 3 (33) 4 (40) 5 (50) 21 (43) 
  II 6 (60) 4 (40) 5 (56) 5 (50) 5 (50) 25 (51) 
  III 0 (0) 1 (10) 1 (11) 1 (10) 0 (0) 3 (6) 
Vecuronium (n10 10 10 10 49 
 Age (yr) [mean (sd)] 48 (10) 47 (9) 46 (9) 45 (10) 47 (10) 47 (9) 
 Weight (kg) [mean (sd)] 73 (15) 73 (13) 76 (21) 75 (11) 68 (13) 73 (15) 
 Height (cm) [mean (sd)] 170 (8) 170 (9) 169 (6) 169 (8) 167 (9) 169 (8) 
 Female/male [n (%)] 8/2 (80/20) 7/3 (70/30) 7/3 (70/30) 7/3 (70/30) 7/2 (78/22) 36/13 (73/27) 
 ASA class [n (%)] 
  I 4 (40) 3 (30) 6 (60) 6 (60) 4 (44) 23 (47) 
  II 5 (50) 7 (70) 4 (40) 4 (40) 5 (56) 25 (51) 
  III 1 (10) 0 (0) 0 (0) 0 (0) 0 (0) 1 (2) 

All patients in the all-subjects-treated population received propofol (for anaesthesia induction), sevoflurane (for maintenance), and an opioid. The most frequently administered opioid in the rocuronium group was fentanyl (n=40), followed by remifentanil (n=9), piritramide (n=7), and sufentanil (n=1) and in the vecuronium group was fentanyl (n=44), followed by piritramide (n=9) and remifentanil (n=5). Additionally, nitrous oxide was used in a limited number of patients; 12 patients in each NMBA group. The overall range of sevoflurane end-tidal concentrations given before and after study drug administration in the rocuronium group was 0.1–2.9% and 0.3–2.3%, respectively. The corresponding concentrations in the vecuronium group were similar: 0.1–3.1% and 0.1–2.7%, respectively. During the study period (time interval from study drug administration until reaching a TOF ratio of 0.9), the sevoflurane concentration was constant for 17 patients in the rocuronium group and 16 in the vecuronium group. For these patients, the mean (standard deviation) sevoflurane concentration was 1.3 (0.4)% and 1.1 (0.2)%, respectively.

Sugammadex produced a dose-dependent reduction in time to recovery of the T4/T1 ratio to 0.9 in both NMBA groups. In the rocuronium group, the mean time to recovery decreased from 96.3 min in the placebo group to 1.4 and 1.5 min in the sugammadex 2.0 and 4.0 mg kg−1 groups, respectively. In the vecuronium group, the mean time to recovery decreased from 79.0 min in the placebo group to 3.4 and 3.0 min in the sugammadex 2.0 and 4.0 mg kg−1 groups (Table 2). These trends were also apparent in median recovery times, indicating that a plateau (i.e. limit of recovery) was reached.

Table 2

Mean (sd) time (min) from the start of administration of sugammadex or placebo to recovery of the T4/T1 ratio to 0.9 (PP population). Data excluded because: *administration of disallowed concomitant medication (n=2) and no data (n=1); TOF data unavailable (n=2); unreliable TOF trace (n=1); administration of disallowed concomitant medication (n=1); §TOF data unavailable (n=1); unreliable or no TOF data (n=2). sd, Standard deviation

 Placebo Sugammadex dose (mg kg−1)
 
  0.5 1.0 2.0 4.0 
Rocuronium group 
n 10* 10 9 
 Mean (sd96.3 (33.1) 16.3 (20.6) 4.6 (6.0) 1.4 (0.5) 1.5 (0.4) 
 Min–max 55.7–153.0 1.3–55.5 1.5–19.3 0.7–2.4 1.2–2.2 
Vecuronium group 
n 9 10§ 10 9 
 Mean (sd79.0 (26.0) 35.5 (42.1) 5.1 (2.4) 3.4 (1.9) 3.0 (2.2) 
 Min–max 59.8–141.1 3.5–113.5 1.6–8.8 2.1–7.1 1.3–8.5 
 Placebo Sugammadex dose (mg kg−1)
 
  0.5 1.0 2.0 4.0 
Rocuronium group 
n 10* 10 9 
 Mean (sd96.3 (33.1) 16.3 (20.6) 4.6 (6.0) 1.4 (0.5) 1.5 (0.4) 
 Min–max 55.7–153.0 1.3–55.5 1.5–19.3 0.7–2.4 1.2–2.2 
Vecuronium group 
n 9 10§ 10 9 
 Mean (sd79.0 (26.0) 35.5 (42.1) 5.1 (2.4) 3.4 (1.9) 3.0 (2.2) 
 Min–max 59.8–141.1 3.5–113.5 1.6–8.8 2.1–7.1 1.3–8.5 

In both NMBA groups, the estimated dose–response curve adequately fitted observed data for recovery of the T4/T1 ratio to 0.9 over the sugammadex dose range studied (Fig. 2). As parameters in the exponential part of the model were significantly different from zero, a dose–response effect could be demonstrated. From this, it was estimated that for an average patient in the rocuronium and vecuronium groups the fastest achievable time to recovery of the T4/T1 ratio to 0.9 was 1.4 and 3.1 min, respectively.

Fig 2

Estimated dose–response relationship between recovery of T4/T1 ratio to 0.9 and the dose of sugammadex administered after (a) rocuronium 0.9 mg kg−1 and (b) vecuronium 0.1 mg kg−1, with 95% confidence intervals (CI; PP subjects).

Fig 2

Estimated dose–response relationship between recovery of T4/T1 ratio to 0.9 and the dose of sugammadex administered after (a) rocuronium 0.9 mg kg−1 and (b) vecuronium 0.1 mg kg−1, with 95% confidence intervals (CI; PP subjects).

Results from the ITT population were comparable with those from the PP population, with the exception of two patients with relatively long recovery times to a T4/T1 ratio of 0.9, both of whom had TOF traces that were difficult to interpret. The recovery times to T4/T1 ratios of 0.7, 0.8, and 0.9 for these two patients were 1.2, 1.2, and 41.4 min, respectively (rocuronium group, sugammadex 4.0 mg kg−1) and 5.3, 36.3, and 44.6 min, respectively (vecuronium group, sugammadex 2.0 mg kg−1). For the ITT population rocuronium group, the mean time to recovery decreased from 87.9 min in the placebo group to 1.5 min in the sugammadex 2.0 mg kg−1 group. However, because one patient in the 4.0 mg kg−1 group had a very prolonged recovery time, the mean time to recovery in this dose group was 5.5 min [median (range), 1.4 (1.2 to 41.4) min]. In the vecuronium group, the mean time to recovery decreased from 83.8 min in the placebo group to 3.0 min in the 4.0 mg kg−1 group. The mean recovery time in the 2.0 mg kg−1 group was 8.0 min, as a result of the one prolonged recovery time stated previously.

In both NMBA groups, the median plasma concentration of sugammadex increased with increasing sugammadex dose. Dose normalization [(µg ml−1)/(mg kg−1)] demonstrated the absence of any large deviation from dose-proportionality, although in both NMBA groups, the highest dose-normalized concentrations were seen for sugammadex 0.5 mg kg−1 (Fig. 3).

Fig 3

Median total (sum of free and bound) plasma concentration–time profiles of sugammadex administered after (a) rocuronium 0.9 mg kg−1 and (b) vecuronium 0.1 mg kg−1 (all subjects pharmacokinetically evaluable). The inset graphs show dose-normalized concentrations of sugammadex [(µg ml−1)/(mg kg−1)] vs time (min) after sugammadex administration.

Fig 3

Median total (sum of free and bound) plasma concentration–time profiles of sugammadex administered after (a) rocuronium 0.9 mg kg−1 and (b) vecuronium 0.1 mg kg−1 (all subjects pharmacokinetically evaluable). The inset graphs show dose-normalized concentrations of sugammadex [(µg ml−1)/(mg kg−1)] vs time (min) after sugammadex administration.

The median rocuronium plasma concentration showed a transient increase after sugammadex administration (0.5–4.0 mg kg−1) followed by a decrease, whereas rocuronium concentrations in the placebo group showed a steady decline (Fig. 4a). A similar transient increase was evident for vecuronium in the sugammadex 0.5 and 1.0 mg kg−1 dose groups but not for sugammadex 2.0 and 4.0 mg kg−1. A modest unexpected increase in median total vecuronium plasma concentration was observed at 2 min with placebo but this was inconsistent with arithmetic and geometric mean concentrations (Fig. 4b).

Fig 4

Median plasma concentration–time profiles of (a) rocuronium after administration of rocuronium 0.9 mg kg−1 followed by sugammadex 0.5–4.0 mg kg−1 or placebo and (b) vecuronium after administration of vecuronium 0.1 mg kg−1 followed by sugammadex 0.5–4.0 mg kg−1 or placebo (all subjects pharmacokinetically evaluable). The inset graphs show concentrations of rocuronium and vecuronium (ng ml−1) vs time (min) after sugammadex administration.

Fig 4

Median plasma concentration–time profiles of (a) rocuronium after administration of rocuronium 0.9 mg kg−1 followed by sugammadex 0.5–4.0 mg kg−1 or placebo and (b) vecuronium after administration of vecuronium 0.1 mg kg−1 followed by sugammadex 0.5–4.0 mg kg−1 or placebo (all subjects pharmacokinetically evaluable). The inset graphs show concentrations of rocuronium and vecuronium (ng ml−1) vs time (min) after sugammadex administration.

Forty-five of 49 patients in the rocuronium group (91.8%) and 40 of 49 patients (81.6%) in the vecuronium group experienced at least one AE. The most frequently reported AEs were procedural pain (49.0% and 32.7% of patients in the rocuronium and vecuronium groups, respectively), nausea (42.9% and 28.6%), and vomiting (20.4% and 16.3%). Fourteen patients experienced 19 AEs considered by the investigator to be possibly or probably related to the study drug: nine patients (18.4%) in the rocuronium group (placebo, n=3; sugammadex, n=6) and five patients (10.2%) in the vecuronium group (sugammadex, n=5). The incidence of individual AEs in each group was low (≤4%) and there was no dose–response relationship for occurrence of potentially drug-related AEs.

One patient in the rocuronium group (sugammadex 2.0 mg kg−1) and two in the vecuronium group (sugammadex 0.5 mg kg−1) experienced a total of six SAEs; none were considered related to sugammadex and no patient discontinued the trial because of an AE.

In the rocuronium group, two AEs related to vital signs were considered to be study drug-related. One patient who received 2.0 mg kg−1 sugammadex experienced moderate hypotension, and one patient who had low systolic and diastolic arterial pressure reported as moderate procedural hypotension within the first 10 min after sugammadex 4.0 mg kg−1. In the vecuronium group, one patient had mild procedural hypotension after sugammadex 2.0 mg kg−1, considered to be study drug-related.

Overall, haematology, biochemistry, and urinalysis (i.e. laboratory) variables were comparable between sugammadex doses in both the rocuronium and the vecuronium groups.

Reoccurrence of NMB was reported in five patients in the rocuronium group (sugammadex 0.5 mg kg−1, n=4; 2.0 mg kg−1, n=1) and in two patients in the vecuronium group (sugammadex 0.5 mg kg−1, n=2). The patient in the rocuronium group who demonstrated reoccurrence of NMB after receiving sugammadex 2.0 mg kg−1 had a rapid initial recovery to a TOF ratio of 0.9 at 1.4 min after sugammadex. Sevoflurane was discontinued ∼5 min before the TOF ratio decreased to a lowest value of 0.6 at 24.7 min after sugammadex. Additionally, the patient's hand moved during dressing after surgery ∼1 min before the lowest TOF value. Both these events may have contributed to the low TOF ratio recording. At the point of this lowest value, the patient started to wake up and the TOF-Watch was switched off. No clinical symptoms of reoccurrence of NMB were observed. In only one case in the vecuronium group was reoccurrence of NMB associated with confirmatory clinical evidence and reported as an AE (general muscular weakness). This patient (who received sugammadex 0.5 mg kg−1) was not able to lift her head for more than 3 s on admission to the recovery room.

Central body temperature was maintained at ≥35°C in all patients except six in the rocuronium group and three in the vecuronium group. No interaction of sugammadex with an endogenous or exogenous compound, other than rocuronium or vecuronium, was reported.

Discussion

This study showed that during sevoflurane anaesthesia, sugammadex can provide rapid and safe reversal of moderate NMB after administration of rocuronium (0.9 mg kg−1) or vecuronium (0.1 mg kg−1) in surgical patients. A clear dose–response relationship, apparent in both NMBA groups, was demonstrated between the dose of sugammadex administered after single or multiple doses of rocuronium or vecuronium, and the time taken to restore the T4/T1 ratio to 0.7, 0.8, and 0.9; a plateau (i.e. limit of recovery) was reached for the 2.0 and 4.0 mg kg−1 sugammadex doses in each NMBA group.

In the rocuronium group, the mean time to recovery of the T4/T1 ratio to 0.9 was 1.4 and 1.5 min in the sugammadex 2.0 and 4.0 mg kg−1 groups. In the vecuronium group, these times were 3.4 and 3.0 min, respectively. Furthermore, the estimated dose–response curve was found adequately to fit observed data for recovery of the T4/T1 ratio to 0.9 over the sugammadex dose range studied. Parameters in the exponential part of the model were significantly different from zero; thus demonstrating a dose–response effect. From this, it was estimated that for an average patient in the rocuronium and vecuronium groups, the fastest achievable time to recovery of the T4/T1 ratio to 0.9 was 1.4 and 3.1 min, respectively. The recovery times for sugammadex reversal of rocuronium-induced NMB tend to be shorter than after vecuronium-induced block. This may be due to the higher affinity of sugammadex for rocuronium than for vecuronium where rocuronium forms a complex with sugammadex at a faster rate than vecuronium, and hence produces shorter recovery times. Future studies are needed to clarify this.

Plasma concentrations of rocuronium and, to a lesser extent, vecuronium increased after sugammadex administration but not placebo. This increase can be attributed to redistribution of NMBA to the plasma compartment after forming a complex with sugammadex. This has been observed in several other studies evaluating sugammadex pharmacokinetics during reversal of rocuronium-induced NMB.2,10,18

The concentration of sevoflurane used in the current study reflected the clinical needs of the patient, and most patients received a range of sevoflurane end-tidal concentrations before and after sugammadex or placebo administration. The concentration of sevoflurane is likely to affect the level of NMB produced by rocuronium or vecuronium;13–15 however, the time of administration of sugammadex or placebo was at a predetermined level of NMB (reappearance of T2) and therefore the concentration of sevoflurane was not anticipated to affect recovery times in the different dose groups.

To the best of our knowledge, this study is the first in which the full dose–response relationship of sugammadex and rocuronium- or vecuronium-induced moderate NMB has been assessed during sevoflurane anaesthesia. The findings of dose-dependent decreases in recovery times with increasing sugammadex dose are consistent with those from previously reported dose–response studies in surgical patients under propofol maintenance anaesthesia.1,4,7 This finding is significant because sevoflurane is known to enhance the neuromuscular blocking effect of rocuronium13–15 and, theoretically, the efficacy of sugammadex could be diminished during sevoflurane anaesthesia. Recent studies suggest that sugammadex is similarly effective in reversing rocuronium-induced NMB during either propofol or sevoflurane maintenance anaesthesia.11,19 The mean time to recovery of the T4/T1 ratio to 0.9 of 1.4 min for sugammadex 2.0 mg kg−1 in our study is comparable with the mean time of 1.8 min to that reported for sugammadex 2.0 mg kg−1 reversal of moderate rocuronium-induced block under sevoflurane or propofol.11 It has also been shown that sugammadex 4.0 mg kg−1 is equally effective for reversal of NMB induced by a continuous infusion of rocuronium during maintenance anaesthesia with sevoflurane or propofol.19 The efficacy and safety of sugammadex 2.0 mg kg−1 has also been compared with that of neostigmine 50 µg kg−1 for reversal of moderate vecuronium-induced block in patients during sevoflurane maintenance anaesthesia. Time to a T4/T1 ratio of 0.9 was shown to be significantly faster with sugammadex than neostigmine (2.7 vs 17.9 min; P<0.0001).20

Sugammadex was well tolerated in the current study; this is in agreement with an independent systematic review of the efficacy and safety of sugammadex which showed no difference overall in unwanted effects between patients receiving sugammadex or placebo.21 Six SAEs were reported in the current trial, none of which were considered study drug-related. Reoccurrence of NMB was observed with neuromuscular monitoring in seven patients after sugammadex administration (rocuronium, n=5; vecuronium, n=2). Six of these patients had received a suboptimal sugammadex dose (0.5 mg kg−1) and one patient had received sugammadex 2.0 mg kg−1. One patient in the vecuronium group (sugammadex 0.5 mg kg−1) showed clinical evidence of residual or recurrence of block (inability to lift head for ≥3 s on admission to the recovery room) associated with a transient decrease in twitch response during reversal of NMB. This may have been secondary to a phenomenon previously described as muscle relaxation rebound,22 in which a suboptimal dose of sugammadex may be insufficient for complex formation in the peripheral compartment, allowing unbound NMBA molecules to redistribute into the central compartment with a resultant temporary increase in muscle relaxation intensity.22

In conclusion, sugammadex effectively decreases recovery time for reversal of moderate rocuronium- and vecuronium-induced NMB in a dose-dependent manner in surgical patients during sevoflurane maintenance anaesthesia and is well tolerated. Sugammadex 2.0 mg kg−1 resulted in a reversal time during sevoflurane anaesthesia comparable with that reported for propofol maintenance. Linear pharmacokinetics of sugammadex were observed, when administered in combination with rocuronium or vecuronium.

Conflict of interest

F.K.P. and B.K. have received speaker and consultancy fees from MSD, Oss, The Netherlands. W.v.D. is an employee of MSD, Oss, The Netherlands, and M.H. was formerly an employee of MSD, Oss, The Netherlands.

Funding

Financial support was provided by MSD, Oss, The Netherlands.

Acknowledgement

Editorial assistance was provided by Melanie More at Prime Medica Ltd (Knutsford, Cheshire, UK).

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