Sugammadex Versus Neostigmine for Reversal of Rocuronium Neuromuscular

• Sponsor: The Cleveland Clinic (Other)
• Overall Status: Completed
• CT.gov ID: NCT03322657
• Collaborator: (none)
• Enrollment: 69
• Location: 1
• Arms: 2
• Actual Duration (Months): 38.6
• Patients Per Site Per Month: 1.8

Study Details

Study Description

Brief Summary

The aim of this study is to evaluate whether the use of Sugammadex for reversing the neuromuscular blocking effects of rocuronium during neurointerventional procedures can speed recovery of neuromuscular function. Half of participates will receive Neostigmine with glycopyrrolate, while the other half will receive Sugammadex.

Condition or Disease	Intervention/Treatment	Phase
Neuromuscular Blockade; Anesthesia	Drug: Neostigmine; Drug: Glycopyrrolate; Drug: Sugammadex	Phase 4

Detailed Description

Incomplete recovery from neuromuscular blocking agents (NMBAs) residual block after anesthesia and surgery continues to be a common problem in the postanesthesia care (PACU).

Neostigmine remains the most common acetylcholinesterase inhibitor in the United States. However, administration of the drug significantly impairs genioglossus muscle activity when administered after full recovery from neuromuscular block. Moreover, doses of neostigmine exceeding 0.06 mg/kg increase the risk of respiratory complications independent of NMBAs effects.

Sugammadex is a modified γ-cyclodextrin that rapidly reverses that effect of the steroidal nondepolarizing NMBAs rocuronium and vecuronium. Sugammadex forms a stable, inactive 1:1 complex with rocuronium or vecuronium, reducing the amount of free NMBA available to bind to nicotinic acetylcholine receptors at the neuromuscular junction. Unlike neostigmine, sugammadex completely reverses even dense neuromuscular blocks.

Patients having catheter-based neurointerventional procedures are kept deeply anesthetized. It is common to find patients nearly completely paralyzed at the end of neurointerventional procedures and have a markedly delayed emergence while waiting for muscle function to recover sufficiently to safely antagonize with neostigmine.

Study Design

• Study Type: Interventional
• Actual Enrollment: 69 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Care Provider)
• Primary Purpose: Treatment
• Official Title: Sugammadex Versus Neostigmine for Reversal of Rocuronium Neuromuscular Block in Patients Having Catheter-based Neurointerventional Procedures
• Actual Study Start Date: Nov 14, 2017
• Actual Primary Completion Date: Dec 31, 2020
• Actual Study Completion Date: Feb 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Neostigmine with glycopyrrolate Neostigmine 0. 07 mg/kg with glycopyrrolate 0.01 mg/kg with ceiling dose of 5 mg neostigmine with 1 mg of glycopyrrolate at the end surgery	Drug: Neostigmine; Neostigmine injection; Drug: Glycopyrrolate; Glycopyrrolate injection
Experimental: Sugammadex Sugammadex 4 mg/kg at the end surgery	Drug: Sugammadex; Sugammadex injection

Outcome Measures

Primary Outcome Measures

1. Time in Minutes to Reach Train of Four (TOF) Ratio ≥ 0.9 After the Administration of Reversal Agent [within 90 minutes after endotracheal extubation]

   The primary outcome was a time-to-TOF ratio ≥ 0.9 after the administration of the reversal agent. The TOF ratio was measured in a continuous manner every 12 seconds from the administration of the reversal drug until TOF ratio ≥ 0.9 or until 90 minutes after administration of the reversal agent.

2. TOF Ratio at 90 Min [at 90 minutes after the administration of the reversal agent]

   TOF (train of four), also known as a peripheral nerve stimulator, is used to assess nerve function in patients receiving neuromuscular blocking agents (paralytic medications). Before giving the medications, the baseline must be measured because this tells how much electrical stimulation the patient needs for nerve stimulation without any paralytic on board. Our primary outcome TOF ratio between TOF at 90 minutes after the administration of the reversal agent versus the TOF at baseline tells us how well the treatment is working to reverse the rocuronium Neuromuscular. This is a sensitivity analysis of primary analysis.

Secondary Outcome Measures

1. The Time for Extubation After Administration of Reversal Agents [Up to 4 hours after administration of reversal agents]

   Time from administration of reversal agent to tracheal extubation

2. Change of Diaphragmatic Contractility Speed- Sniff (Breathing From the Nose), cm/s [from baseline to 90 minutes after the administration of the reversal agent]

   The change of diaphragmatic contractility speed was defined as baseline minus postoperative diaphragmatic contraction.

3. Change of Diaphragmatic Contractility Speed, Deep Breathing From Mouth, cm/s [from baseline to 90 minutes after the administration of reversal agent]

   The change of diaphragmatic contractility speed was defined as baseline minus postoperative diaphragmatic contraction.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age ≥ 18 years;

• American Society of Anesthesiologists (ASA) physical status 1-3;

• Scheduled for catheter-based neurointerventional procedures including coiling and stent insertion;

• General anesthesia.

Exclusion Criteria:

• Suspected difficult intubation;

• Neuromuscular disorder;

• Renal impairment creatinine ≥ 2 mg /dl;

• Hepatic dysfunction;

• History of malignant hyperthermia;

• Allergy to neuromuscular blocking drugs, Sugammadex, neostigmine or glycopyrrolate;

• Perioperative respiratory infections and/or pneumonia;

• Intubated or unresponsive;

• Pregnancy or breastfeeding.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic	Cleveland	Ohio	United States	44195

Sponsors and Collaborators

• The Cleveland Clinic

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 17, 2017

More Information

Publications

None provided.

• Responsible Party: Ehab Farag, MD, Ehab Farag, M.D., The Cleveland Clinic
• ClinicalTrials.gov Identifier: NCT03322657
• Other Study ID Numbers: 17-764
• First Posted: Oct 26, 2017
• Last Update Posted: Nov 16, 2021
• Last Verified: Oct 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Ehab Farag, MD, Ehab Farag, M.D., The Cleveland Clinic: Sugammadex; Neostigmine; Reversal of neuromuscular block
• Additional relevant MeSH terms: Glycopyrrolate; Neostigmine

Study Results

Participant Flow

Arm/Group Title	Neostigmine With Glycopyrrolate	Sugammadex
Arm/Group Description	Neostigmine 0. 07 mg/kg with glycopyrrolate 0.01 mg/kg with ceiling dose of 5 mg neostigmine with 1 mg of glycopyrrolate at the end surgery Neostigmine: Neostigmine injection Glycopyrrolate: Glycopyrrolate injection	Sugammadex 4 mg/kg at the end surgery Sugammadex: Sugammadex injection
Period Title: Overall Study
STARTED	34	35
COMPLETED	33	35
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Neostigmine With Glycopyrrolate	Sugammadex	Total
Arm/Group Description	Neostigmine 0. 07 mg/kg with glycopyrrolate 0.01 mg/kg with ceiling dose of 5 mg neostigmine with 1 mg of glycopyrrolate at the end surgery Neostigmine: Neostigmine injection Glycopyrrolate: Glycopyrrolate injection	Sugammadex 4 mg/kg at the end surgery Sugammadex: Sugammadex injection	Total of all reporting groups
Overall Participants	33	35	68
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59 (12)	54 (15)	56 (14)
Sex: Female, Male (Count of Participants)
Female	19 57.6%	27 77.1%	46 67.6%
Male	14 42.4%	8 22.9%	22 32.4%
Race/Ethnicity, Customized (Count of Participants)
Afirican American	3 9.1%	3 8.6%	6 8.8%
Asian	1 3%	0 0%	1 1.5%
Caucasian	29 87.9%	32 91.4%	61 89.7%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	90 (32)	92 (38)	91 (35)
ASA (Count of Participants)
II	3 9.1%	3 8.6%	6 8.8%
III	32 97%	32 91.4%	64 94.1%
Arterial hypertension (Count of Participants)
Count of Participants [Participants]	20 60.6%	23 65.7%	43 63.2%
Asthma (Count of Participants)
Count of Participants [Participants]	3 9.1%	3 8.6%	6 8.8%
Chronic pulmonary disease (Count of Participants)
Count of Participants [Participants]	5 15.2%	3 8.6%	8 11.8%
Obstructive sleep apnea (Count of Participants)
Count of Participants [Participants]	6 18.2%	4 11.4%	10 14.7%
Diabetes mellitus (Count of Participants)
Count of Participants [Participants]	4 12.1%	6 17.1%	10 14.7%
Myocardial infarction (Count of Participants)
Count of Participants [Participants]	1 3%	1 2.9%	2 2.9%
Ischemic heart disease (Count of Participants)
Count of Participants [Participants]	0 0%	2 5.7%	2 2.9%
Neurologic diseases (Count of Participants)
Count of Participants [Participants]	9 27.3%	7 20%	16 23.5%
Chronic pain requiring opioids (Count of Participants)
Count of Participants [Participants]	0 0%	1 2.9%	1 1.5%
Current smoker (Count of Participants)
Count of Participants [Participants]	5 15.2%	8 22.9%	13 19.1%
Current recreational drug user (Count of Participants)
Count of Participants [Participants]	0 0%	0 0%	0 0%
Alcohol abuse (Count of Participants)
Count of Participants [Participants]	0 0%	1 2.9%	1 1.5%
Cancer (Count of Participants)
Count of Participants [Participants]	0 0%	2 5.7%	2 2.9%
No medical history (Count of Participants)
Count of Participants [Participants]	3 9.1%	3 8.6%	6 8.8%
Intraoperative remifentanil (Count of Participants)
Count of Participants [Participants]	14 42.4%	8 22.9%	22 32.4%
Intraoperative remifentanil, μg (μg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [μg]	0	0	0
Intraoperative fentanyl (Count of Participants)
Count of Participants [Participants]	33 100%	35 100%	68 100%
Intraoperative fentanyl, mg (mg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg]	0.10	0.10	0.10
Intraoperative propofol, mg (mg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg]	200	200	200
Intraoperative midazolam, mg (mg) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg]	0	0	0
Intraoperative Phenylephrine (Count of Participants)
Count of Participants [Participants]	25 75.8%	25 71.4%	50 73.5%
Intraoperative Ephedrine (Count of Participants)
Count of Participants [Participants]	7 21.2%	9 25.7%	16 23.5%
Intraoperative Norepinephrine (Count of Participants)
Count of Participants [Participants]	0 0%	0 0%	0 0%
Time-weighted average minimum alveolar concentration (percent at 1 atmosphere) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percent at 1 atmosphere]	0.79	0.78	0.78

Outcome Measures

1. Primary Outcome

Title	Time in Minutes to Reach Train of Four (TOF) Ratio ≥ 0.9 After the Administration of Reversal Agent
Description	The primary outcome was a time-to-TOF ratio ≥ 0.9 after the administration of the reversal agent. The TOF ratio was measured in a continuous manner every 12 seconds from the administration of the reversal drug until TOF ratio ≥ 0.9 or until 90 minutes after administration of the reversal agent.
Time Frame	within 90 minutes after endotracheal extubation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Neostigmine With Glycopyrrolate	Sugammadex
Arm/Group Description	Neostigmine 0. 07 mg/kg with glycopyrrolate 0.01 mg/kg with ceiling dose of 5 mg neostigmine with 1 mg of glycopyrrolate at the end surgery Neostigmine: Neostigmine injection Glycopyrrolate: Glycopyrrolate injection	Sugammadex 4 mg/kg at the end surgery Sugammadex: Sugammadex injection
Measure Participants	33	35
Median (95% Confidence Interval) [minutes]	8	3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Neostigmine With Glycopyrrolate, Sugammadex
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Cox proportional hazard model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	3.8
	Confidence Interval	(2-Sided) 95%; 2.2 to 6.5
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	TOF Ratio at 90 Min
Description	TOF (train of four), also known as a peripheral nerve stimulator, is used to assess nerve function in patients receiving neuromuscular blocking agents (paralytic medications). Before giving the medications, the baseline must be measured because this tells how much electrical stimulation the patient needs for nerve stimulation without any paralytic on board. Our primary outcome TOF ratio between TOF at 90 minutes after the administration of the reversal agent versus the TOF at baseline tells us how well the treatment is working to reverse the rocuronium Neuromuscular. This is a sensitivity analysis of primary analysis.
Time Frame	at 90 minutes after the administration of the reversal agent

Outcome Measure Data

Analysis Population Description

Eight patients were removed due to missing TOF at 90 min or TOF count not larger than 4.

Arm/Group Title	Neostigmine With Glycopyrrolate	Sugammadex
Arm/Group Description	Neostigmine 0. 07 mg/kg with glycopyrrolate 0.01 mg/kg with ceiling dose of 5 mg neostigmine with 1 mg of glycopyrrolate at the end surgery Neostigmine: Neostigmine injection Glycopyrrolate: Glycopyrrolate injection	Sugammadex 4 mg/kg at the end surgery Sugammadex: Sugammadex injection
Measure Participants	28	32
Median (Inter-Quartile Range) [ratio]	1.07	1.16

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Neostigmine With Glycopyrrolate, Sugammadex
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.13
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Final Values)
	Estimated Value	6.3
	Confidence Interval	(2-Sided) 95%; -2.0 to 14
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	The Time for Extubation After Administration of Reversal Agents
Description	Time from administration of reversal agent to tracheal extubation
Time Frame	Up to 4 hours after administration of reversal agents

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Neostigmine With Glycopyrrolate	Sugammadex
Arm/Group Description	Neostigmine 0. 07 mg/kg with glycopyrrolate 0.01 mg/kg with ceiling dose of 5 mg neostigmine with 1 mg of glycopyrrolate at the end surgery Neostigmine: Neostigmine injection Glycopyrrolate: Glycopyrrolate injection	Sugammadex 4 mg/kg at the end surgery Sugammadex: Sugammadex injection
Measure Participants	33	35
Median (95% Confidence Interval) [minutes]	8	8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Neostigmine With Glycopyrrolate, Sugammadex
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.30
	Comments
	Method	Cox proportional hazard model
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.43 to 1.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Change of Diaphragmatic Contractility Speed- Sniff (Breathing From the Nose), cm/s
Description	The change of diaphragmatic contractility speed was defined as baseline minus postoperative diaphragmatic contraction.
Time Frame	from baseline to 90 minutes after the administration of the reversal agent

Outcome Measure Data

Analysis Population Description

There were 6 (17%) missing in sugammadex group and 5 (15%) missing in neostigmine group on diaphragmatic function outcomes.

Arm/Group Title	Neostigmine With Glycopyrrolate	Sugammadex
Arm/Group Description	Neostigmine 0. 07 mg/kg with glycopyrrolate 0.01 mg/kg with ceiling dose of 5 mg neostigmine with 1 mg of glycopyrrolate at the end surgery Neostigmine: Neostigmine injection Glycopyrrolate: Glycopyrrolate injection	Sugammadex 4 mg/kg at the end surgery Sugammadex: Sugammadex injection
Measure Participants	28	29
Mean (Standard Deviation) [cm/s]	-0.04 (0.85)	0.29 (1.13)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Neostigmine With Glycopyrrolate, Sugammadex
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.21
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.33
	Confidence Interval	(2-Sided) 95%; -0.35 to 1.00
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change of Diaphragmatic Contractility Speed, Deep Breathing From Mouth, cm/s
Description	The change of diaphragmatic contractility speed was defined as baseline minus postoperative diaphragmatic contraction.
Time Frame	from baseline to 90 minutes after the administration of reversal agent

Outcome Measure Data

Analysis Population Description

There were 6 (17%) missing in sugammadex group and 5 (15%) missing in neostigmine group on diaphragmatic function outcomes.

Arm/Group Title	Neostigmine With Glycopyrrolate	Sugammadex
Arm/Group Description	Neostigmine 0. 07 mg/kg with glycopyrrolate 0.01 mg/kg with ceiling dose of 5 mg neostigmine with 1 mg of glycopyrrolate at the end surgery Neostigmine: Neostigmine injection Glycopyrrolate: Glycopyrrolate injection	Sugammadex 4 mg/kg at the end surgery Sugammadex: Sugammadex injection
Measure Participants	28	29
Mean (Standard Deviation) [cm/s]	-0.02 (1.43)	0.80 (1.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Neostigmine With Glycopyrrolate, Sugammadex
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.04
	Comments
	Method	t-test, 2 sided
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; -0.18 to 1.81
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Until hospital discharge or 30 days after surgery, which came first
Arm/Group Title	Neostigmine With Glycopyrrolate		Sugammadex
Arm/Group Description	Neostigmine 0. 07 mg/kg with glycopyrrolate 0.01 mg/kg with ceiling dose of 5 mg neostigmine with 1 mg of glycopyrrolate at the end surgery Neostigmine: Neostigmine injection Glycopyrrolate: Glycopyrrolate injection		Sugammadex 4 mg/kg at the end surgery Sugammadex: Sugammadex injection
All Cause Mortality
	Neostigmine With Glycopyrrolate		Sugammadex
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/35 (0%)
Serious Adverse Events
	Neostigmine With Glycopyrrolate		Sugammadex
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/35 (0%)
Other (Not Including Serious) Adverse Events
	Neostigmine With Glycopyrrolate		Sugammadex
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/33 (0%)		0/35 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.