American Journal of Therapeutics 0, 1–9 (2015)

Safety and Efficacy of Rocuronium With Sugammadex Reversal Versus Succinylcholine in Outpatient Surgery—A Multicenter, Randomized, Safety Assessor–Blinded Trial Roy Soto, MD,1* Jonathan S. Jahr, MD,2 Janet Pavlin, MD,3 Daniel Sabo, MD,4 Beverly K. Philip, MD,5 Talmage D. Egan, MD,6 Everton Rowe, PhD,7 Joris de Bie, PhD,7 and Tiffany Woo, MS7

Complex surgical procedures are increasingly performed in an outpatient setting, with emphasis on rapid recovery and case turnover. In this study, the combination of rocuronium for neuromuscular blockade (NMB) reversed by single-dose sugammadex was compared with succinylcholine followed by spontaneous recovery in outpatient surgery. This multicenter, randomized, safety assessor–blinded study enrolled adults undergoing a short elective outpatient surgical procedure requiring NMB and tracheal intubation. Patients were randomized to NMB with either rocuronium 0.6 mg/kg for tracheal intubation with incremental doses of rocuronium 0.15 mg/kg and subsequent reversal with sugammadex 4.0 mg/kg at 1–2 posttetanic counts or succinylcholine 1.0 mg/kg for intubation with spontaneous recovery. The primary efficacy end point was the time from sugammadex administration to recovery of the train-of-four ratio to 0.9; for succinylcholine, time from administration to recovery of the first twitch (T1) to 90% was assessed. From 167 patients enrolled, 150 received treatment. The all-subjects-treated population comprised 70 patients in the rocuronium–sugammadex group and 80 in the succinylcholine group. Geometric mean (95% confidence interval) time from the start of sugammadex administration to recovery of the train-of-four ratio to 0.9 was 1.8 (1.6–2.0) minutes. Geometric mean (95% confidence interval) time from succinylcholine administration to recovery of T1 to 90% was 10.8 (10.1–11.5) minutes. Health outcome variables were similar between the groups. Adverse events were reported in 87.1% and 93.8% of patients for rocuronium–sugammadex and succinylcholine, respectively. In conclusion, rocuronium for intubation followed by sugammadex for reversal of NMB offers a viable treatment option in outpatient surgery without prolonging recovery duration or jeopardizing safety. Keywords: neuromuscular blockade, outpatient, rocuronium, succinylcholine, sugammadex

1

Department of Anesthesiology, Beaumont Health System, Royal Oak, MI; 2Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, CA; 3Department of Anesthesiology and Pain Medicine, University of Washington Medical Center, Seattle, WA; 4 Department of Anesthesiology, UPMC Shadyside Hospital, Pittsburgh, PA; 5Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA; 6Department of Anesthesiology, University of Utah Health Sciences Center, Salt Lake City, UT; and 7Merck Sharp & Dohme Corp, Whitehouse Station, NJ. Supported by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co. Inc, Whitehouse Station, NJ. Medical writing support was provided by Caroline Shapland and Neil Venn from Prime Medica Ltd (Knutsford, Cheshire, United Kingdom) during the preparation of this manuscript, supported by Merck Sharp & Dohme Corp, a subsidiary of Merck & Co. Inc. Responsibility for opinions, conclusions, and interpretation of the data lies with the authors. R. Soto, J. Pavlin, D. Sabo, and B. Philip work for institutions that received research funding from Merck for the conduct of this study. J. S. Jahr works for an institution that has received research funding from Merck for the conduct of this study and others, has served as part of a speaker’s bureau for Merck, and has received travel support from Merck. T. Egan has received research support from Merck. E. Rowe and J. de Bie were employees of Merck at the time of the study. T. Woo is currently an employee of Merck. Everton Rowe is currently affiliated with Novo Nordisk, Princeton, NJ. Joris de Bie is currently affiliated with Mesoblast, New York, NY. *Address for correspondence: Anesthesia and Pain Research, William Beaumont Hospital, 3601 West Thirteen Mile Road, Royal Oak, MI 48073-6769. E-mail: [email protected] 1075–2765 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

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INTRODUCTION Advances in surgical technology, particularly the use of laparoscopic surgery, have facilitated conversion of many operations into outpatient procedures, so that most surgeries in the United States are performed on an outpatient basis.1 These advances in surgical approaches have necessitated adaptation by anesthesiologists to provide safe and effective anesthesia with greater emphasis on rapid recovery and discharge.2 Laparoscopic surgery in particular requires significant muscle relaxation until the end of surgery,3 meaning a greater need for precise control of neuromuscular blockade (NMB). Ideally, a neuromuscular blocking agent (NMBA) should provide rapid onset of paralysis, coupled with rapid and reliable reversibility from a deep level of paralysis to facilitate case turnover in an outpatient facility.4 A well-established option for NMB in outpatients is the use of succinylcholine for tracheal intubation, followed by small doses of an intermediate-duration nondepolarizing NMBA to maintain NMB as required. This approach exposes patients to side effects of both drugs. Adverse events (AEs) associated with succinylcholine include arrhythmias, myalgias, and malignant hyperthermia. Moreover, with a nondepolarizing NMBA, there is the possibility of inadequate reversal and therefore delayed recovery, slowed case turnover, and/or potential respiratory distress if the trachea is extubated prematurely.4,5 Furthermore, incomplete recovery of neuromuscular function may contribute to adverse respiratory events in the postanesthesia care unit (PACU).5 Using a single NMBA of intermediate duration for the intubation usually requires a high dose for optimal onset, but this may in turn increase the likelihood of prolonged paralysis if the case duration is short. In current practice, NMB induced by nondepolarizing NMBAs is typically reversed with an anticholinesterase combined with an anticholinergic, both of which also have potential AEs.6,7 Thus, the use of muscle relaxants has traditionally been minimized in outpatient surgery because of the complexities associated with ensuring the timely and complete recovery of neuromuscular function. However, the availability of sugammadex for the reversal of rocuronium-induced NMB may provide an American Journal of Therapeutics (2015) 0(0)

Soto et al

alternative approach in the management of NMB during ambulatory surgery. In this article, we report the results of a preplanned secondary analysis to evaluate the use of sugammadex reversal of rocuronium-induced NMB in patients undergoing relatively short outpatient surgery (the primary safety end point of the trial assessing change in potassium level from baseline has been reported previously).8 NMB was maintained at relatively deep levels from the time of induction until the end of surgery to test the hypothesis that patients could be rapidly and safely reversed without altering the duration of recovery and time to discharge. We compared this with another typical NMB regimen for short outpatient procedures, a single dose of succinylcholine for tracheal intubation, from which the patient was allowed to recover spontaneously, with no further muscle relaxant administered. Prolonged deep relaxation was not required for the surgical procedures in either group; it was maintained deliberately in the rocuronium group as part of the study protocol to test the hypothesis that prolonged deep relaxation until the end of surgery would be readily reversible without causing delayed recovery or serious AEs (SAEs) when compared with minimal use of a relaxant exclusively for intubation.

METHODS This was a multicenter, randomized, safety assessor– blinded, parallel-group, active-controlled trial in adult patients scheduled for short surgical procedures in hospital outpatient surgical departments (NCT00751179) and incorporated a 7-day follow-up to assess tolerability.8 This study was conducted in accordance with principles of Good Clinical Practice and was approved by each facility’s institutional review board and appropriate regulatory agencies. All patients provided written informed consent before enrollment. Methods for the study have been reported previously8 and are also outlined in brief below. Patients were eligible for inclusion if they were 18 years and older, American Association of Anesthesiologists Class I, II, or III, had a body mass index of ,35 kg/m2, and were scheduled to undergo an elective outpatient procedure of anticipated short duration (#1 hour from completion of intubation to completion of suturing/ stapling of skin) under general anesthesia requiring www.americantherapeutics.com

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Safety and Efficacy of Sugammadex in Outpatient Surgery

neuromuscular relaxation for tracheal intubation. Patients were excluded if they met any of the following conditions: ischemic heart disease or a history of myocardial infarction, difficult intubation expected, neuromuscular disorder impairing NMB (eg, myasthenia gravis), use of a pneumatic tourniquet required during the surgical procedure, had significant renal (creatinine clearance ,30 mL/min) or hepatic dysfunction, personal or family history of malignant hyperthermia, allergy to medications used during general anesthesia, hypersensitive to sugammadex or other cyclodextrins, or rocuronium bromide, contraindication to the study drugs, expected to require postoperative admission to intensive care and/or hospital, or expected to receive an intraoperative intravenous administration of fluids containing potassium. NMB monitoring was performed using an appropriately calibrated TOF-Watch SX device (Organon Ireland Ltd, a subsidiary of Merck and Co, Swords, Co. Dublin, Ireland) affixed to an outstretched arm, and each study site was given training on the setup of the TOF-Watch SX to reduce variability between sites and between individual patients at each site. Neuromuscular function was monitored continuously with acceleromyography at the adductor pollicis muscle with the TOF-Watch SX device, starting after induction of anesthesia, through to the end of anesthesia until the train-of-four (TOF) ratio was $0.9 (in the rocuronium–sugammadex group) or the first twitch of the TOF (T1) was $90% of baseline (in the succinylcholine group). Treatments Patients were randomized on a 1:1 basis to receive either rocuronium 0.6 mg/kg for tracheal intubation, with rocuronium 0.15 mg/kg administered to maintain NMB as required, followed by reversal of NMB with a single 4.0 mg/kg dose of sugammadex delivered at a target depth of blockade of 1–2 posttetanic count (PTC) (ie, deep blockade), or succinylcholine 1.0 mg/kg for tracheal intubation. Patients who received succinylcholine were allowed to recover spontaneously from NMB. The administration of sugammadex at a target depth of 1–2 PTC was at a deeper level of blockade than is appropriate for administration of anticholinesterases, which are only effective once moderate blockade (reappearance of the second twitch of the TOF) has been attained. The latter typically requires considerably longer to be achieved than the first signs of recovery demonstrated by posttetanic contractions as used in this study. Anesthesia was induced and maintained with propofol and inhalation agents. www.americantherapeutics.com

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Evaluations The primary efficacy end point was the time from the start of administration of sugammadex at deep blockade to recovery of the TOF ratio to 0.9. Nondepolarizing NMBAs, such as rocuronium, produce characteristic TOF and tetanic fade, likely by blocking presynaptic nicotinic receptors. Succinylcholine does not inhibit these presynaptic receptors at clinically relevant concentrations, and tetanic fade is not observed in succinylcholine-induced NMB.9 Therefore, to evaluate neuromuscular recovery in the succinylcholine group, a different monitoring procedure was implemented, and the time from the start of administration of succinylcholine to T1 reaching 90% of baseline was assessed. In the rocuronium–sugammadex group, other efficacy variables assessed were the depth of blockade at the administration of sugammadex and the TOF ratio at tracheal extubation. In the succinylcholine group, the T1 value at tracheal extubation was measured. Health outcome variable measures were the time from patient admission to the operating room until the patient was considered ready for discharge from the operating room, and the time from admission to the PACU until the patient was considered ready for discharge from the PACU. Evidence of residual NMB or recurrence of NMB was assessed, indicated by a significant postoperative decrease in the TOF ratio or based on clinical evidence as indicated by a significant change in respiratory rate or significant decrease in blood oxyhemoglobin saturation percent after the administration of sugammadex or succinylcholine. Safety assessments included AEs, heart rate, blood pressure, respiratory rate, and pulse oximetry. The study incorporated a safety follow-up assessment at 7 days after surgery, either by telephone or visit, which comprised recording any concomitant medication intake, assessment of AEs and SAEs, enquiring whether the female subject or the spouse/partner of a male subject is pregnant or not, and completion of the end of trial form. Postoperative nausea and vomiting (PONV) risk factors10 were assessed for each patient before surgery, and the incidence of PONV was assessed based on AE reports of procedural nausea, nausea, procedural vomiting, and vomiting. All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA version 12.1); a MedDRA lowest level term was chosen that best matched or approximated the investigator’s actual description, adhering to MedDRA rules and conventions. SAEs were defined as any untoward medical occurrence that at any dose resulted in American Journal of Therapeutics (2015) 0(0)

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death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, or was a congenital anomaly/birth defect.

Soto et al Table 1. Summary of patient baseline characteristics (all-subjects-treated population [n 5 150]).

Populations The all-subjects-treated population included all randomized patients who received any dose of rocuronium, sugammadex, or succinylcholine. The intent-to-treat population included all randomized patients who received sugammadex or succinylcholine and had at least 1 efficacy and 1 safety measurement. Statistical analyses Recovery times from NMB and other efficacy parameters are presented as mean (SD), geometric mean [95% confidence interval (CI)], median, and range. Because recovery times to a TOF ratio of 0.9 after sugammadex administration were expected to follow a log-normal distribution,11 the response variable was the logarithm of the recovery times. A 95% CI for geometric mean recovery time was calculated on the log scale and transformed back to the original scale (time). As different end points for recovery from NMB were used for the rocuronium–sugammadex and succinylcholine treatment groups in this study, no statistical comparisons on time to recover from NMB were performed. The Wilcoxon rank-sum test was used to compare the other clinical outcome measures between treatment groups where appropriate (with P , 0.05 indicating significance). The sample size for the study, which required enrollment of 70 patients per group, was based on the primary safety objective of this trial (changes in potassium level from baseline at the 5-minute postdose time point after administration of rocuronium, sugammadex, and succinylcholine, respectively); these results have been reported previously.8

RESULTS The study was conducted between December 2008 and December 2009 at 13 sites in the United States and 1 site in Canada. A total of 167 patients were enrolled; 76 patients were randomized to receive rocuronium and sugammadex and 85 patients were randomized to receive succinylcholine. The allsubjects-treated population comprised 70 patients in the rocuronium–sugammadex group and 80 patients in the succinylcholine group; the intent-to-treat population comprised 65 patients in the rocuronium–sugammadex group and 77 patients in the succinylcholine group.8 American Journal of Therapeutics (2015) 0(0)

Male, n (%) Mean (range) age, yrs Mean (range) BMI, kg/m2 Race, n (%) White Black or African American Asian Other ASA class, n (%) I II III

Rocuronium– sugammadex (n 5 70)

Succinylcholine (n 5 80)

21 (30) 40 (18–70)

27 (34) 45 (21–80)

26 (18–34)

28 (19–35)

52 (74) 10 (14)

67 (84) 9 (11)

4 (6) 4 (6)

1 (1) 3 (4)

28 (40) 41 (59) 1 (1)

26 (33) 46 (58) 8 (10)

ASA, American Society of Anesthesiologists; BMI, body mass index.

Patient characteristics were generally comparable between the 2 treatment groups (Table 1). The surgical procedures performed during the trial were coded manually by body system affected (no authoritative dictionary was used for classification). Patients most frequently had surgical procedures involving gynecologic surgery, the eye and adjacent structures, or the digestive system and spleen. Although none of the specified procedures required prolonged relaxation after intubation was completed, these procedures could also be performed at a deeper level of block and effectively reversed with sugammadex. Efficacy The geometric mean (95% CI) recovery time to a TOF ratio of 0.9 (primary efficacy end point) after the administration of sugammadex was 1.8 (1.6–2.0) minutes, with 98% of patients recovering to a TOF ratio of 0.9 within 5 minutes and all patients having recovered within 6 minutes (Table 2; Figure 1A). In the succinylcholine group, the geometric mean (95% CI) time to recovery of T1 to 90% (primary efficacy end point) after the administration of succinylcholine was 10.8 (10.1–11.5) minutes (Table 2; Figure 1B). At extubation, the geometric mean (95% CI) TOF ratio was 1.0 (1.0– 1.1) in the rocuronium–sugammadex group (Table 2; Figure 1C); in the succinylcholine group, the geometric mean (95% CI) T1 value (% of baseline) was 87.8 (82.7– 93.1) (Table 2; Figure 1D). www.americantherapeutics.com

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Safety and Efficacy of Sugammadex in Outpatient Surgery Table 2. Time to recovery of neuromuscular function in patients randomized to rocuronium–sugammadex or succinylcholine (intent-to-treat population). Rocuronium–sugammadex Time (minutes) to TOF ratio of 0.9 n Geometric mean (95% CI) Median Range TOF ratio at extubation n Geometric mean (95% CI) Median Range Succinylcholine Time (minutes) to recovery of T1 to 90 % n Geometric mean (95% CI) Median Range Time (minutes) to recovery of T1 to 10% n Geometric mean (95% CI) Median Range T1 value (% of baseline) at tracheal extubation n Geometric mean (95% CI) Median Range

room discharge to the patients being ready for discharge from the postanesthesia recovery room, and time from admission to the postanesthesia recovery room to the patient being ready for discharge (Table 3). Safety

59 1.8 (1.6–2.0) 1.8 0.5–5.8 62 1.0 (1.0–1.1) 1.0 0.8–1.2

77 10.8 (10.1–11.5) 11.3 2.6–18.3

77 6.7 (6.2–7.2) 6.7 1.1–12.8

68 87.8 (82.7–93.1) 87.5 51.0–139.0

T1, first twitch.

In the rocuronium–sugammadex group, the depth of NMB was measured immediately before the administration of sugammadex for NMB reversal; the mean (SD) number of PTCs was 2.85 (3.02) and the median was 2.00 (range: 1.00–15.00). Thirty of these subjects had received maintenance doses of rocuronium to maintain the relatively deep NMB (1-2 PTC) until the end of the procedure as specified in the protocol. Outcome variables Health outcome measure variables were generally similar between treatment groups (Table 3). Summary statistics were calculated for certain outcome measure variables where appropriate, and there was no statistically significant difference between the treatment groups for these measures, that is, time from operating www.americantherapeutics.com

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Sixty-one (87.1%) of the 70 patients in the rocuronium– sugammadex group and 75 (93.8%) of the 80 patients in the succinylcholine group experienced AEs, as reported from the time period just before intubation through the follow-up visit (all-subjects-treated population; Table 4). Of these, 21 AEs were reported in 16 patients in the rocuronium–sugammadex group and 20 AEs were reported in 13 patients in the succinylcholine group after the day of surgery during the 7-day follow-up period after surgery. Most AEs were resolved within the follow-up period, with the exception of 5 events in the rocuronium–sugammadex group (cystitis, abscess rupture, incision site blister, procedural pain, and urinary tract infection in 1 patient each) and 2 events in the succinylcholine group (cystitis and wound dehiscence in 1 patient each). In the rocuronium–sugammadex group, 1 patient experienced an SAE of procedural nausea that was not considered to be related to the study medication. Three patients in the succinylcholine group experienced 1 SAE each [rectal hemorrhage, medical observation (patient had methicillin-resistant Staphylococcus aureaus and underwent surgery for an infected abscess), and decreased oxygen saturation], none of which were considered to be related to the study medication. Incidence of PONV (from the time of extubation through the postanesthetic visit) was determined from AE reports (MedDRA preferred terms of nausea, procedural nausea, vomiting, or procedural vomiting). After sugammadex administration, there was a numerically slightly higher incidence of PONV: 16 (22.9%) patients compared with 14 (17.5%) patients in the succinylcholine group (Table 5), which was not statistically significant. The majority of patients received prophylaxis for nausea and vomiting (88.6% in the rocuronium–sugammadex group and 88.8% in the succinylcholine group). There was no evidence of residual or recurrence of NMB measured by the TOF-Watch SX device or by clinical signs (indicated by a significant change in respiratory rate or significant decrease in blood oxygen level) in either treatment group.

DISCUSSION This multicenter, randomized, safety assessor–blinded study was the first study to examine the use of the American Journal of Therapeutics (2015) 0(0)

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Soto et al

FIGURE 1. Recovery of neuromuscular function (intent-to-treat populations). (A) Individual patient recovery times (minutes) from administration of sugammadex 4.0 mg/kg to a TOF ratio $0.9 (n 5 59). (B) Individual patient recovery times (minutes) from administration of succinylcholine 1.0 mg/kg to first twitch (T1) 90% (n 5 77). (C) Individual patient TOF ratios at the time of extubation, rocuronium–sugammadex group (n 5 62). (D) Individual patient T1 values at the time of extubation, succinylcholine group (n 5 68).

combination of rocuronium and sugammadex in outpatient surgery in comparison with a single dose of succinylcholine administered for intubation. Importantly, patients were followed up for 7 days after surgery to provide an indication of safety in the days after surgery. A previous study, performed to evaluate the use of rocuronium and mivacurium compared with succinylcholine in ambulatory surgery, found that rocuronium was an acceptable alternative to succinylcholine, providing good to excellent intubating conditions in all patients12 but a significantly longer recovery time (T1 of the TOF to 25% of the control) with rocuronium compared with succinylcholine, with rocuronium’s longer duration of action increasing the need for reversal drugs. However, this particular study was performed before the availability of sugammadex. This study suggests that, in the outpatient setting, sugammadex reversal of rocuronium-induced NMB offers a viable alternative to the traditional approach of facilitating American Journal of Therapeutics (2015) 0(0)

tracheal intubation with succinylcholine followed by spontaneous recovery of neuromuscular function. It also demonstrates that prolongation of deep NMB (although not necessary in our patient population) was well tolerated and readily reversible without impairing safety or speed of recovery when compared with limited use of paralysis by a short-acting drug (succinylcholine) exclusively for intubation. The geometric mean (95% CI) time to recovery of the TOF ratio to 0.9 was 1.8 (1.6–2.0) minutes, following the administration of sugammadex, demonstrating rapid recovery from deep NMB (1–2 PTC), a depth of NMB beyond that which can usually be reversed by neostigmine.11 The recovery time observed in this study was of a similar magnitude to that seen in previous trials of sugammadex for the reversal of deep rocuronium-induced NMB.11,13 The geometric mean (95% CI) time from the administration of succinylcholine to recovery of T1 to 90% was 10.8 (10.1–11.5) minutes. It should be noted that, as different levels of www.americantherapeutics.com

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Safety and Efficacy of Sugammadex in Outpatient Surgery Table 3. Outcome variable end points in the rocuronium–sugammadex and succinylcholine treatment groups (intent-to-treat population).

7 Table 4. Summary of safety and AEs (all-subjects-treated population).

Rocuronium– sugammadex Succinylcholine Time from the end of surgery to tracheal extubation (minutes) n Mean (SD) Median Range Time from OR admission to OR discharge ready (minutes) n Mean (SD) Median Range Time from tracheal extubation to OR discharge ready (minutes) n Mean (SD) Median Range Time from OR discharge ready to PACU discharge ready (minutes) n Mean (SD) Median Range Time from PACU admission to PACU discharge ready (minutes) n Mean (SD) Median Range

64 8.8 (6.9) 7.0 0–31.0

63 91.6 (28.0) 85.0 44.0–168.0

69 7.6 (5.7) 7.0* 0–27.0

71 87.3 (28.9) 82.0* 45.0–207.0

63 5.1 (3.6) 5.0 0–17.0

69 3.3 (3.0) 3.0* 0–16.0

63 76.5 (49.0) 80.0 4.0–284.0

71 98.1 (95.8) 82.0* 4.0–723.0

64 72.9 (48.7) 76.5 0.0–280.0

72 93.3 (95.5) 76.5* 0.0–720.0

Mean values shown are arithmetic means. *P 5 not significant. OR, operating room.

recovery were measured in the sugammadex and succinylcholine groups, the geometric mean recovery times cannot be directly compared. However, the www.americantherapeutics.com

Patients with AEs Deaths SAEs Discontinuation because of AEs AEs of severe intensity AEs occurring in .10% of patients in either group, n (%) Procedural pain Procedural hypotension Nausea Vomiting

Rocuronium– sugammadex (n 5 70)

Succinylcholine (n 5 80)

61 (87.1) 0 (0) 1 (1.3) 0 (0)

75 (93.8) 0 (0) 3 (3.8) 1 (1.3)

5 (7.1)

9 (11.3)

45 (64.3) 4 (5.7)

50 (62.5) 17 (21.3)

13 (18.6) 7 (10.0)

10 (12.5) 5 (6.3)

observed times to spontaneous recovery of T1 to 10% and to 90% in this study are consistent with other studies using the same dose of succinylcholine (1.0 mg/kg).14,15 Health outcome measures, including time from admission to the operating room to the patient being ready for discharge from the operating room and time from admission to the PACU to the patient being ready for discharge from the PACU, were similar between the treatment groups (Table 3). These outcomes were similar for both groups although patients in the sugammadex group often received repeated doses of rocuronium as required to maintain deep NMB, even until the end of surgery. The number of patients reporting AEs overall was similar in both treatment groups. There was a relatively low incidence of AEs in the follow-up period up to 7 days after surgery, during which the number of AEs reported, and the number of patients reporting events was similar between the 2 groups (21 events in 16 patients in the rocuronium–sugammadex group and 20 events in 13 patients in the succinylcholine group). In the follow-up period, procedural pain was the most commonly reported AE in both groups (n 5 4 in each group). SAEs were experienced by 1 patient in the rocuronium–sugammadex group and 3 patients in the succinylcholine group, none of which were considered to be related to the study drug. In this study, the TOF-Watch SX device was meticulously calibrated to accurately detect residual blockade. When acceleromyography is unavailable, qualitative monitors of NMB such as peripheral nerve American Journal of Therapeutics (2015) 0(0)

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Soto et al

Table 5. Number of Apfel PONV risk factors* at baseline and incidence of PONV after sugammadex and succinylcholine administration (all-subjects-treated population). Rocuronium–sugammadex (n 5 70) Number of risk factors at baseline* 0 1 2–4

Succinylcholine (n 5 80)

Patients with risk factors

Patients experiencing PONV

Patients with risk factors

Patients experiencing PONV

1 (1.4) 12 (17.1) 57 (81.4)

0 (0) 1 (1.4) 15 (21.4)

5 (6.3) 11 (13.8) 64 (80.0)

0 (0) 2 (2.5) 12 (15.0)

*The Apfel risk factors for PONV are female gender, history of PONV or motion sickness, being a nonsmoker, and postoperative administration of opioids.10

stimulators may be used to evaluate neuromuscular recovery.16 However, in contemporary practice, the use of a peripheral nerve stimulator for monitoring NMB during surgery is not universally applied, and although the clinical methods of evaluation of NMB may be straightforward to perform, they are subjective and not as accurate as objective methods such as acceleromyography.17 For patients in whom NMB is maintained until the end of surgery, particularly in surgical centers that are not equipped to monitor NMB accurately by using devices with this level of sensitivity, it is prudent to ensure that NMB is fully reversed to avoid residual blockade in the PACU. Traditionally, this reversal would be performed with neostigmine in combination with a muscarinic antagonist such as glycopyrrolate. However, these agents can be associated with side effects such as cardiovascular, gastrointestinal, and respiratory AEs.6,7 Most importantly, however, neostigmine is less effective if a certain degree of spontaneous recovery has not already taken place (ie, the reappearance of at least 2 contractions of a TOF stimulus).11 This study demonstrates the potential utility of continuing deep relaxation until the close of surgery in an outpatient population without compromising safety, efficiency, or time to recovery and discharge. Because of the differing nature of the 2 treatment regimens being compared, parallel treatment in the 2 experimental groups was not considered appropriate when designing the study. The use of an NMBA was primarily for the sake of intubation and, therefore, the succinylcholine group received no further relaxation. In contrast to succinylcholine, sugammadex allows for rapid reversal of deep rocuronium-induced blockade, and the rocuronium–sugammadex group was treated with maintenance doses of relaxant sufficient to maintain deep relaxation throughout the period of surgery as needed. Maintenance of deep levels of relaxation until the end of surgery may allow improved operating conditions, such as optimal surgical access and enhanced view of the visual field. This design permitted assessment of the American Journal of Therapeutics (2015) 0(0)

ability to rapidly reverse rocuronium in an outpatient population and describe any potential associated side effects. The use of the succinylcholine control group allowed for comparison of recovery parameters and AEs using an anesthesia protocol that is commonly used in ambulatory surgery for patients who require relaxation solely for intubation. However, despite a more prolonged effect on neuromuscular function in the rocuronium–sugammadex group by experimental design, there were no significant AEs or instances of impaired reversal, lending further credence to the conclusion that the rocuronium–sugammadex combination may offer an additional option to more traditional approaches in various types of ambulatory surgery requiring muscle relaxation. In this study, there was no evidence of any residual or recurrence of blockade in either treatment group detected by either the TOF-Watch SX device or by clinical signs. For other alternatives, such as intermediate-duration nondepolarizing NMBAs, literature suggests that up to 33%–64% of patients who have received them may have residual blockade when arriving in the PACU, even if an acetylcholinesterase inhibitor has been given for reversal.5,18,19 Residual or recurrence of NMB may have a significant impact on patient safety; for example, a study of inpatient surgeries by Murphy et al5 found residual blockade to be a contributing factor in the development of postoperative respiratory complications in the PACU. This was the first study to evaluate the use of the rocuronium–sugammadex combination in outpatients and showed that rocuronium for intubation followed by sugammadex for reversal of NMB may offer a good option for use in outpatient surgery. Compared with the traditional approach of providing NMB with succinylcholine followed by spontaneous recovery, sugammadex reversal of rocuronium-induced NMB yielded similar outcomes in terms of both therapeutic and adverse effects. A potential advantage of the rocuronium–sugammadex combination is that deep www.americantherapeutics.com

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Safety and Efficacy of Sugammadex in Outpatient Surgery

NMB may be maintained throughout the procedure without significant concern over the ability to restore neuromuscular function fully at the end of the operation, thus potentially allowing facilitation of optimal surgical conditions. Future use of this combination will confirm the utility of sugammadex in the outpatient setting.

ACKNOWLEDGMENTS The authors thank all the following investigators involved in the conduct of the study: Joseph Foss, MD (The Cleveland Clinic Foundation, Cleveland, OH); Dawn Desiderio, MD (Memorial Sloan Kettering, New York, NY); Vincent Odenigbo, MD (Drexel University, Philadelphia, PA); Scott Siegel, MD (St. Peter’s University Hospital, New Brunswick, NJ); Enrico Camporesi, MD (Tampa General Hospital, Tampa, FL); Robert Redfern, MD (Shands Jacksonville Medical Center, Jacksonville, FL); Nancy Wilkes, MD (University of North Carolina, Chapel Hill, NC); Michael Sutherland, MD (Fletcher Allen Health Care, Colchester, VT); Ian Black, MD (Fletcher Allen Health Care, Colchester, VT); Benoit Boure, MD (Hopital du SacreCoeur de Montreal, Montreal, Canada); Scott Beattie, MD [University Health Network (Princess Margaret Hospital), Toronto, Canada]; and Michael Tessler, MD (SMDB-Jewish General Hospital, Montreal, Canada).

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Safety and Efficacy of Rocuronium With Sugammadex Reversal Versus Succinylcholine in Outpatient Surgery-A Multicenter, Randomized, Safety Assessor-Blinded Trial.

Complex surgical procedures are increasingly performed in an outpatient setting, with emphasis on rapid recovery and case turnover. In this study, the...
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