Low Dose of Sugammadex vs Neostigmine and Glycopyrrolate for the Reversal of Rocuronium

Study Overview
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Brief Summary
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The aim of this study is to compare the use of a low dose sugammadex and neostigmine combined to glycopyrrolate to reverse a rocuronium induced moderate neuromuscular blockade.

Detailed Description
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Neuromuscular blocking agents (NMBAs) are administered by anesthesiologists for general anesthesia to facilitate endotracheal intubation and/or surgical conditions. Unfortunately, postoperative residual neuromuscular blockade (rNMB), is an adverse event usually observed after extubation in the postanesthesia care unit (PACU) after surgery. rNMB is associated with upper airway obstruction, reduced pharyngeal muscle coordination, decreased functional residual capacity, and impaired hypoxic ventilatory response and may lead to critical cardiopulmonary complications.To prevent those complications, monitoring NMBAs activity as well as appropriate reversal are crucial. In the light of the strong evidence proving the superiority of sugammadex for the reversal of NMB, the investigators chose to examine whether a quarter dose (0.5 mg.kg-1) of sugammadex would be superior to neostigmine for the reversal of moderate NMB (TOF 1 to 3). The investigators believe that this strategy will encourage the routine use of sugammadex because of a drastically reduced cost per patient with an increased safety and less adverse events compared to neostigmine reversal. This study will be conducted in a single center, double blinded, randomized controlled study. Type of surgery: any surgery under general anesthesia in ASA 1-3 patients, fully consented. In the OR, the investigators will place a standardized monitoring: ECG, non-invasive blood pressure and SpO2. The investigators will monitor the depth of anesthesia using the BIS index (Medtronic, Canada) and the intraoperative nociception balance using the NOL index (Medasense Ltd., Ramat Gan, Israel). Finally, the investigators will monitor neuromuscular blockade using TOF-scan® (Draeger, Mississauga, Canada). The stimulation electrodes will be placed on the forearm of the patient to monitor the response to ulnar stimulation of the adductor pollicis muscle. The investigators will use adjusted body weight for the administration of the drugs used in our anesthesia protocol except for rocuronium, sugammadex and neostigmine that will be given based on the real actual body weight. The primary objective of the study: To compare the mean time for recovery of the TOF ratio to 0.9 (90%) at the end of the surgery for rocuronium induced moderate neuromuscular blockade (TOF 1 to 3 at the end of the surgery) in two groups: Group N for neostigmine and group S for sugammadex. Group N will receive the standard reversal (neostigmine 50 µg.kg-1 and glycopyrrolate 7 µg.kg-1) and group S will receive sugammadex 0.5 mg.kg-1. Secondary objectives are listed below. Based on a 2-sided alpha < 0.05 and 80% power, the investigators calculated that 64 patients per group was required to detect a clinically relevant effect size of 0.5 favouring S group. The sample size will be inflated to 144 (72 per group) to account for 10% withdrawals and loss of follow-up. Study Duration: 12 months. Study Center: Maisonneuve-Rosemont Hospital, CIUSSS de l'Est de l'Ile de Montreal (CEMTL), University of Montreal, Montreal, Quebec, Canada. Adverse Events: None expected.

Official Title
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A Randomized Clinical Study to Compare Low Dose of Sugammadex to Standard Dose of Neostigmine and Glycopyrrolate for the Reversal of Rocuronium Induced Moderate Neuromuscular Block

Conditions
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Neuromuscular Blockade

Intervention / Treatment
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* Drug: Neostigmine and glycopyrrolate
* Drug: Sugammadex


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ASA 1-3 patients, Undergoing general anesthesia with rocuronium induced NMB, TOF 1-3 at the end of surgery, BMI < 36 kg.m-2, Age > 18 years old Exclusion Criteria: History of coronary artery disease and unstable before surgery History of serious cardiac arrhythmia (including atrial fibrillation) Renal or hepatic dysfunction Obstructive sleep apnea requiring continuous positive airway pressure (CPAP) machine Neuromuscular disease Allergy to any drug used in the study protocol

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two groups of patients randomized into Group N for neostigmine and group S for sugammadex for a total of 144 participants.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group N for Standard reversal<br>Standard reversal of 50 µg.kg-1 neostigmine (up to a maximum dose of 5mg) and 7 µg.kg-1 glycopyrrolate at the end of surgery (when surgeons finish deep tissues closure) with starting TOF 1-3. | Drug: Neostigmine and glycopyrrolate<br>* See arm descriptions<br>|
| Experimental: Group S for Sugammadex<br>Sugammadex 0.5 mg.kg-1 IV will be performed at the end of surgery (when surgeons finish deep tissues closure) with starting TOF 1-3. | Drug: Sugammadex<br>* See arm descriptions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time for recovery from moderate NMB | Time, in minutes, for recovery of the TOF ratio to 0.9 at the end of the surgery for rocuronium induced moderate neuromuscular blockade (TOF 1 to 3 at the end of the surgery). | Intra-operative (from T0 = incision until Tend = start dressing) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time for awakening and extubation | The time, in minutes for awakening and extubation. Time for awakening will start at the injection of the reversal agent and end when the patient is opening his eyes. Time for extubation will start at the same time point and will end when extubation is complete. | Intra-operative (from T0 = incision until Tend = start dressing) | 
| Incidence of reoccurrence of NMB | The incidence of rNMB (defined as TOF ratio < 0.9 30 min after the end of reversal agent administration) and the incidence of NMB reoccurrence (defined as a decrease in TOF ratio from ≥ 0.9 to < 0.8 for at least 3 consecutive TOF values) | Intra-operative (from T0 = incision until Tend = start dressing) | 
| Incidence of critical respiratory event | The incidence of critical respiratory event (CRE). A CRE will be defined as the occurrence of one of the following criteria: Upper airway obstruction requiring an intervention Moderate hypoxemia: SpO2 of 90-93% on 2 L.min-1 nasal cannula O2 that was not improved after active interventions Severe hypoxemia: SpO2 < 90% on 2 L.min-1 nasal cannula O2 that was not improved after active interventions Signs of respiratory distress or impeding ventilatory failure Inability to beath deeply when requested to by a PACU nurse Patient complaining of symptoms of respiratory or upper airway muscle weakness Patient requiring reintubation in the PACU Clinical evidence or suspicion of pulmonary aspiration after tracheal extubation | Every 15 minutes until discharge from PACU, up to 2 hours | 
| Vital signs changes - Mean arterial pressure | Difference between pre-reversal values and values for mean arterial pressure (mmHg) obtained 2, 5, 10 and 30 min after reversal. | Every 15 minutes until discharge from PACU, up to 2 hours | 
| Vital signs changes - Heart rate | Difference between pre-reversal values and values for heart rate (bpm) obtained 2, 5, 10 and 30 min after reversal. | Every 15 minutes until discharge from PACU, up to 2 hours | 
| Vital signs changes - Oxygen saturation | Difference between pre-reversal values and values for SpO2 (%) obtained 2, 5, 10 and 30 min after reversal. | Every 15 minutes until discharge from PACU, up to 2 hours | 
| Vital signs changes - Respiratory rate | Difference between pre-reversal values and values for respiratory rate (respiration per minute) obtained 2, 5, 10 and 30 min after reversal. | Every 15 minutes until discharge from PACU, up to 2 hours | 
| PACU scores - Aldrete | Difference in Aldrete's score at rest between group and time to reach scores to discharge between groups. 5 criterias : I-Consciousness level II-Respiration III- Hemodynamics IV-Motricity V- Oxygen saturation Minimum score : 0 Maximum score : 10 | Every 15 minutes until discharge from PACU, up to 2 hours | 
| PACU scores - Maisonneuve-Rosemont PACU score | Difference in Maisonneuve-Rosemont PACU score at rest between groups and time to reach scores to discharge between groups. 8 criterias : I-Consciousness level II-Respiration III- Hemodynamics IV-Motricity V- Oxygen saturation VI- Pain VII- Nausea/Vomiting VIII- Surgical bleeding Minimum score : 0 Maximum score : 16 | Every 15 minutes until discharge from PACU, up to 2 hours | 
| PACU scores - PONV score | Difference in Postoperative nausea and vomiting (PONV) score at rest between groups and time to reach scores to discharge between groups. 0- No nausea/vomiting Nausea without the need of a treatment Nausea needing a treatment Nausea and vomiting | Every 15 minutes until discharge from PACU, up to 2 hours | 
| PACU scores - POSS score | Difference in Pasero Opioid-induced Sedation Scale (POSS) score at rest between groups and time to reach scores to discharge between groups. S- Normal sleep easy awakening Awake and alert Sometimes drowsy, easy awakening Drowsy, wakes up but falls asleep during conversation Sleeps soundly, wakes up with difficulty or not at all to stimulation | Every 15 minutes until discharge from PACU, up to 2 hours | 
| PACU scores - NRS pain score | Difference in Nnumeric Rating Scale (NRS) pain score at rest between groups and time to reach scores to discharge between groups. Scale between 0 meaning no pain and 10 meaning the worst pain imaginable | Every 15 minutes until discharge from PACU, up to 2 hours | 
| Time spent in PACU | Total time, in minutes spent in PACU | Every 15 minutes until discharge from PACU, up to 2 hours | 
| Cost of reversal agent | Cost, in CAD, associated with reversal agent | Intra-operative (from T0 = incision until Tend = start dressing) | 
| Overall cost | Cost evaluation, in CAD, associated with extubation time in the operating room and PACU stay. | Intra-operative (from T0 = incision until Tend = start dressing) to PACU discharge, up to 2 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sugammadex, neostigmine, general anesthesia