Clinical trial NCT03322657
Conditions: Neuromuscular Blockade Anesthesia
Keywords: Sugammadex Neostigmine Reversal of neuromuscular block
Sponsor: The Cleveland Clinic
Start date: 2017-11-14; Completion date: 2021-02-01
Enrollment: 69 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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.

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.

Arms: arm 1: 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 arm 2: Sugammadex 4 mg/kg at the end surgery
Interventions: intervention 1: Neostigmine intervention 2: Glycopyrrolate intervention 3: Sugammadex
Intervention descriptions: intervention 1: Neostigmine injection intervention 2: Glycopyrrolate injection intervention 3: Sugammadex injection

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Sugammadex versus neostigmine for reversal of rocuronium 
neuromuscular block in patients having catheter-based 
neurointerventional procedures 
 
Dated: April 17, 2017 (Version 1.0) 
 
 
Names and Addresses of: 
 
Principal Investigator 
Name: 
Ehab Farag, MD 
Address: Cleveland Clinic 
Department of General Anesthesiology 
9500 Euclid Avenue  
Cleveland, OH 44195 
 
Tel: 
216-444-7550 
Email: 
farage@ccf.org 
Study Coordinator 
Name: 
TBA 
Address: Cleveland Clinic 
Department of General Anesthesiology 
Outcomes Research 
9500 Euclid Avenue  
Cleveland, OH 44195 
 
Tel: 
 
Email: 
 
 
 
 
 
 
 
 
 
 
 


 
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Study Summary 
 
Title 
Sugammadex versus neostigmine for reversal of rocuronium 
neuromuscular block in patients having catheter-based 
neurointerventional procedures 
Principal Investigator 
Ehab Farag, MD 
Primary Objectives 
 The aim of this study is test the hypothesis the use of Sugammadex 
for reversing the neuromuscular blocking effects of rocuronium 
during neurointerventional procedures speeds recovery of 
neuromuscular function to TOF ratio more than 0.9 as primary 
outcome. Secondarily, we will test the hypothesis that use of 
Sugammadex reduces the extubation time of the trachea, returns the 
diaphragmatic contractility to baseline faster than neostigmine and 
associated with less incidence of postoperative pneumonia.    
 
Primary Endpoints 
- 
Time in minutes to reach TOF ratio ≥ 0.9 after the 
administration of reversal agent.  
 
Secondary Objectives 
- 
Time in minutes from the administration of reversal agent to 
tracheal extubation. 
- 
Diaphragmatic function excursion in centimeters 
measurement and speed (slope) in both groups shortly after 
recovery from general anesthesia.  
- 
Postoperative pulmonary infections. 
- 
Economic analysis from the hospital perspective, considering 
drug costs and the time required between the end of surgery 
and extubation. 
- 
 
Study Design 
A single institution study 
Inclusion Criteria 
1- Age ≥ 18 years;  
2- ASA physical status 1-3;  
3- Scheduled for catheter-based neurointervential procedures 
including coiling and stent insertion; 
4- General anesthesia. 
 
Exclusion Criteria 
1- Suspected difficult intubation;  
2- Neuromuscular disorder; 
3- Renal impairment creatinine ≥ 2 mg /dl; 
4- Hepatic dysfunction; 
5- History of malignant hyperthermia; 
6- Allergy to neuromuscular blocking drugs, Sugammadex, 
neostigmine or glycopyrrolate;  


 
3 
7- Perioperative respiratory infections and/or pneumonia; 
8- Intubated or unresponsive;  
9- Pregnancy or breast-feeding. 
 
Expected Sample Size 
50 Patients  
Statistical 
Methodology 
We will assess the primary hypothesis that patients who receive 
sugammadex for reversing the neuromuscular blocking effects of 
rocuronium during neurointerventional procedures will have quick 
recovery of neuromuscular function to TOF ratio ≥ 0.9 as compared 
with patients who receive neostigmine. The primary outcome of time 
to reach TOF ratio ≥ 0.9 will be measured in continuous manner every 
12 seconds from the administration of the reversal drug. The effect of 
sugammadex on time to reach TOF ratio ≥ 0.9 will be assessed using 
student t-test or multivariable linear regression adjusting for 
imbalanced variable, if any. Missing outcome will be imputed based on 
observed other recovery data from the same patients such as time to 
TOF ratio ≥ 0.7. Logarithmic transformation will be used to meet the 
normality assumption if needed.  
 
As a sensitivity analysis, we will compare the two groups on TOF ratio 
by 90 minutes after administration of the reversal drug. For patients 
who fail to reach TOF ratio ≥ 0.9 by 90 minutes, the outcome will be 
censored at 90 minutes in the analysis.  The effect of sugammadex on 
time to reach TOF ratio ≥ 0.9 will be assessed using a multivariable Cox 
proportional hazards regression, adjusting for imbalanced variables, if 
any. Secondly, we will compare the randomized groups on time to 
reach TOF ratio ≥ 0.9, using Kaplan-Meier analysis with the log-rank 
test. Kaplan-Meier estimates for the two groups with equal precision 
(EP) 95% confidence bands will be calculated and plotted.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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List of Abbreviations 
 
 
 
 
Abbreviation                    
Definition 
DB 
 
 
 
Deep Breathing 
EP 
 
 
 
Equal Precision 
MAP  
 
 
Mean Arterial Blood Pressure 
NMBA  
 
Neuromuscular Blocking Agents 
PACU  
 
 
Post Anesthesia Recovery Unit 
PORB  
 
 
Postoperative residual neuromuscular 
TOF 
 
 
 
Train of four 
VS 
 
 
 
Voluntary Sniff 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Background 
 
Incomplete recovery from neuromuscular blocking agents (NMBAs) residual block 
after anesthesia and surgery continues to be a common problem in the post 
anesthesia care (PACU). The routine use of anticholinesterase reversal agents has 
not guaranteed adequate antagonism of the residual effects of intermediate –acting 
NMBAs as 20%-40% 0f patients continue to arrive in the PACU with objective 
evidence of postoperative residual neuromuscular block (PORB), defined as TOF 
ratio less than 0.9 (1,2).   
 
PORB is associated with impaired pharyngeal function, increased aspiration risk, 
upper airway muscle weakness, and partial upper airway obstruction.  These 
symptoms have been observed among patients with TOF ratios between 0.7 and 0.9 
(3). Therefore, those patients with residual neuromuscular blocking effects are 
prone to impaired breathing or diminished protective airway reflexes, which are 
essential in order to avoid respiratory complications (4). A recent retrospective 
analysis showed that intraoperative use of intermediate nondepolarizing NMBAs is 
associated with postoperative pneumonia, and that nonreversal augmented risk (2).  
 
Neostigmine remains the most common acetylcholinesterase inhibitor in the United 
States. However, use of neostigmine for reversal of NMBAs is not without 
complications. Administration of the drug significantly impairs genioglossus muscle 
activity when administered after full recovery from neuromuscular block. Moreover, 
the high doses of neostigmine more than 0.06 mg/kg increases the risk of 
respiratory complications independent of NMBAs effects (1, 5). 
 
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; this reducing the 
amount of free NMBA available to bind to nicotinic acetylcholine receptors at the 
neuromuscular junction, resulting in reversal of neuromuscular blockade (6). Unlike 
neostigmine, sugammadex completely reverses even dense neuromuscular blocks. 
 
Neurointerventional procedures have become the mainstay for the management of 
neurovascular pathologies like cerebral aneurysms, venous arterial malformation, 
management of cerebral vasospasm after subarachnoid hemorrhage, intra-arterial 
thrombolysis of cerebral thrombosis and management of cerebral vessels stenosis. 
The anesthetic management for neurointerventional procedures requires the 
patients to completely relax to avoid coughing or movement during the procedure. 
Either can cause serious complications including cerebral hemorrhage from 
perforation of cerebral vessel by the guide wire or mis-placement of stents or coils. 
Consequently, patients having catheter-based neurointerventional procedures are 


 
6 
keep deeply anesthetized and fully paralyzed. Unlike routine surgery there is usually 
no warning of when the procedure will finish. Consequently, 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. 
 
The aim of this study is test the hypothesis the use of Sugammadex for reversing the 
neuromuscular blocking effects of rocuronium during neurointerventional 
procedures speeds recovery of neuromuscular function to TOF ratio more than 0.9 
as primary outcome. Secondarily, we will test the hypothesis that use of 
Sugammadex reduces the extubation time of the trachea, returns the diaphragmatic 
contractility to baseline faster than neostigmine and associated with less incidence 
of postoperative pneumonia.    
 
 
Primary Outcomes 
 
1- Time in minutes to reach TOF ratio ≥ 0.9 after the administration of reversal 
agent.  
 
Secondary Outcomes  
 
1- Time in minutes from the administration of reversal agent to tracheal 
extubation. 
2- Diaphragmatic function excursion in centimeters measurement and speed 
(slope) in both groups shortly after recovery from general anesthesia.  
3- Postoperative pulmonary infections. 
4- Economic analysis from the hospital perspective, considering drug costs and 
the time required between the end of surgery and extubation. 
 
Methodology  
 
Inclusion criteria: 
1. Age ≥ 18 years;  
2. ASA physical status 1-3;  
3. Scheduled for catheter-based neurointervential procedures including coiling 
and stent insertion; 
4. General anesthesia. 
 
Exclusion Criteria: 
1. Suspected difficult intubation;  
2. Neuromuscular disorder; 
3. Renal impairment creatinine ≥ 2 mg /dl; 
4. Hepatic dysfunction; 
5. History of malignant hyperthermia; 


 
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6. Allergy to neuromuscular blocking drugs, Sugammadex, neostigmine or 
glycopyrrolate;  
7. Perioperative respiratory infections and/or pneumonia; 
8. Intubated or unresponsive;  
9. Pregnancy or breast-feeding. 
 
 
 
 
Anesthetic Management 
 
Patients will be randomly assigned to either Sugammadex 4 mg/kg or neostigmine 
0. 07 mg/kg with glycopyrrolate 0.01 mg/kg with ceiling dose of 5 mg neostigmine 
with 1 mg of glycopyrrolate. Randomization (1:1 without stratification) will be 
based on computer-generated codes (SAS Institute, Cary, NC, USA), which will be 
accessed via a secure web system a few minutes before the start of anesthesia start. 
Consequently, allocation will remain concealed until the last practical moment.   
 
Anesthesia will be induced using propofol and rocuronium (0.6 mg/kg) in both 
groups. The anesthesia will be maintained using sevoflurane (inspired 
concentration 2.5%) in both groups. Inspired oxygen concentrations will 50% in air. 
The mean arterial blood pressure (MAP) will be kept within 10% of preoperative 
value. Narcotics use will be according to the anesthesiologist discretion.  
 
Rocuronium will be given in infusion in the dose of 3-10 µg/kg (lean body weight = 
ideal + 20% in morbidly obese patients) to maintain one twitch of the train of four 
(TOF) in the neostigmine group (moderate block) or at a post-tetanic count of 1-2 of 
sugammadex group (deep neuromuscular block) till the end of the procedure.  
 
At the end of procedure, depending on randomized assignments, patients will be 
given: 1) neostigmine 0.0 7 mg/kg with 0.01mg of glycopyrrolate with ceiling dose 
of 5 mg of neostigmine with 1 mg of glycopyrrolate with TOF of two twitches; or, 
2) sugammadex 4 mg/kg at the post-tetanic count of two (7,8). 
In case of neostigmine group if the patient has only one twitch of TOF, we will wait 
till the patient will have two twitches before reversal by neostigmine. However, in 
sugammadex group if the patient has one twitch in the TOF at the end of the 
procedure the patient will be kept in the sugammadex group and we do a 
conventional intention-to treat analysis. 
The endotracheal tube will be removed when patients are awake and fulfilling the 
criteria for extubation according to the managing anesthesia team. 
 
Measurements  
1- The time for extubation in minutes after administration of reversal 
agents. 


 
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2-  The TOF ratio twitches ≥ 0.9 will be measured in continuous manner 
every 12 seconds from the administration of the reversal drug. The TOF 
ratio will be measured by the acceleromygraphy of the force developed in 
the adductor pollicis muscle using the TOF scan (new acceleromygraphy 
monitor). The patients will be monitored for the TOF ratio for 90 minutes 
after endotracheal extubation.  
3- The amount of vasopressors used during the procedure to maintain the 
MAP within the required range in both groups.  
4- The number of patients who will fail extubation due to unsuccessful 
reversal of   the neuromuscular agents will be considered in the following 
conditions: a- Failure to maintain good tidal volume, b- hypoxia c- 
hypercarbia, d- reintubation, e- continuation of postoperative mechanical 
ventilation due to weak motor power tested by TOF twitches.    
5- Pneumonia will defined according to NSQIP criteria for pneumonia as the 
presence of at least one definite chest radiologic examination and at least 
one sign of pneumonia (fever, leukopenia, leukocytosis, or altered mental 
status with no other cause), as well as at least one microbiologic 
laboratory finding (positive cultures from blood, bronchoalveolar lavage, 
or pleural fluid specimens) or at least two symptoms (new onset of 
purulent sputum, new onset of or worsening, cough, dyspnea or 
tachypnea, ales or rhonchi breath sounds, or worsening gas exchange).  
 
Diaphragmatic Function Measurement 
 
Diaphragmatic function will be measured using M-mode ultrasonography. 
With the patient in semi sitting position with the head elevated 
approximately 30 degrees, 4 –MHz curvilinear ultrasound probe in the b-
mode will used to scan subcostally between the midclavicular and 
anterior axillary lines, using liver as an acoustic window. The probe will 
be directed medially, cephalad, and dorsally such as the beam focuses on 
the posterior third of the right hemidiaphragm. When optimal images will 
be obtained, the ultrasound machine will be set to M-mode. In M-mode, 
the diaphragm appears as a crisp white, hyperechoic line slowly 
undulating through the respiratory cycle.  
 
Patients will be asked to perform 2 discrete breathing maneuvers: the 
first will “voluntary sniff” [VS] test, for which patients will be asked to 
forcefully inhale through the nose in sniffing fashion. In the M –mode the 
slope (speed cm/s) of diaphragmatic contraction will be calculated, as 
diaphragmatic excursion in cm and the inspiratory time in seconds will 
be measured as well.   Diaphragmatic excursion from baseline will be 
measured in centimeters using digital calipers on the ultrasound 
machine. Two measurements will be performed and the average will be 
taken. Second patients will be asked to perform a “deep breathing” (DB) 
maneuver, inhaling deeply through the mouth up to vital capacity and 
then slowly exhaling. The test will be performed twice and the average 


 
9 
will be taken (9, 10, and 11). Diaphragmatic function will be measured at 
baseline before the procedure and before discharging from the post 
anesthesia recovery unit (PACU). 
 
Data analysis 
 
Randomized groups will be compared for balance on baseline variables using 
standard summary statistics (i.e., mean ± standard deviation, median [Q1, Q3], or N 
(%) as appropriate).  Balance will be assessed using the standardized difference (i.e., 
the difference in means or proportions divided by the pooled standard deviation). 
Any covariable with a standardized difference greater than 0.2 in absolute value will 
be regarded as a potential confounder, and will be adjusted for when comparing 
sugammadex and neostigmine on all the outcomes.  All analyses will be on the 
modified intention-to-treat basis; all patients who receive any treatment will be 
included in the analysis 
 
Primary analysis.  
 
We will assess the primary hypothesis that patients who receive sugammadex for 
reversing 
the 
neuromuscular 
blocking 
effects 
of 
rocuronium 
during 
neurointerventional procedures will have quick recovery of neuromuscular function 
to TOF ratio ≥ 0.9 as compared with patients who receive neostigmine. The primary 
outcome of time to reach TOF ratio ≥ 0.9 will be measured in continuous manner 
every 12 seconds from the administration of the reversal drug. The effect of 
sugammadex on time to reach TOF ratio ≥ 0.9 will be assessed using student t-test or 
multivariable linear regression adjusting for imbalanced variable, if any. Missing 
outcome will be imputed based on observed other recovery data from the same 
patients such as time to TOF ratio ≥ 0.7. Logarithmic transformation will be used to 
meet the normality assumption if needed.  
 
As a sensitivity analysis, we will compare the two groups on TOF ratio by 90 minutes 
after administration of the reversal drug. For patients who fail to reach TOF ratio ≥ 
0.9 by 90 minutes, the outcome will be censored at 90 minutes in the analysis.  The 
effect of sugammadex on time to reach TOF ratio ≥ 0.9 will be assessed using a 
multivariable Cox proportional hazards regression, adjusting for imbalanced 
variables, if any. Secondly, we will compare the randomized groups on time to reach 
TOF ratio ≥ 0.9, using Kaplan-Meier analysis with the log-rank test. Kaplan-Meier 
estimates for the two groups with equal precision (EP) 95% confidence bands will be 
calculated and plotted.  
 
Secondary analyses.  
 
We will assess the effect of sugammadex on the following 4 secondary outcomes are 
(1) time from administration of reversal agent to tracheal extubation, (2) 
diaphragmatic function before discharging from PACU, (3) postoperative pulmonary 


 
10 
infection, and (4) drug costs and the time required from end of surgery to extubation. 
The neostigmine will be spilt among the patients according to our pharmacy rules as 
well as the glycopyrrolate. However, the sugammadex will not be split. The Holm 
Bonferroni correction will be used to control the hypothesis-wise 2-sided type I error 
for the secondary outcomes at 0.05  
 
We will compare the randomized groups on time from administration of reversal 
agent to tracheal extubation, using a multivariable Cox proportional hazards 
regression. Outcome for patients who fail extubation due to unsuccessful reversal of 
the neuromuscular agents will be censored at the maximum observed time, and 
labeled as a failure in the analysis.  
 
We will assess the difference between the sugammadex and the neostigmine groups 
on diaphragmatic function before discharging from PACU, using multivariable liner 
regression adjusting for diaphragmatic function at baseline before the procedure and 
imbalanced covariables, if any. Logarithm transformation on the outcome will be 
made, if necessary.    
 
Incidence of postoperative pulmonary infection will be compared between the 
randomized groups, using Chi-square test or Fisher exact test, or multivariable 
logistic regression, as appropriate.  
 
A cost-effectiveness analysis will be conducted to determine the optimal strategy for 
economic outcomes related to recovery of neuromuscular function. In a cost-
effectiveness analysis, costs are measured in monetary terms and benefits are 
measured in a unit of effect. For this study, the costs will be considered from the 
perspective of the hospital. The benefits will be evaluated on the cost to decrease the 
recovery time.  For this cost-effectiveness analysis, the incremental difference in costs 
and effects between interventions being evaluated will determine the optimal 
strategy of choice. 
 
 
Sample size considerations.  
 
The sample size consideration was based on the test for the primary hypothesis that 
patients who receive sugammadex for reversing the neuromuscular blocking effects 
of rocuronium during neurointerventional procedures will have quick recovery of 
neuromuscular function to TOF ratio ≥ 0.9 as compared with patients who receive 
neostigmine. 
 
We would need 46 patients to have more than 90% power at a 2-sided alpha level of 
0.05 to detect a mean difference of 5 minutes or more, assuming a standard deviation 
of 5 minutes. In addition to the 46 patients, we will enroll 4 pilot patients to test 
feasibility of recruitment, protocol adherence, randomization process, and data 
collection.  


 
11 
 
SAS software version 9.4 for Windows (SAS Institute, Cary, NC) will be used for all 
statistical analyses and graphics. 
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blocking agents, reversal, and risk of postoperative pneumonia. 
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sugammadex 
and 
neostigmine 
at 
different 
depths 
of 
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10- 
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Petrar S, Seltenrich ME, Head SJ, Schwarz SK: Hemidiaphragmatic 
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