A Prospective, Randomized, Double-Blind Clinical Trial Evaluating the Speed of Recovery and Safety of Reversal of Neuromuscular Blockade With Sugammadex (Bridion™) Versus Neostigmine in Geriatric Patients Undergoing Spine Surgery
Phase: PHASE4
Conditions: Spine Surgery
Sponsor: University of Missouri-Columbia

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Date:   __09/13/2017__________________    
Version Number: ___2_______________ 
Principal Investigator: __Boris Mraovic, MD_ 
Application Number:  Review ID 224556__ 
IRB project number:  2008066                             
 
 
Application Title:  
 
A Prospective, Randomized, Double-Blind Clinical Trial Evaluating the Speed of 
Recovery after Reversal of Neuromuscular Blockade with Sugammadex 
(Bridion™) versus Neostigmine in Geriatric Patients undergoing Spine Surgery 
 
PI: Boris Mraovic, MD1 
Associate Professor 
 
Co-PI: Terri G. Monk, MD, MS1 
Professor  
 
Co-I: Theodore J. Choma, MD2 
Professor 
 
Co-I: Christina L. Goldstein, MD2 
Assistant Professor 
 
Co-I: Ali Nourbakhsh, MD2 
Assistant Professor 
 
Co-I: Adam Zino1 
Research Specialist 
 
Statistician: Greg Petroski, Ph.D3. 
Research Assistant Professor 
 
 
 
 
 
 
 
 
 
 

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1Department of Anesthesiology and Perioperative Medicine 
2 Department of Orthopedic Surgery 
3Department of Health Management and Informatics, Office of Medical Research 
University of Missouri 
Columbia, Missouri 65212 
 
 
Contact: Boris Mraovic, MD 
Department of Anesthesiology and Perioperative Medicine 
University of Missouri-Columbia 
One Hospital Drive, 3w-40F; DC005.00 
Columbia, MO 65212 
Telephone: (573)-882-2568 
Fax: (573)-882-2226 
Email: mraovicb@health.missouri.edu 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Protocol 
 
 
2.1 Objectives: 
This prospective, randomized, double-blind trial will randomize elderly patients 
undergoing posterior back surgery in the prone position to reversal of neuromuscular 
blockade (NMB) with either neostigmine or sugammadex  
 
Primary Endpoint: 
1. Speed of neuromuscular recovery from a moderate NMB with rocuronium in 
elderly patients measured by recovery of theT4:T1 ratio ≥  0.9 (measured with a 
TOF-watch) 
 
Secondary Endpoints: 
1. Time from NMB reversal to tracheal extubation  
2. Time from NMB reversal to exit from OR 
3. Hemodynamic stability after administration of the neuromuscular reversal agent 
4. Vitals and outcomes (nausea, vomiting) in the Postanesthesia Care Unit (PACU) 
5. Readiness for PACU discharge (length of PACU stay)  
6. Time to first ambulation after the surgery 
7. Postoperative patient satisfaction scores 
8. Health economic data: OR cost and PACU cost difference between groups 
 
2.2 Clinical Hypotheses: 
Primary Hypothesis: 
We hypothesize that reversal of neuromuscular blockage (NMB) in geriatric patients will 
be faster with sugammadex than with neostigmine in geriatric patients.  As a result, OR 
efficiency will be improved as measured by time from end of surgery to departure from 
the OR suite and PACU. 

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Exploratory Hypotheses: 
We hypothesize that the use of sugammadex (versus neostigmine) for NMB reversal 
will: 
1. result in less hemodynamic instability (tachycardia, bradycardia, dysrhythmias) 
after the administration of NMB reversal 
2. improve SpO2 levels in PACU 
3. decrease length of stay in the PACU 
4. decrease postoperative pain and the need for postoperative pain medication after 
surgery 
5. decrease postoperative nausea and vomiting 
6. improve patient satisfaction levels after surgery 
7. decreased OR and PACU costs 
8. decrease time to first ambulation after the surgery 
 
3.1 Background & Rationale: 
The elderly (age ≥ 65 years) population is the fastest growing segment of the American 
population.  Spine surgery is one of the most common operative procedures in the 
United States and, as the population ages, a larger percentage of geriatric patients will 
require this procedure. In addition, spinal surgery is often more complex in the elderly 
population, resulting in longer surgical times.1   Deyo et al.1 reported that the rate of 
complex procedures increased 15-fold in Medicare recipients.  Spine surgery is 
performed in the prone position and neuromuscular blockade (NMB) is maintained until 
the patient is returned to the supine position at the end of surgery to avoid the risk of 
patient movement, injury, and inadvertent tracheal extubation while prone.  Currently, 
NMB is reversed with neostigmine immediately after turning the patients back to the 
supine position at the end of the procedure.   
 

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Rocuronium bromide, an intermediate-acting neuromuscular blocking agent (NMBA), is 
used in approximately 60% of surgical cases in the United States and is commonly used 
for muscle relaxation during spinal surgery.2  With aging, the clearance and half-life of 
rocuronium is prolonged resulting in a wide variability in the duration of action and time 
to reversal 3,4  Until recently, the only medication available for the reversal of 
neuromuscular blockade was neostigmine and postoperative residual neuromuscular 
block (PRNB) was common, especially in elderly patients.  A recent study reported that 
PRNB occurred in 58% of elderly patients who were maintained at a moderate level (2 
twitches in the TOF) of muscle relaxation with rocuronium during elective surgery.4   As 
a result, these older adults experienced an increased incidence of airway obstruction, 
hypoxemic events, muscle weakness, postoperative pulmonary complications, and 
increased PACU and hospital lengths of stay.4  
 
A new neuromuscular reversal agent sugammadex (Bridion®) has the ability to rapidly 
reverse both moderate and deep rocuronium-induced NMB.  McDonagh et al.5 reported 
that the mean time to complete reversal (TOF ratio ≥ 0.9) of a moderate block (2 
twitches in the TOF) with sugammadex in geriatric patients was 2.9 minutes, which was 
only 1 minute longer than in younger patients.  Reversal of NMB with neostigmine is 
much slower and it is reported to take approximately 19 minutes to achieve complete 
reversal in middle-aged patients.6   There is little available data on the NMB reversal 
time in older adults, but it will likely be even longer because the age-related physiologic 
changes prolong neuromuscular recovery. Thus, sugammadex has the potential to 
more rapidly reverse NMB in geriatric patients at the end of surgery.  As a result, the 
use of sugammadex should decrease time in the OR and possibly PACU time and 
result in cost savings.   
 
 Neostigmine has cardiac muscarinic effects and, therefore, has to be administered with 
an anticholinergic agent such as glycopyrrolate to counteract these effects. A previous 
study found a 16% incidence of cardiac dysrhythmias in elderly patients who received 
neostigmine/glycopyrrolate NMB reversal.7 The ability of sugammadex to completely 

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reverse NMB without the addition of an anticholinesterase agent should result in an 
improved safety profile in elderly patients. 
The goal of this prospective, randomized, double-blinded controlled trial is to test the 
hypothesis that the reversal of neuromuscular blockage with sugammadex as compared 
to neostigmine in geriatric patients will provide a shorter time to complete recovery of 
neuromuscular function, improve the workflow in the operating room and decrease 
operative costs.   
4.1 Study Design: 
Study design:  prospective, randomized, double-blinded controlled trial that will be 
performed at a single academic hospital.  The surgeons, anesthesiologists, subjects, 
and individuals performing the postoperative assessments will be blinded to the study 
group assignment.  All subjects will receive a standardized general anesthetic.  
Rocuronium will be administered to facilitate endotracheal intubation and a moderate 
(reappearance of T1-2 on TOF-watch) NMB will be maintained with a rocuronium 
infusion for the remainder of the surgical procedure.   
After the patient is turned to the supine position at the end of surgery, NMB will be 
reversed (per a randomization schedule) with either sugammadex, 2 mg/kg, or 
neostigmine, 50 micrograms/kg (not to exceed 5 mg) and glycopyrrolate, 10 
micrograms/kg (not to exceed 1 mg).  The reversal agent will be prepared in a blinded 
fashion. Dosing of reversal agents will be based on actual body weight not ideal body 
weight. Tracheal extubation will occur when the T4:T1 ratio is ≥ 0.90.   
 
 
 
 
 
 

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4.2 Study Design: 
 
 
 
 
 
 
 
4.3 Study Procedures: 
I. 
Patient population: this study will enroll 40 elderly adults undergoing elective 
posterior lumbar spinal surgery.   
 
II. 
Inclusion criteria: 
a. Age ≥ 65 years 
b. ASA I-III 
 
III. 
Exclusion criteria: 
a. Inability to obtain written informed consent 
b. Allergy to rocuronium or anesthetic agents used in the protocol 
c. Known or suspected neuromuscular disorders  
d. Significant renal disease with a serum creatinine ≥ 2 mg/dl 
e. Significant liver disease  
f. A family history of malignant hyperthermia 
 
IV. 
Randomization:  On the day of surgery, patients will be randomized to one of two 
groups:  
40 elderly patients undergoing 
spinal surgery in prone position  
Randomized on DOS 
20 patients 
Reversal with 
sugammadex 
20 patients 
Reversal with 
neostigmine 

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1.) N group: neostigmine, 50 micrograms/kg (not to exceed 5 mg) and 
glycopyrrolate, 10 micrograms/kg (not to exceed 1 mg) iv for reversal of NMB; or 
2.) S group: 2 mg/kg of sugammadex IV for reversal of NMB.   
Dosing will be based on actual body weight not ideal body weight. 
Randomization will be stratified for the two groups so that the young elderly (65 
to 75 years) and the old elderly (≥ 75 years) are equally distributed between the 
groups.   
 
V. 
Blinding: The surgeon, anesthesiologist, operating room staff, patients, personnel 
in the postanesthesia care unit (PACU) as well as the investigators collecting the 
postoperative data will be blinded to the group allocation. The rocuronium 
infusions will be prepared in a standard fashion. The anesthesia providers 
administering the anesthesia will be unaware of the treatment assignment. The 
reversal agent will be prepared in a room away from any of the blinded personnel 
and the syringe will be wrapped in foil.    
 
VI. 
Anesthetic management 
a. Monitoring 
1. All patients will be monitored with standard monitors including ECG, 
non-invasive blood pressure, pulse oximetry, esophageal 
temperature and capnography. 
2. Muscle relaxant monitoring – neuromuscular function will be 
monitored using acceleromyography with the TOF-Watch® SX 
(Organon Ireland Ltd, a subsidiary of Merck and Co., Inc., Swords, 
Co. Dublin, Ireland).  The TOF tracing will be stabilized after 
induction of anesthesia (prior to the administration of muscle relaxant 
drugs) according to the manufacturer’s recommended protocol.   
 
b. Anesthetic Technique – all patients will receive a standardized general 
anesthetic technique and all anesthetic medications (with the exception of 
sugammadex) will be dosed on the ideal body weight rather than actual weight.  

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1. Premedication – none 
2. Preoxygenation with 100% oxygen for a minimum of 3 minutes 
3. Induction – propofol, 1 mg/kg iv, lidocaine 1 mg/kg iv, and fentanyl, 2 
micrograms/kg iv.  Additional propofol or fentanyl may be 
administered at the discretion of the anesthesia provider 
4. Intubation – rocuronium 0.6 mg/kg iv after loss of consciousness to 
facilitate tracheal intubation 
5. Maintenance – ventilation with air/oxygen to achieve a FiO2 = 0.6 and 
inhaled sevoflurane adjusted to maintain a BIS level of 40-60,  
Additional fentanyl, 25-50 micrograms iv may be administered as 
determined by the anesthesia provider.  The FiO2 of oxygen can also 
be increased if determined necessary by the anesthesia provider.  
6. Maintenance of muscle relaxation – a rocuronium infusion will be 
started at the reappearance of 1 twitch and adjusted to maintain 1-2 
twitches throughout the procedure 
 
c. Reversal of neuromuscular blockade - The rocuronium infusion will be continued 
until the surgery is completed.  At that point, the rocuronium infusion will be 
discontinued.  The patient with be turned prone and the level of NMB will be 
assessed with the TOF watch. The patients will be reversed with sugammadex 
or neostigmine after assessment of the TOF ratio (using actual body weight).as 
described above.   
 
d. Extubation: Prior to extubation, patients will be following verbal commands 
(opening eyes, squeezing hands, head lift) and the T4:T1 ratio ≥ 0.90.  
 
VII. 
Postoperative Pain Management 
a. Hydromorphone 0.5 mg, IV will be given at the end of the surgery prior to turning 
patient supine. 
b. Additional doses of hydromorphone 0.2 mg, IV will be given in PACU as needed  

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c. Hydromorphone PCA will be started in PACU room and continued for the first 24 
– 48 hours after surgery.   
 
VIII. 
Perioperative assessments 
a. Perioperative time variables including the duration of surgery (incision to 
end of surgery),  the duration of anesthesia (intubation to extubation), 
time from administration of NMB reversal to T4:T1 ratio ≥ 0.9, time from 
end of surgery to extubation and exit from the OR, time in the PACU, time 
to the first ambulation and length of hospital stay 
b. Evidence of cardiac dysrhythmias after administration of NMB reversal 
agents.  Criteria for significant dysrhythmias will be defined as: 1.) heart 
rate > 100 beats per minute or < 60 beats per minute, or increase or 
decrease of ≥20% in heart rate form the baseline heart rate prior to 
administration of NMB reversal 
2.) electrocardiographic evidence of a conduction defect not observed 
prior to administration of reversal, 3.) new atrial or ventricular premature 
contraction or a three-fold or greater increase in the frequency of any 
atrial or ventricular premature contraction noted preoperatively7 
c. Postoperative opioid requirements will be assessed daily and data 
collected from the PCA devices.  Verbal pain scores (VAS) will also be 
collected daily until hospital discharge.  
d. Postoperative complications including the need for postoperative 
mechanical ventilation, re-intubation, residual paralysis, pneumonia, 
infections, and other adverse events during the hospital stay.  The need 
for ICU admission and length of hospital stay will also be collected.   
e. Patient satisfaction evaluated during an interview on POD1 using the 
perioperative questionnaire developed by Bauer et al.8 
 
4.4 Study Duration: 

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The Orthopedic Department at the University of Missouri-Columbia performs over 660 
posterior spinal surgery procedures per year. About 150 are done in elderly ≥65 years 
old. The majority of spine cases are done by Dr. Choma, Dr. Goldstein and Dr. 
Nourbakhsh. They are co-investigators on the study. We estimate that we can enroll 40 
patients in nine months.   
We will need an additional 3 months after enrollment is complete for data analysis and 
abstract/manuscript preparation. 
 
5.1 Statistical Analysis and Sample Size Justification: 
The primary endpoint is the time from sugammadex or neostigmine administration to 
recovery of the T4:T1 ratio to ≥ 0.9.  The sample size calculation was based on 
literature findings that, in geriatric patients, full recovery (T4:T1 ≥  0.90) from a moderate 
NMB (2 twitches) occurs in 2.9 ± 1.6 min after sugammadex reversal,3 Recovery  after 
neostigmine reversal is very variable with reported times from 6 minutes to 20 
minutes.6,9,10 
We are going to enroll 40 subjects (20 per group). Assuming the standard deviations of 
50%, with 20 subjects per group we will have power of 90% to detect a significant 
difference in means of as little as 6 minutes.  
In addition, we wanted to have an adequate sample size to show a difference in PACU 
time.  We anticipate that the group reversed with neostigmine will have a PACU stay 
that is at least 12 minutes longer than the group reversed with sugammadex.  For 80% 
power and alpha of 0.05, a sample size of 20 per group would detect a difference of 12 
minutes or greater. 
Secondary outcomes will be time to extubation, hemodynamics on emergence of 
anesthesia (difference heart rate and blood pressure during emergence), PACU 
readiness/discharge time, total pain medication requirements, time to ambulation and 
OR cost and PACU cost difference.  Data will be analyzed using chi-square and t-tests 
as appropriate with p<0.05 considered significant.   

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1. Deyo RA, Mirza SK, Martin BI, Kreuter W, Goodman DC, Jarvik JG. Trends, Major 
medical complications, and charges associated with surgery for lumbar spinal 
stenosis in older adults. JAMA 2010; 303:1259-65  
2. Personal communication from Lisa Wilt, R.Ph., Lead Executive Specialty Hospital 
Representative, Merck Global Human Health   
3. Arain SR, Kern S, Ficke DJ, Ebert TJ.  Variability of duration of action of 
neuromuscular blocking drugs in elderly patients. Acta Anaesthesiol Scand 2005; 
49: 312-15 
4. Murphy GS, Szokol JW, Avram MJ, Greenberg SB, Shear TD, Vender JS, Parikh 
KN, Patel BA, Patel A. Residual neuromuscular block in the elderly: Incidence and 
Clinical Implications. Anesthesiology 2015; 123: 1322-26 
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Efficacy, safety, and pharmacokinetics of sugammadex for the reversal of 
rocuronium-induced neuromuscular blockade in elderly patients.  Anesthesiology 
2011; 114:319-29 
6. Blobner M, Eriksson LI, Scholz J, Motsch J,Della Rocca G, Prins ME. Eur J 
Anaesthesiol 2010; 27: 874-81 
7. Murachick S. Owens WD, Felts JA. Glycopyrrolate and cardiac dysrhythmias in 
geriatric patients after reversal of neuromuscular blockade.  Canad Anaesth Soc J 
1979; 26:22-5   
8. Bauer M, Böhrer H, Aichele G, Bach A, Martin E. Measuring patient satisfaction with 
anaesthesia: Perioperative questionnaire versus standardized face-to-face interview. 
Acta Anaesthesiol Scand 2001; 45: 65-72 
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rocuronium block during anesthesia with sevoflurane, isoflurane or propofol. Can J 
Anesth 2001; 48: 351-54 

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Lize Xiong, Casper Claudius, Yun Yue, Yuguang Huang, Esther Abels, Henk 
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Anesthesiology 2014, 14:53