Topic 2 DQ 1 (Obj. 2.4, 2.5, and 2.6)

Journal of Clinical Anesthesia (2012) 24, 289–297

Original Contribution

Use of sugammadex in patients with a history of pulmonary disease☆,☆☆,★

Rasheed Amao MD (Staff Anesthesiologist)a,⁎, Mark H. Zornow MD (Professor)b, Robert McTaggart Cowan MD, FRCPC (Clinical Assistant Professor)c, Davy C. Cheng MD, MSc, FRCPC (Professor)d, Jovino B. Morte MD (Senior Clinical Scientist)e, Martin W. Allard MBChB, FRCA (Professor)f

aDepartment of Anesthesiology, Creighton University Medical Center, Omaha, NE 68131, USA bDepartment of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR 97239, USA cDepartment of Anesthesia, Foothills Medical Center, Calgary, AB T2N 2T9, Canada dDepartment of Anesthesia and Perioperative Medicine, The University of Western Ontario, London, ON N6A 3K7, Canada eMerck Sharp & Dohme Corp., Whitehouse Station, NJ 08889, USA fDepartment of Anesthesiology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA

Received 6 September 2010; revised 27 July 2011; accepted 9 September 2011

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Keywords: Bronchospasm; Chronic obstructive pulmonary disease;

Neuromuscular blockade; Pulmonary disease; Rocuronium; Sugammadex

Abstract Study Objective: To evaluate the safety and efficacy of sugammadex for reversal of rocuronium- induced neuromuscular blockade in patients with pulmonary disease. Design: Phase III, randomized, multicenter, parallel-group, comparative, safety-assessor blinded study. Setting: Nine hospital sites. Patients: 77 ASA physical status 2 and 3 patients, aged ≥ 18 years, with a history of pulmonary disease, and scheduled for surgery with general anesthesia requiring neuromuscular blockade. Interventions: Following anesthesia induction, patients received rocuronium 0.6 mg/kg with 0.15 mg/kg maintenance doses as needed. Patients were randomized to receive sugammadex 2 mg/kg or 4 mg/kg after the last rocuronium dose at reappearance of the second twitch. Measurements: Safety evaluations included adverse events, laboratory parameters, vital signs, and evidence of recurrent or residual neuromuscular blockade. Efficacy was evaluated as the time from sugammadex administration to recovery of the train-of-four (TOF) ratio to ≥ 0.9.

☆ Funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Whitehouse Station, NJ, USA. Editorial assistance provided by Melanie ore, Prime Medica (Knutsford, Cheshire, UK) during the preparation of this manuscript, funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & o., Inc., Whitehouse Station, NJ, USA.

☆☆ Presented in part at the Annual Meeting of the American Society of Anesthesiologists, San Francisco, Oct. 13-17, 2007. ★ Conflict of interest: Davy Cheng has received research grants from Novo Nordisk, Baxter HealthCare, and Merck. Jovino B. Morte is an employee of

erck Sharp & Dohme Corp., Whitehouse Station, NJ. Rasheed Amao, Robert McTaggart Cowan, Mark Zornow, and Martin Allard have no conflicts of terest to declare. ⁎ Correspondence: Rasheed Amao, MD, Department of Anesthesiology, Mercy Medical Center, 801 Fifth St., Sioux City, IA 51101, USA. Tel.: +1 712 279

077; fax: +1 712 279 2404. E-mail address: [email protected] (R. Amao).

952-8180/$ – see front matter © 2012 Elsevier Inc. All rights reserved. oi:10.1016/j.jclinane.2011.09.006

290 R. Amao et al.

Main Results: Safety was comparable between doses, with no evidence of residual or recurrent neuromuscular blockade. Two bronchospasm cases were reported (4 mg/kg group), both in patients with asthma who received desflurane for anesthesia maintenance. Geometric mean (95% confidence interval) times to a TOF ratio of ≥ 0.9 were 2.1 (1.7 - 3.1) min (2 mg/kg) and 1.8 (1.5 - 2.7) min (4 mg/kg). Conclusion: Sugammadex 2 mg/kg and 4 mg/kg were well tolerated and effective in patients with a history of pulmonary disease. Bronchospasm is a possibility when administering sugammadex to patients with underlying pulmonary disease. © 2012 Elsevier Inc. All rights reserved.

1. Introduction

Although general anesthesia is usually administered safely and without complication in healthy patients, pulmonary complications during general anesthesia are possible [1]. Patients with a history of asthma or chronic obstructive pulmonary disease (COPD) have an increased risk of intraoperative bronchospasm and hypoxemia [1-3]. In addition, the risk of postoperative pulmonary complications such as pneumonia, respiratory failure with prolonged mechanical ventilation, atelectasis, and exacerbation of underlying chronic lung disease [4-7] is also increased in these patients.

The use of short-acting or intermediate-acting neuromus- cular blocking agents in anesthesia is generally considered to be safe [8]. However, judicious use of these agents is necessary in patients with COPD, and others with reduced respiratory reserves, because of a risk of residual paralysis [9-11], which may lead to postoperative respiratory insuffi- ciency [8,12].

Conventionally used cholinesterase inhibitor reversal agents such as neostigmine may cause bradycardia, bron- chospasm, increased airway secretions, and increased airway resistance through undesired stimulation of muscarinic receptors [13,14]. As such, neostigmine should be used with caution in patients with asthma [15]. While muscarinic antagonists such as glycopyrrolate and atropine are often coadministered with neostigmine to counteract cardiopul- monary side effects, they themselves are associated with adverse events such as blurred vision, dry mouth, and tachycardia [16]. Furthermore, muscarinic antagonists may not reliably prevent the adverse pulmonary effects of neostigmine, as suggested by a case report of bronchospasm in an asthmatic patient given neostigmine and atropine for the reversal of neuromuscular blockade [17].

Sugammadex is a gamma-cyclodextrin and the first in a new class of selective relaxant binding agents [18]. Sugammadex is safe and efficacious during Phase II and Phase III clinical development when used for the reversal of both rocuronium-induced and vecuronium-induced neuro- muscular blockade [19-25]. Furthermore, the mechanism of action of sugammadex depends on chemical encapsulation of the neuromuscular blocking agent molecule, does not involve direct interaction with the cholinergic system, and

thus should avoid the undesired adverse effects associated with neostigmine. The objective of this study was to evaluate the safety and clinical effectiveness of two routinely recommended doses of sugammadex (2 mg/kg and 4 mg/ kg) in patients diagnosed with, or having a past history of, pulmonary disease.

2. Materials and methods

2.1. Study design

This Phase III, randomized, multicenter, parallel group, comparative, safety-assessor blinded study was designated the Wave study, and was registered on May 17, 2007 (Clinicaltrials.gov identifier: NCT00475215; Merck protocol no. P05392). The study was conducted in three Canadian and 6 U.S. centers, and was designed primarily to evaluate the safety of sugammadex (2 mg/kg and 4 mg/kg) in patients with a history of pulmonary disease. A secondary objective of the study was to evaluate recovery from neuromuscular blockade after reversal of rocuronium at the second twitch (T2) with 2 mg/kg and 4 mg/kg sugammadex. The study protocol was approved by the Institutional Review Board or Independent Ethics Committees of each trial center, was conducted in accordance with principles of Good Clinical Research Practice (GCRP), and approved by the appropriate institutional review boards and regulatory agencies. Written, informed consent was obtained from all patients.

Enrolled patients were randomized 1:1 to receive either sugammadex 2 mg/kg or 4 mg/kg using a central computer- generated randomization schedule, stratified by center.

2.2. Patients

Patients were eligible for inclusion in the study if they were aged ≥ 18 years, categorized as ASA physical status 2 or 3, and diagnosed with current pulmonary disease or having a previous history of any form of pulmonary disease. All patients were scheduled to undergo a noncardiac surgical procedure during general anesthesia in the supine position using rocuronium for tracheal intubation and maintenance of neuromuscular blockade. Patients were excluded from the study if they were expected to have a difficult intubation due

291Sugammadex in pulmonary patients

to anatomical malformations, or known or suspected to have neuromuscular disorders that impair neuromuscular block- ade, significant renal dysfunction, a (family) history of malignant hyperthermia, or an allergy to opioids, muscle relaxants, or other medications used during general anesthe- sia. Patients receiving medication at a dose and/or at a time point known to interfere with the action of neuromuscular blocking agents such as anticonvulsants, magnesium salts, and certain types of antibiotics, including those of the macrolide or aminoglycoside groups, were also excluded. Female patients who were pregnant, breast feeding, or of childbearing potential, not using any reliable method of birth control, or only using hormonal contraception, and patients who had already participated in a sugammadex trial or in another clinical trial not preapproved within 30 days of entering the study also were excluded.

2.3. Study procedures

Anesthesia was induced and maintained with an intravenous (IV) opioid, an anesthetic agent, and other agents/medications based on the routine practices at the individual study center and the clinical need of the patient. After induction of anesthesia but before administration of rocuronium, the TOF-Watch® SX acceleromyograph (Or- ganon Ireland Ltd, a subsidiary of Merck and Co, Inc, Swords, Co. Dublin, Ireland) was affixed to the arm with the IV cannula used for drug administration and stabiliza- tion and calibration performed in the operating room (OR). Neuromuscular function was monitored at the adductor pollicis muscle using the TOF-Watch SX, and monitoring continued until the end of anesthesia, at least until recovery of the train-of-four (TOF) ratio to ≥ 0.9. The TOF-Watch SX procedures were in compliance with GCRP guidelines in place at the time of the study [26], with no preload used and normalization not performed. In the case of difficulty in the recording or interpretation of TOF, for example, where patient movement resulted in unstable tracings, recordings were sent to a Central Independent Adjudication Committee (CIAC) for assessment. The CIAC accepted or rejected the deviation according to prespecified standards and/or their expert opinion. In the case of a difference of opinion between the investigator and the CIAC, the judgment of the CIAC was used for statistical analysis. Data were collected on the time to recovery of the TOF ratio to 0.7, 0.8, and 0.9. Peripheral body temperature was monitored continuously using a thermister at the thenar eminence of the palm, and maintained at ≥ 32°C during the entire period of neuromuscular monitoring.

Before the surgical procedure, patients received a single intubating IV bolus dose of rocuronium 0.6 mg/kg followed by maintenance bolus doses of 0.15 mg/kg as needed. At the end of surgery, after administration of the last dose of rocuronium and at the reappearance of the T2, patients received a single IV bolus dose of 2 mg/kg or 4 mg/kg sugammadex according to the randomization schedule. The

syringes used to administer sugammadex were covered with foil after preparation to conceal the treatment administered to the patient, and only the person who prepared the syringes was unblinded for that particular patient. He or she was not allowed to disclose the randomization code to other staff and was also not permitted to perform any subjective safety assessments after anesthesia for the patient. The safety assessor was blinded and was not permitted to witness the preparation of the study drug.

Patients were not permitted to receive any muscle relaxant other than rocuronium, or a second dose of sugammadex, during neuromuscular monitoring. If further muscle relaxa- tion was required after administration of sugammadex, a nonsteroidal muscle relaxant was given.

2.4. Study endpoints

2.4.1. Safety and efficacy The primary objective was to evaluate the safety of

sugammadex 2 mg/kg or 4 mg/kg in patients diagnosed with or having a history of pulmonary disease. This was assessed by adverse events (AEs) and serious AEs (SAEs), vital signs, laboratory analyses, oxygen saturation, respiratory rate (RR), physical examination, and cardiac monitoring.

The primary efficacy variable was the time from administration of the study drug to recovery of the TOF ratio to≥ 0.9. Secondary efficacy variables included the time from administration of the study drug to recovery of the TOF ratio to 0.7 and 0.8. These secondary efficacy variables were included to provide some benchmarking if one were to consider results from older studies that did not report the time to TOF to 0.9.

2.5. Safety assessments

A physical examination was performed before surgery and during the postanesthetic visit. Venous blood samples were collected before administration of rocuronium, 4 to 6 hours after administration of sugammadex, and at the postanesthetic visit (the day after surgery and at least 10 hours after administration of sugammadex) for laboratory analyses. Urine samples were collected before leaving for the OR, or the day before surgery, and at the postanesthetic visit. Patients were also monitored for clinical evidence of recurrent or residual neuromuscular blockade (ie, respiratory problems or a significant decrease in the TOF ratio to b 0.8) during the study, starting from the administration of sugammadex and continuing until the end of anesthesia.

Oxygen saturation as measured by pulse oximetry (SpO2) and RR were monitored for at least 60 minutes after recovery of the TOF ratio to ≥ 0.9, and continuous cardiac monitoring of the QT interval was performed intraoperatively and postoperatively according to routine procedures at each site. Vital signs (heart rate and blood pressure) were recorded before surgery, at stable anesthe- sia (just before administration of an intubating dose of

292 R. Amao et al.

rocuronium), before administration of sugammadex, at 2, 5, 10, and 30 minutes after the start of administration of sugammadex, and at the postanesthetic visit.

After extubation in the OR and before discharge from the recovery room, patients were assessed for clinical signs of neuromuscular recovery every 15 minutes until they were able to lift their head for 5 seconds. Patients were also assessed for level of consciousness, ie, whether the patient was awake and oriented, arousable with minimal stimulation, or responsive only to tactile stimulation. For those patients who were considered to be cooperative, the 5-second head-lift test and a check for general muscle weakness were performed. Patients were also monitored until the postoperative visit for clinical signs of a possible interaction of sugammadex with endogenous compounds or with exogenous compounds other than rocuronium, such as a greater or lesser than expected drug effect. The safety assessor evaluated all subjective safety parameters such as AEs. A study-blinded safety assessor monitored all patients for AEs including SAEs, and all AEs and SAEs were coded using MedDRA version 9.1 (Intl. Federation of Pharmaceutical Manufacturers and Associations, Geneva, Switzerland). To remain blinded, the safety assessor did not perform the randomization and did not prepare or administer the trial medication.

2.6. Statistical analysis

Eighty patients were aimed to be enrolled at 8 centers with 10 patients per center (ie, 5 pts per sugammadex dose group per center). The study was conducted with a view to determining the safety and tolerance of sugammadex in this special patient population, and the choice of sample size was based on these clinical considerations, with no formal sample size calculation performed. The safety analysis evaluated the all-subjects-treated group, which consisted of all subjects who received a dose of sugammadex, while the efficacy analysis was based on the intent-to-treat (ITT) population, comprising all randomized subjects who had received sugammadex and had at least one postbaseline efficacy assessment.

Efficacy data were summarized by dose group as geometric mean, median, and minimum and maximum values. In addition, two-sided 95% confidence intervals (CIs) were calculated by dose group for the recovery times of the primary and secondary efficacy variables (time to recovery of TOF to 0.9, and time to recovery of TOF to 0.7 and 0.8, respectively). Recovery times follow a lognormal distribu- tion, which renders the geometric mean the most appropriate method for summarizing the 2 mg/kg and 4 mg/kg groups. For categorical variables, frequency counts and percentages were presented. A statistical comparison of recovery times achieved with the two sugammadex doses was not performed as this was not the primary objective of this study and, as both the 2 and 4 mg/kg doses were given at the same time point (reappearance T2), it was expected that the higher dose

would be somewhat faster and thus a formal comparison would not test a hypothesis of interest.

3. Results

The study was carried out between October 2005 and August 2006. A total of 86 patients were randomized (sugammadex 2 mg/kg, n = 44; 4 mg/kg dose, n = 42), of whom 77 were treated/completed the study and had at least one postbaseline efficacy assessment (2 mg/kg, n = 39; 4 mg/kg, n = 38). Nine randomized patients discontinued the study prematurely without receiving sugammadex. Reasons for discontinuation included problems with TOF-Watch SX measurements (n = 3), surgery-related issues (n = 1), withdrawal of consent (n = 1), cancellation/change of surgery (n = 2), inability to maintain good air movement (n = 1), and decrease in SpO2 as a pretreatment AE (n = 1) (Fig. 1). Baseline characteristics were generally comparable between the sugammadex dose groups (Table 1).

The majority of patients had concurrent pulmonary disease. In addition, 10 patients were included with rhinosinusitis or tobacco use who had a past history of pulmonary disease, and therefore also qualified for inclusion in the study, but had no associated pulmonary findings at the time of the study (2 mg/kg, n = 4; 4 mg/kg, n = 6). Tobacco use was more prevalent among the 4 mg/kg group [n = 18 (47%)] than the 2 mg/kg group [n = 9 (23 %)]. Asthma, COPD, and bronchitis were among the most frequently reported preexisting medical conditions. In total, 71% of patients received sevoflurane maintenance anesthesia, while 21% received desflurane and 8% received isoflurane.

3.1. Safety

In both dose groups, the most common AEs in the 2 mg/ kg and 4 mg/kg sugammadex groups, respectively, were: procedural pain (69.2% and 71.1%), nausea (33.3% and 23.7%), incision site complication (20.5% and 18.4%), and vomiting [17.9% and 13.2% (Table 2)]. All AEs of severe intensity were considered unrelated to sugammadex. In the 2 mg/kg and 4 mg/kg groups, severe incision site complications were reported for 5 and 4 patients, respec- tively, while severe procedural pain was reported by one and three patients, respectively.

Seven patients had SAEs after the administration of sugammadex. These included poor peripheral circulation (n = 1), operative hemorrhage (n = 1), coronary artery blockage [caused by coronary artery disease (n = 1)], constipation (n = 1) in the 2 mg/kg group, and seroma (n = 1) and bronchospasm (n = 2) in the 4 mg/kg group. Of the 7 reported SAEs, only the two reports of bronchospasm (one of moderate and one of severe intensity) were considered by the investigator to be possibly related to sugammadex. Both bronchospasm SAEs occurred in patients with a history of

Fig. 1 Patient flow through the study. AST = all-subjects-treated, ITT = intent-to-treat, TOF-Watch SX (Organon Ireland Ltd, a subsidiary of Merck and Co, Inc, Swords, Co. Dublin, Ireland).

293Sugammadex in pulmonary patients

asthma, and in both cases symptoms resolved within 5 minutes of initiation of treatment. One patient, who underwent bilateral mammoplasty and had a history of severe asthma, received one puff of beclomethasone, two puffs of

Table 1 Baseline characteristics (all-subjects-treated population)

Sugammadex dose group

Total (n = 77)

2 mg/kg (n = 39)

4 mg/kg (n = 38)

Age (yrs), mean (SD) 49 (17) 46 (14) 47 (15) Weight (kg), mean (SD) 74 (17) 81 (16) 77 (16) Height (cm), mean (SD) 164 (10) 167 (11) 165 (11) Gender, n (%) female 30 (77) 27 (71) 57 (74) Male 9 (23) 11 (29) 20 (26) Race, n (%) Asian 3 (8) 0 (0) 3 (4) White/Caucasian 32 (82) 30 (79) 62 (81) Other 4 (10) 8 (21) 12 (16) ASA physical status, n (%) 2 28 (72) 30 (79) 58 (75) 3 11 (28) 8 (21) 19 (25) Respiratory, thoracic and mediastinal disorders, n (%) a

Asthma 28 (72) 24 (63) 52 (68) chronic bronchitis 4 (10) 5 (13) 9 (12) COPD 2 (5) 5 (13) 7 (9)

COPD = chronic obstructive pulmonary disease. a Only the most frequently occurring conditions are shown.

albuterol and salbutamol (Combivent), two puffs of albuterol for asthma prophylaxis prior to the surgical procedure, and dexamathasone 4 mg/kg IV during the procedure, experi- enced an episode of severe bronchospasm before extubation and 55 minutes after sugammadex administration. This patient had been suctioned during deep anesthesia. Desflur- ane had been discontinued and the patient was receiving 100% oxygen when the bronchospasm occurred. Ventilation

Table 2 Most common adverse events (≥ 10% of pts in either dose group; all-subjects-treated population)

Adverse event Sugammadex 2 mg/kg (n = 39)

Sugammadex 4 mg/kg (n = 38)

Total (n = 77)

Procedural pain 27 (69.2) 27 (71.1) 54 (70.1) Nausea 13 (33.3) 9 (23.7) 22 (28.6) Incision site complication

8 (20.5) 7 (18.4) 15 (19.5)

Vomiting 7 (17.9) 5 (13.2) 12 (15.6) Pruritus 5 (12.8) 2 (5.3) 7 (9.1) Constipation 4 (10.3) 3 (7.9) 7 (9.1) Postprocedural nausea

3 (7.7) 4 (10.5) 7 (9.1)

Flatulence 4 (10.3) 2 (5.3) 6 (7.8) Hemoglobin decrease 5 (12.8) ⁎ 1 (2.6) 6 (7.8) Postprocedural complication

4 (10.3) 0 (0) 4 (5.2)

Dizziness 4 (10.3) 0 (0) 4 (5.2)

⁎ One case of hemoglobin decrease was considered by the investigator to be possibly related to sugammadex.

Table 3 Time (min) from start of administration of sugammadex 2 mg/kg and 4 mg/kg to recovery of the train-of- four (TOF) ratio to 0.9, 0.8, and 0.7 (intent-to-treat population)

Sugammadex

2 mg/kg (n = 39)

4 mg/kg (n = 38)

Time to TOF ratio of 0.9 n a 33 33 geometric mean 2.1 1.8 95% confidence interval 1.7–3.1 1.5–2.7 median 2.1 1.9 range 0.8–12.0 0.7–11.5 Time to TOF ratio of 0.8 n b 35 35 geometric mean 1.7 1.5 95% confidence interval 1.5–2.0 1.4–1.8 median 1.6 1.5 range 0.7–4.7 0.7–3.0 Time to TOF ratio of 0.7 n c 36 35 geometric mean 1.4 1.3 95% confidence interval 1.3–1.7 1.2–1.5 median 1.4 1.2 range 0.7–3.0 0.7–2.4

a Data missing/unreliable for 11 patients: TOF Watch SX malfunc- tion (2 mg/kg, n = 1; 4 mg/kg, n = 1; Organon Ireland Ltd, a subsidiary of Merck and Co, Inc, Swords, Co. Dublin, Ireland); time to TOF 0.9 unreliable (2 mg/kg, n = 4; 4 mg/kg, n = 2); TOF ratio of 0.9 not achieved (2 mg/kg, n = 1; 4 mg/kg, n = 2).

b Data missing/unreliable for 7 patients: TOFWatch SXmalfunction (2 mg/kg, n = 1; 4 mg/kg, n = 1); time to TOF 0.8 unreliable (2 mg/kg, n = 3; 4 mg/kg, n = 2).

c Data missing/unreliable for 6 patients: TOFWatch SXmalfunction (2 mg/kg, n = 1; 4 mg/kg, n = 1); time to TOF 0.7 unreliable (2 mg/kg, n = 2; 4 mg/kg, n = 2).

Table 4 Clinical signs of recovery before transfer to and before discharg

Before transfer to after extubation

2 mg/kg (n = 39)

Level of consciousness (n, %) a

awake and oriented 17 (43.6) arousable with minimal stimulation 16 (41.0) responsive only to tactile stimulation 6 (15.4) Cooperative (n, %) yes 28 (71.8) no 11 (28.2) Able to perform 5-sec head lift (n, %) b

yes 23 (60.5) no 5 (12.8) General muscle weakness (n, %) no 25 (64.1) yes 3 (7.7)

a Level of consciousness assessment missing for one patient in the “Before b If patient was not cooperative, the head lift test and general muscle weakn

294 R. Amao et al.

proved difficult in this patient; her SpO2 was 60%. She was manually ventilated and treated with albuterol (two puffs). The other patient, who had a history of moderate asthma and who underwent knee arthroscopy and intra-articular surgery, experienced moderate bronchospasm that occurred one minute postextubation and 4 minutes after sugammadex administration while the patient was fully awake and oriented. This patient had received two puffs of fluticasone with salmeterol (Advair) 250 μg prior to surgery for asthma prophylaxis, and received desflurane (3.9% - 4.4%) for anesthesia maintenance, which was stopped 4 minutes before the bronchospasm occurrence. The bronchospasm was treated with two puffs of terbutaline. In addition to these two cases, 4 patients (5.2%) experienced AEs that were considered to be possibly or probably related to sugammadex, which included: headache (n = 1), hematology/biochemistry/ urinalysis changes [decreased erythrocyte, hematocrit, he- moglobin, blood protein, albumin, calcium, haptoglobin, and potassium levels, and increased beta-N-acetyl-D-glucosami- nidase levels (n = 1)], postprocedural nausea (n = 1) in the 2 mg/kg group, and procedural hypertension (n = 1) in the 4 mg/kg group (Table 2).

There was one report of increased body temperature in each dose group. Other than this, there were no clinically significant changes from baseline in vital signs after administration of sugammadex 2 mg/kg or 4 mg/kg, and there were no clinically significant differences between the two dose groups in this respect. There was no evidence of residual or recurrent neuromuscular blockade in either sugammadex dose group in the Postanesthesia Care Unit, no reported evidence of interaction between sugammadex and compounds other than rocuronium, and no patient died or discontinued the study as a result of an AE.

e from the recovery room (intent-to-treat population)

recovery room Before discharge from recovery room

4 mg/kg (n = 38)

2 mg/kg (n = 39)

4 mg/kg (n = 38)

22 (57.9) 38 (97.4) 38 (100.0) 13 (34.2) 1 (2.6) 0 (0) 2 (5.3) 0 (0) 0 (0)

34 (89.5) 39 (100.0) 38 (100.0) 4 (10.5) 0 (0) 0 (0)

29 (76.3) 39 (100.0) 37 (97.4) 5 (13.2) 0 (100.0) 1 (2.6)

30 (78.9) 35 (89.7) 32 (84.2) 4 (10.5) 4 (10.3) 6 (15.8)

transfer to recovery room after extubation, 4 mg/kg” group. ess were not assessed.

295Sugammadex in pulmonary patients

3.2. Efficacy

Time from the start of administration of sugammadex to recovery of the TOF ratio to 0.9 for the ITT population is summarized in Table 3. The geometric mean (95% CI) time to recovery to a TOF ratio of ≥ 0.9 was 1.8 (1.5 - 2.7) minutes in the sugammadex 4 mg/kg group, compared with 2.1 (1.7 - 3.1) minutes in the 2 mg/kg dose group. Times to recovery of the TOF ratio to 0.7 and 0.8 are also shown in Table 3. At discharge from the recovery room, the clinical signs of recovery were similar in the two groups, with 76 of 77 patients (99%) awake and oriented, cooperative, and able to perform the 5-second head lift (Table 4). Ten of 77 patients (13%) experienced some general muscle weakness at discharge; generalized muscle weakness was not an unexpected finding for these particular patients, and in- vestigators did not consider this finding an AE.

4. Discussion

This is the first study to evaluate the safety and efficacy of sugammadex in patients with current pulmonary disease or a past history of pulmonary disease. It showed that sugamma- dex at doses of 2 mg/kg and 4 mg/kg was effective and generally well tolerated in reversing rocuronium-induced neuromuscular blockade when administered at reappearance of T2 in this patient population.

It is well recognized that patients with preexisting pulmonary disease have an increased risk of perioperative pulmonary complications [2,3,5,6]. The processes of surgery, general anesthesia, and the anesthetic drugs themselves may all have an effect on the respiratory system. However, the mechanism of action of sugammadex is dependent on chemical encapsulation of the neuromuscular blocking agent molecule and does not involve direct interaction with the cholinergic system; therefore, it should avoid the undesired adverse effects associated with acetylcholinesterase inhibitors.

Our study showed that sugammadex 2 mg/kg and 4 mg/kg was generally well tolerated in patients with underlying pulmonary disease. The AE profile in this study was comparable to previous studies, which were not specifically conducted in patients with a history of pulmonary disease, who tolerated sugammadex at doses from 0.5 mg/kg to 8.0 mg/kg [19-24,27]. However, two events of broncho- spasm occurred, both in patients with a history of asthma and who were treated with sugammadex 4 mg/kg, and were classified as SAEs considered to be possibly related to sugammadex. In one patient, the episode of bronchospasm occurred before extubation and 55 minutes after sugamma- dex administration, while in the other patient the event occurred one minute postextubation and while the patient was fully awake and oriented. In both cases, symptoms were treated and resolved within 5 minutes of treatment. Of note is

that both patients with bronchospasm SAEs had received desflurane (3.9% - 4.4% and 3.2% - 5.0%, respectively) for maintenance of anesthesia, an anesthetic that irritates the airways, as manifested by an increase in respiratory resistance [28]. Goff et al [29] showed that desflurane may not be an effective bronchodilating anesthetic in the first 10 minutes of tracheal intubation. In the present study, desflurane was administered to 21% of patients, with most (71%) patients receiving sevoflurane and 8% receiving isoflurane. The choice of anesthetic agents was based on routine practices of the individual study centers.

It is widely recognized that patients with hyperactive airway diseases such as asthma are at increased risk of intraoperative bronchospasm [1-3,30], and this may explain why bronchospasm was observed in these two patients with a history of moderate and severe asthma, respectively. Anticipation of possible bronchospasm is recommended for patients with a history of pulmonary complications who receive sugammadex [31]. The current study aimed to investigate sugammadex in a potential clinical setting, and thus there were limited restrictions on anesthetic regimen. Induction and maintenance of anesthesia was performed with an IV opioid, an anesthetic, and other agents/ medications at a concentration range/dose(s) based on the clinical need of the subject. In normal clinical practice, a range of different anesthetics may be used when operating on pulmonary patients; thus the aim here was to explore the action of sugammadex in patients with pulmonary disease under the anesthetic regimen required for the subject as decided by the investigator.

Several nonsugammadex studies have investigated the incidence of perioperative bronchospasm in both the general patient population and in patients with a history of pulmonary disease. In patients without a history of pulmonary disease, this incidence is close to 0.17% [32]. The same study by Olsson et al [32] states that this incidence may reach 2.2% in patients with obstructive pulmonary disease. In a retrospective review of 706 patients diagnosed with asthma, Warner et al [33] found the risk of bronchospasm to be 1.7%. This figure is comparable to the 2.6% of patients who experienced bronchospasm in the current study. However, there is some degree of variation in the literature in incidence of perioperative and postoperative bronchospasm in patients with asthma, ranging from 0.8% - 20% [30,32-35]. This variation may reflect differences in the activity and severity of the asthma in the patients in these studies. It has been suggested that inadequately controlled asthma is an important risk factor for bronchospasm during general anesthesia and that, as such, prophylactic therapy should be prescribed according to asthma control to reduce the risk of these events [30]. In the registrational phase I to III program of sugammadex studies (including 1,926 pts treated with sugammadex), there were a total of three reports of bronchospasm in patients receiving sugammadex (two among the pulmonary pts described in the current study and one other in a pt with no history of bronchospasm, which

296 R. Amao et al.

was considered by the reporting investigator to be un- related to the study drug [36]). However, the occurrence of bronchospasm may also be a sign or symptom of hypersensitivity, which has been reported in patients treated with sugammadex [31].

The primary purpose of this study was to gain additional information regarding the use of sugammadex in patients with underlying pulmonary disease; a nonsugammadex comparator group was not included. Neostigmine, currently the most widely used acetylcholinesterase inhibitor and the logical comparator for sugammadex, should be used with appropriate caution in patients with asthma as the parasym- pathomimetic action of neostigmine may cause bronchocon- striction [15].

In the present study, recovery of the TOF ratio to ≥ 0.9 was rapid. As expected, there was a trend toward slightly faster recovery of neuromuscular transmission with the 4 mg/kg than the 2 mg/kg dose group (1.8 min vs 2.1 min for recovery to TOF to 0.9). The recovery times reported in our study are comparable to those reported previously with sugammadex doses of 2 mg/kg and 4 mg/kg administered for the reversal of rocuronium-induced neuromuscular blockade in a general population of surgical patients [19-24,27].

5. Conclusions

Sugammadex 2 mg/kg or 4 mg/kg was generally well tolerated, and was effective in the reversal of moderate rocuronium-induced neuromuscular blockade in patients with a diagnosis or history of pulmonary disease. The occurrence of bronchospasm in 2.6% of patients in this study suggests that physicians be prepared for this event when administering sugammadex to patients with underlying pulmonary disease.

Acknowledgments

The authors would like to thank the following in- vestigators and colleagues for their help in the enrollment of patients: Dr Michael Berrigan, MD, PhD, Principal Investigator, The George Washington University, Washing- ton, D.C.; Dr Sam Perov, MD, Principal Investigator, Detroit Medical Center, Detroit, MI; Dr Frances Chung, MD, Principal Investigator, Toronto Western Hospital, Toronto, ON, Canada; Dr David C. Warltier, MD, PhD, Principal Investigator, Zablocki VA Medical Center, Milwaukee, WI; Dr Luis Velez-Pestana, MD, Principal Investigator, The Methodist Hospital, Houston, TX; Ms Lori Kelly, RN, BSN, CCRC, Study Coordinator, Oregon Health and Science University, Portland, OR; Dr Phil Jones and Dr Wojciech Dobkowski (Co-Investigators), Sandy Adam, RN, and Bev Irwin, RN, The University of Western Ontario, London, ON, Canada; Michelle Schincke, BSN and Helene Loginiddou,

MD, Creighton University, Omaha, NE. Statistical analysis of the study data was conducted by Loek J. Bour, MSc (MSD, Oss, Netherlands).

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