A Prospective Randomized Clinical Trial Evaluating Surgical Conditions During Laparoscopic Bariatric Surgery With Deep Versus Moderate Neuromuscular Blockade
Phase: PHASE4
Conditions: Morbid Obesity
Sponsor: University of Missouri-Columbia

1 
 
A Prospective Randomized Clinical Trial Evaluating Surgical Conditions during 
Laparoscopic Bariatric Surgery with Deep versus Moderate Neuromuscular 
Blockade 
 
PI: Terri G. Monk, MD, MS1 
Professor 
 
Co-PI: Purav Patel, MD1 
Resident 
 
Co-I Michael Brown, MD 
Associate Professor 
 
Julie Marshall, MD 
Associate Professor 
 
Co-I: Roger de la Torre, MD2 
Associate Professor 
Director, Missouri Bariatric Services 
 
Statistician: Greg Petroski, Ph.D. 
Research Assistant Professor3 
 
1Department of Anesthesiology and Perioperative Medicine 
2Department of General Surgery, Division of Bariatric Surgery 
3Department of Health Management and Informatics, Office of Medical Research 
University of Missouri 
Columbia, Missouri 65212 
 
 
Version 1: January 5, 2016 
IRB project number: 2004620 
 
 
Contact Information: Terri G. Monk, MD, MS 
Department of Anesthesiology and Perioperative Medicine 
University of Missouri-Columbia 

2 
 
One Hospital Drive, 3w-27F; DC005.00 
Columbia, MO 65212 
Telephone: (573)-882-2568 
Fax: (573)-882-2226 
Email: monkt@health.missouri.edu 
 
 

3 
 
2.1 Objectives: 
This prospective, randomized, single-blind trial will randomize patients undergoing 
laparoscopic bariatric surgery to either deep (0 twitches, 1-2 PTC) or moderate 
(reappearance of T2) neuromuscular blockade (NMB).  Within each NMB group, 
patients the initial insufflation pressure will be either 10 or 15 mm Hg: 
 
Primary Endpoint: 
1. Surgeon initial satisfaction with operating conditions    
Secondary Endpoints: 
1. Percentage of procedures that can be performed at low (10 mm Hg) versus high 
(15 mm Hg) insufflation pressures at each level of NMB 
2. Percentage of procedures requiring additional NMB and/or insufflation pressures 
to achieve satisfactory intraoperative surgical conditions 
3. Quantification of postoperative pain medication requirements with deep versus 
moderate NMB 
 
2.1.1 Clinical Hypotheses: 
Primary Hypothesis: 
We hypothesize that deep neuromuscular block (NMB)  
1. provides better intra-operative surgical conditions than moderate NMB during 
laparoscopic bariatric surgery 
 
Exploratory Hypotheses: 
We hypothesize that deep neuromuscular block (NMB): 
1. allows the use of lower insufflation pressures during laparoscopic bariatric 
surgery 
2. decreases postoperative pain and the need for postoperative pain medication 

4 
 
2.2 Background & Rationale: 
 
Obesity affects more than 78 million adults in the United States and it is estimated that 
35% of the US population is obese (body mass index ≥ 30) with the highest incidence 
(40%) in women aged 40 to 59 years.1  Obese individuals have increased comorbidity 
including an increased risk for coronary heart disease, hypertension, dyslipidemia, type 
2 diabetes, and sleep apnea. The treatment of obesity and its related comorbidities 
costs nearly $150 billion annually and this cost is expected to increase if obesity is not 
stemmed.2 Dieting has proven to be only marginally effective in the treatment of obesity, 
but surgery results in substantial long-term weight loss.3 As a result, more than 179,000 
bariatric procedures are performed in the US each year with the majority of these 
surgeries using laparoscopic techniques.4  
 
Neuromuscular blockade (NMB) is routinely used during laparoscopic surgery to 
optimize both intubating and operating conditions for the anesthesiologist and the 
surgeon, respectively. Recent research has shown that in laparoscopic abdominal 
procedures, deep NMB is associated with superior operating conditions.5-8 However, 
maintaining deep NMB can be a challenge to anesthesiologists concerned about rapid 
emergence and the risk of postoperative residual paralysis.  It is, therefore, obvious that 
surgeons and anesthesia providers have conflicting goals for the level of muscle 
relaxation that should be maintained during many surgical procedures.    
 
The introduction of sugammadex (Bridion®, Merck Sharp & Dohme Corp., Oss, The 
Netherlands), a new neuromuscular reversal agent with the ability to rapidly reverse 
deep rocuronium-induced NMB, will finally provide the anesthesia provider the 
opportunity to maintain deep neuromuscular relaxation throughout the entire surgery 
without compromising time to emergence and increasing post-operative complications.9  
However, sugammadex will undoubtedly cost much more than neostigmine, the 
anticholinesterase inhibitor presently used to reverse NMB, and hospital pharmacies will 

5 
 
have to be convinced that the benefit of improved operating conditions is worth the 
additional cost associated with the use of sugammadex.   
 
Recently, there has also been interest in maintaining low insufflation pressure during 
laparoscopic surgery because lower pressures may decrease postoperative pain.10 It is 
hypothesized that deep NMB will provide good surgical conditions and minimize 
postoperative pain at low insufflation pressures of 7 to 10 mmHg, but this theory has not 
been adequately evaluated, especially in obese patients.   
 
At the present time, there is no conclusive evidence that surgeons need deep NMB for 
laparoscopic bariatric surgery and even that surgeons can discriminate between 
moderate and deep NMB.11 The goal of this prospective, randomized, assessor-blinded 
controlled trial is to test the hypothesis that deep NMB provides optimal surgical 
conditions during laparoscopic bariatric surgery in the morbidly obese patient.  In 
addition, we will determine if deep NMB allows the surgeon to utilize lower insufflation 
pressure and decreases postoperative pain requirements after laparoscopic bariatric 
surgery.    
 
 
2.3 Study Design: 
Study design:  prospective, randomized, assessor-blinded controlled trial that will be 
performed at a single academic hospital.  The surgeons, subjects, and individuals 
performing the postoperative assessments will be blinded to the study group 
assignment.  The anesthesia providers responsible for the clinical care of the patients 
will be aware of the rocuronium NMB treatment group and NMB and insufflation status 
throughout the surgical procedure.   
 
 
 

6 
 
 
2.4 Study Design: 
 
 
140 adult patients 
undergoing 
laparoscopic bariatric 
35 patients 
Deep NMB +  
10 mm  
35 patients 
Deep NMB +  
15 mm  
35 patients 
Moderate NMB 
+ 15 mm  
35 patients 
Moderate NMB 
+ 10 mm  

7 
 
2.5 Study Procedures: 
I. 
Patient population: this study will enroll 145 adults undergoing elective 
laparoscopic bariatric surgery.  Our aim is to randomize 140 patients and this will 
allow 5 subjects to drop out of the study after enrollment. 
 
II. 
Inclusion criteria: 
a. Age ≥ 18 years 
b. ASA I-III 
c. BMI ≥ 35 
 
III. 
Exclusion criteria: 
a. Inability to obtain written informed consent 
b. Pregnancy or breastfeeding 
c. Allergy to rocuronium, sugammadex, or any anesthetic agents used in the 
protocol 
d. Known or suspected neuromuscular disorders  
e. Significant renal disease with a serum creatinine ≥ 2 mg/dl 
f. Significant liver disease  
g. A family history of malignant hyperthermia 
 
IV. 
Randomization:  On the day of surgery, patients will be randomized to one of four 
groups: 1. moderate NMB + 10 mm insufflation pressure (IP); 2. moderate NMB 
+ 15 mm IP; 3. deep NMB + 10 mm IP; or 4. deep NMB + 15 mm IP.  
Randomization will be stratified for the four groups so that obese patients with 
BMI of 35 to 45 and those with a BMI > 45 are equally distributed between the 
groups.   
 
V. 
Blinding: The surgeon, 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 surgeon will also 

8 
 
be blinded to the initial insufflation pressure. The rocuronium infusions will be 
prepared in a room away from any of the blinded personnel.  The anesthesia 
providers administering the anesthesia will be aware of the randomization and 
the dose of rocuronium that the patient is receiving.  The TOF watch will be 
draped so that the surgeons and operating room personnel are unable to 
observe it during the procedure.  The insufflation pressures will also be covered. . 
 
VI. 
Anesthetic management 
a. Monitoring 
1. All patients will be monitored with standard monitors including ECG, 
non-invasive blood pressure, pulse oximetry, esophageal 
temperature, capnography, and a BIS® depth of anesthesia monitor. 
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.  
1. Premedication – midazolam, 1-2 mg iv in the holding area 
2. Preoxygenation with 100% oxygen for a minimum of 3 minutes 
3. Induction – propofol, 2 – 2.5 mg/kg, iv and fentanyl, 2-3 
micrograms/kg, iv.  Additional propofol or fentanyl may be 
administered at the discretion of the anesthesia provider 
4. Intubation – succinylcholine,1.5 mg/kg, iv after loss of consciousness 
to facilitate tracheal intubation 

9 
 
5. Maintenance – ventilation with air/oxygen to achieve a FiO2 = 0.6 and 
inhaled desflurane adjusted to maintain a BIS® level of 40-60,and 
fentanyl, 25-50 micrograms iv as needed 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 – after return of neuromuscular 
function (return of twitches) after intubation with succinylcholine, 
patients will be dosed in accordance with their randomization 
assignment to achieve either moderate or deep NMB during surgery.   
c. The rocuronium dosing protocol during the maintenance phase of anesthesia 
will be: 
1. Moderate NMB group [1-3 twitches in the train of four (TOF)]  – 
rocuronium, 0.2 mg/kg iv, followed by a rocuronium infusion which will 
be started at the appearance of 1 twitch and adjusted to maintain 1-3 
twitches throughout the procedure 
2. Deep NMB group [0-1 posttetanic count (PTC)] – rocuronium, 0.6 
mg/kg iv, followed by a rocuronium infusion at 10 mcg/kg/min. The 
infusion will be adjusted to maintain 0-1 PTC throughout the 
procedure.  
 
d. Reversal of NMJ blockade - The rocuronium infusions will be continued until the 
fascia is closed.  At that point, the rocuronium infusions will be discontinued.  
The level of NMJ block will be assessed with the TOF watch and the patients will 
be reversed with sugammadex (using actual body weight) after assessment of 
the TOF ratio.  Reversal will be dosed as follows: 
1. Deep block (defined as a TOF count of 0 with recovery of 1-2 post-
tetanic counts) will be reversed with sugammadex, 4 mg/kg, iv 
2. Moderate block (defined as the reappearance of T2 in the TOF) will 
be reversed with sugammadex, 2 mg/kg iv 
 

10 
 
e. Extubation: Prior to extubation, patients will be following verbal commands 
(opening eyes, head lift) and will also manifest a sustained tetanic response to 
ulnar nerve stimulation using a standard neuromuscular stimulator.  The 
information in combination with the clinical judgement of the anesthesia provider 
will be used to determine the time of extubation.  The TOF ratio will not be used 
to determine when to extubate the patient but the TOF ratio at the time of 
extubation will be recorded.   
 
VII. 
Postoperative Pain Management 
a. Acetaminophen, 1000 mg iv, will be given during the maintenance phase and 
repeated every 6 hours for the first 24 hours after surgery. 
b. Fentanyl PCA will be started in the postanesthesia recovery room and continued 
for the first 24 – 48 hours after surgery.   
 
VIII. 
Perioperative assessments 
a. Surgeon satisfaction – the primary endpoint is the surgeon’s satisfaction with 
the level of NMB during surgery at the start of the case (the initial score).  The 
satisfaction level will be rated with a five-point ordinal scale ranging from 1 
(extremely poor) to 5 (optimal conditions).  This scale is outlined in detail in 
table 1 (page 15) and is adopted from a previously published studies.6,    For 
each patient, the first surgeon satisfaction rating during the procedure (prior to 
any rescue measure) will be the primary outcome measure.   
 
b. During the laparoscopic procedure, the surgeon will score the surgical working 
conditions.  The first rating will occur when the NMB level is stable at either 
deep or moderate block (per randomization) and the intra-abdominal pressure is 
either 10 or 15 mm Hg per a second randomization list.  The surgeon will be 
blinded to the insufflation pressure at this point.  If the conditions are rated as 
extremely poor or poor (surgical rating of 1-2, Table 1), the following steps will 
be taken in an incremental manner.  The surgeon may also request rescue 

11 
 
treatment if the surgical rating scale is 3 (acceptable), but he anticipates 
deterioration in the surgical condition during the procedure : 
1. Increase the insufflation pressure to a maximum of 15 mm Hg –the 
surgeon will reassess the surgical field after the intra-abdominal 
pressure is stable at 15 mm Hg for 2-3 minutes.  At this point the 
insufflation pressure will remain at 15 mm Hg for the remainder of the 
procedure. 
2. Additional muscle relaxation – if the surgeon rates the working 
conditions as 1 (extremely poor) or 2 (poor) after increasing the 
insufflation pressure to 15 mm Hg, the surgeon may then request 
additional muscle relaxant.  At this point the anesthesia provider will 
check the level of NMB.  If the patient is in the moderate group and 
has 1 or more twitches, the anesthesia provider will administer a 
bolus dose of rocuronium, 0.3 mg/kg iv.  If the patient has only 0-1 
PTC, the anesthesia provider will administer an equal volume of iv 
saline.  The surgeon will rate the surgical working conditions at 2-3 
minutes after the additional dose of medication.   
 
c. Intra-abdominal insufflation pressures and TOF ratio measurements will be 
recorded every 15 minutes during the procedure. 
d. Surgeons will be asked to rate their satisfaction with the surgical field every 30 
minutes during the procedure. 
e. Perioperative variables will also be recorded including the duration of surgery, 
time from administration of NMJ reversal (sugammadex) to extubation, time from 
end of surgery to exit from the OR, time in the PACU, and length of hospital 
stay. 
f. Postoperative verbal pain levels (0 = no pain to 10 = worst imaginable pain) and 
opioid requirements will be assessed daily.  Patients will also be asked about 
the presence or absence of shoulder pain. 

12 
 
g. Postoperative variables 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.   
2.6 Study Duration: 
The Missouri Bariatric Service at the University of Missouri-Columbia performs over 600 
bariatric procedures per year.  The Director for this service, Dr. Roger de la Torre, is a 
co-investigator on the study.  He has 3 full day operating blocks per week and we 
estimate that we can easily enroll 15 patients per month.   
We estimate that patient enrollment can be completed in 9 months.  We will need an 
additional 3 months after enrollment is complete for data analysis and 
abstract/manuscript preparation. 
Statistical Analysis and Sample Size Justification: 
Data analysis will be based on an intent-to-treat approach.  The primary endpoint will be 
the first surgeon satisfaction rating measured on a five-point ordinal scale (Table 1). The 
experimental layout is a randomized two-factor design so the primary analysis will be 
the two-way Analysis of Variance (ANOVA) with interaction.  A statistically significant 
interaction will be followed by pairwise comparisons to identify and estimate treatment 
combination differences.  The standard ANOVA assumes a normally distributed 
outcomes with homogeneous variances and so the robustness of the results will be 
checked against an aligned-rank test for the two-way layout.12   
Secondary outcomes will be time to extubation or discharge, and total pain medication 
requirements.  The same two-way analysis as described for surgeon satisfaction will be 
used for each of these endpoints.  Residuals will be examined and need for a modest 
transformation or rank-based methods considered.  Moderate and deep NMB will also 
be compared with respect to the proportion of cases randomized to low insufflation 
pressure that were completed at low pressure.  The chi-square test of proportions will 
be used for that analysis. 

13 
 
 
Sample size – Sample size estimates are based surgeon satisfaction rating as this is 
the primary outcome.  Figure 3 of Martini et al.6 gives the frequency distribution of the 
surgeon satisfaction score under moderate and deep block.  Scores for the moderate 
block have the greatest variability and so for sample size purpose the proportions from 
Fig. 3 were used to estimate the standard deviation of the surgeon satisfaction score (σ 
= 1.1).  Based on literature and clinical judgement we powered the study to have at 
least 80% power to detect statistically significant (p < 0.05) effects for the main effects 
and interaction term in a two-way analysis of variance assuming the following 
configuration of mean satisfaction scores and a common standard deviation of 1.1. 
Pressure 
10mmHG 15mmHG 
Block 
Moderate 
2.5 
4.0 
Deep 
4.3 
4.8 
 
Power curves for each of the ANOVA effects are displayed in Figure 1.  The required 
minimum sample size is 108 subjects, allocated 27 per treatment combination.  To 
guard against potential optimism in these calculations (actual variances could be larger 
or effects smaller) we intend to recruit 35 subject per treatment combination for a total 
sample size of 140. 
 

14 
 
Power calculations were carried out using GLMPOWER procedure in SAS v 9.3.   
Specific Drug Supply Requirements: 
The anesthetic agents utilized in this study (including rocuronium) are routinely used for 
this type of surgery and are acceptable patient costs.  However, sugammadex just 
received FDA approval in December 2015 and is not currently used for NMB reversal at 
our institution. We will receive adequate supplies of sugammadex from Merck &Co. so 
that there will be no charge to the patients for this medication.   
 
 
 
 
 
 
 
 
 
 
  
.    
 
 
 
 

15 
 
2.11 References: 
1. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the 
management of overweigh and obesity in adults: a report of the American College of 
Cardiology/American Heart Association task force on practice guidelines and the obesity 
society.  Circulation 2014; 129:S102-38. 
 
2. Finkelstein EA, Trogdon JG, Cohen JW, Dietz W. Annual medical spending attributable 
to obesity: payer and service-specific estimates. Health Aff (Millwood) 2009; 28: w822-
w831. 
 
3. Livingston EH, Zylke JW. Progress in obesity research: reasons for optimism. JAMA 
2012; 308:1162-5.  
 
4. American Society of Metabolic and Bariatric Surgery website. 
http://connect.asmbs.org/may-2014-bariatric-surgery-growth.html, accessed 4/3/2015. 
 
5. Blobner, M. Frick CG, Stäuble RB et al. Neuromuscular blockade improves surgical 
conditions (NISCO). Surg Endosc 2015; 29: 627-36. 
 
6. Martini CH, Boon M, Bevers RF, Aarts LP, Dahan A. Evaluation of surgical conditions 
during laparoscopic surgery in patients with moderate vs. deep neuromuscular block. Br 
J Anaesth 2013; 112:498-505. 
 
7. Dubois PE, Putz L, Jamart J, Marotta ML, Gourdin M, Donnez O. Deep neuromuscular 
block improves surgical conditions during laparoscopic hysterectomy. Eur J 
Anaesthesiol. 2014; 31:430-6. 
 
8. Madsen MV, Carron M, Veronese S, Foletto M, Ori C.. Neuromuscular blockade for 
optimising surgical conditions during abdominal and gynaecological surgery: a 
systematic review. Acta Anesthesiol Scand 2015; 59:1-16. 
 
9. Carron M, Veronese S, Foletto M, Ori C. Sugammadex allows fast-track bariatric 
surgery. Obes Surg. 2013; 23:1158-63.  
 
10. Gurasamy KS, Vaughan J, Davidson BR. Low pressure versus standard pressure 
pneumoperitoneum in laparoscopic cholecystectomy. Cochrane Database Syst Rev 
2014; 3:CD006930. 
 
11. Kopman AF, Naguib M. Laparoscopic surgery and muscle relaxants: Is deep block 
helpful? Anesth Analg 2015; 120:51-8. 
 
12. H. Mansouri R, Paige L, Surles JG.. Aligned rank transform techniques for analysis of 
variance and multiple comparisons. Communications in Statistics - Theory and Methods 
2004; 33:2217-32. 
 
 
 

16 
 
Table 1: The surgical rating scale£ 
 
1.  Extremely poor conditions; the surgeon is unable to work because of coughing or 
because of the inability to obtain a visible laparoscopic field because of inadequate 
muscle relaxation.  Insufflation pressure must be increased and/or additional 
neuromuscular blocking agents must be given. 
 
2. Poor conditions: there is a visible laparoscopic field, but the surgeon is severely 
hampered by inadequate muscle relaxation (continuous muscle contractions, 
movements or both with the hazard of tissue damage) or inadequate insufflation 
pressure (inadequate space in the operative field) or both.  Insufflation pressure must 
be increased and/or additional neuromuscular blocking agents must be given. 
 
3. Acceptable conditions: there is an acceptable visible laparoscopic field but muscle 
contractions, movements or both occur regularly causing some interference with the 
surgeon’s work.  The surgeon may request an increase in the insufflation pressure 
and/or additional neuromuscular blocking agents to prevent deterioration. 
 
4. Good conditions: there is a wide laparoscopic working field with sporadic muscle 
contractions, movements, or both.  There is no immediate need for additional 
neuromuscular blocking agents or an increase in the insufflation pressure unless there 
is the fear of deterioration.   
5. Optimal conditions: there is a wide visible laparoscopic working field without any 
movements or contractions.  There is no need for additional neuromuscular blocking 
agents or increased insufflation pressure. 
 
£Adapted from reference 6. 
 

17 
 
2.12 Publication Plan 
 
We plan to present this data at both anesthesia and bariatric surgery meetings.  We 
will target the American Society for Metabolic and Bariatric Surgery and the American 
Society of Anesthesiologists Annual meetings for abstract presentations and the 
journal Anesthesiology for publication of the final data.