A Randomized, Blinded-assessor, Single Center Study to Determine if Administration of Sugammadex, When Used to Reverse Deep Neuromuscular Blockade (NMB) After Open Abdominal Surgery, Impacts Hospital Efficiency
Phase: PHASE4
Conditions: Neuromuscular Blockade
Sponsor: University of South Florida

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
Efficiency 
 
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A randomized, blinded-assessor, single center study to determine if administration of 
Sugammadex, when used to reverse deep neuromuscular blockade (NMB) after open 
or closed abdominal surgery, impacts hospital efficiency 
 
Study Site: 
Tampa General Hospital, Tampa, FL  
 
 
Principal Investigator: 
Name  
 
 
Enrico Camporesi, MD  
 
 
 
 
 
 
TeamHealth Anesthesia 
Address 
 
 
1 Tampa General Circle Suite A-327 
Address 
 
 
Tampa, FL 33606 
Telephone  
 
813-600-9094 
Fax 
 
 
        813-844-4467 
e-mail address        enrico_camporesi@teamhealth.com 
 
Co-Investigators 
Name:  
 
 
Devanand Mangar, MD 
 
e-mail:  
 
 
devanand_mangar@teamhealth.com 
 
 
Initial version: [01/23/15] 
Amended: 
[6/5/2015]  
Amended: 
[6/30/2015] 
Amended: 
[7/17/2015] 
Amended  
[10/5/2015] 
Amended  
[10/9/2015] 
Amended 
[12/18/15] 
Amended 
[02/22/16] 
Amended  
[6/01/16] 
Amended  
[08/02/16] 
Amended  
[9/12/16]

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
Efficiency 
 
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Study Summary 
Title 
A, randomized, blinded-assessor, single center study to determine if 
administration of Sugammadex, when used to reverse deep 
neuromuscular blockade (NMB) after open or closed abdominal 
surgery, impacts hospital efficiency 
Short Title 
Deep NMB Reversal and Hospital Turnover Efficiency 
Protocol Number 
TGH015 
Phase 
Phase 4 
Methodology 
Randomized, blind-assessor, parallel, active control trial  
Study Duration 
12 months 
Study Center(s) 
Single-center (Tampa General Hospital, Tampa, FL) 
Objectives 
Primary Objective:  
To measure operating room (OR) turnover when using Sugammadex 
instead of combination of Neostigmine and Glycopyrrolate. 
 
Secondary Objectives:  
To evaluate the impact of reversal with 4.0 mg.kg-1 of Sugammadex 
after sustained deep neuromuscular blockade induced by rocuronium 
on patients reversal timing in comparison with standard reversal with 
Neostigmine 0.06 mg/kg and Glycopyrrolate 0.004mg/kg iv 
 
 To determine the incidence of side effects, including postoperative 
nausea and vomiting, post-operative pain, and post-operative 
complications  
Number of Subjects 
50 Patients (25/group) 
Diagnosis and Main 
Inclusion Criteria 
Open or Closed Ventral Hernia Repair or Open or Closed Colectomy 
Study Product, Dose, 
Route, Regimen 
Sugammadex 4.0 mg/kg iv, single bolus 
Neostigmine 0.06 mg/kg and Glycopyrolate 0.004mg/kg iv  
Duration of 
administration 
The bolus dose of Sugammadex will be administered within 1 minute 
into a fast running venous infusion. Sugammadex is dosed on the actual 
body weight of the subjects. 
Neostigmine plus Glycopyrrolate will also be injected over 1 minute. 
Reference therapy 
 
Statistical 
Methodology 
Analysis of Variance (ANOVA)  
Mixed Models 
Pearson Chi-squared/Fisher Exact Test 
 
 
 
 

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
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A. Background/Rationale for Study 
 
In some patients, optimal clinical management requires continuing 
neuromuscular paralysis until conclusion of the surgical procedure. Reversal of residual 
neuromuscular paralysis at the end of a surgical procedure is an important step in 
reconstituting spontaneous muscle tone and re-establishing effective spontaneous 
ventilation and patient motility, cough effectiveness and natural muscular defenses. 
Slow reversal of muscle paralysis delays post-operative turnover time in the operating 
room (OR).   
The cholinesterase inhibitor neostigmine remains the most commonly used 
neuromuscular blocking agent antagonist, but neostigmine causes bradycardia, 
alteration of gastrointestinal motility and increased gastric secretions. Furthermore, 
neostigmine has a slow onset, and slow peak-effect, up to 10 to 15 min, and is thought 
to increase the risk of postoperative nausea and vomiting (PONV) [1,2], possibly by 
provoking gastric spasms. The frequent addition of atropine or glycopyrrolate to the 
neostigmine attenuates the onset of bradycardia, though the combination of 
neostigmine and atropine may be emetogenic [3]. Neostigmine alone in doses larger 
than 2.5 mg increases the incidence of PONV [4]. 
A newer reversal agent called Sugammadex is available in the United States and 
has previously been available in Europe and other countries. Sugammadex is a new 
selective relaxant-binding agent thathas a different mechanism of action from 
anticholinesterase neuromuscular antagonists, based on physico-chemical 
characteristics. Specifically, Sugammadex encapsulates in a rapid and selective way 
steroidal neuromuscular blocking agents, leading to ultra-rapid clearance of free 
neuromuscular agent from the tissues into plasma and rapid renal elimination, devoid of 
parasympathetic side-effects: nevertheless Sugammadex has been reported to cause 
other minor various side effects in less than 10% of patients, including mild headache, 
nausea, injection site irritation, dry mouth, fatigue, a cold sensation at the injection site, 
and oral discomfort [5-8]. Furthermore, the most common adverse effect of 
Sugammadex is also nausea [10]. A systematic review evaluating the use of 

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
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Sugammadex instead of Neostigmine for reversal found Sugammadex to reduce all signs 
of residual postoperative paralysis. Furthermore, there were no differences observed in 
critical respiratory events, though this result was not statistically significant. 
Sugammadex was also noted to reduce drug-related side effects but no difference was 
noted in the rate of postoperative nausea or the rate of postoperative vomiting [10]. In 
summary, selective relaxant binding agent antagonism with Sugammadex speeds 
recovery of neuromuscular strength. Improvement to PONV compared with 
neostigmine and atropine might be small. There was also no benefit in terms of time to 
oral intake, recovery of gastrointestinal function, or ambulation [11]. Non-depolarizing 
neuromuscular blocking agents (ND-NMBAs) are used during general anesthesia to 
facilitate tracheal intubation and to optimize surgical conditions. However, due to the 
variability of their duration of action, residual effects of ND-NMBA can last longer than 
clinically necessary. 
Patients with large abdominal open wounds, such as patients requiring repair of 
large abdominal hernias or open colectomies, need profound neuromuscular relaxation 
during the crucial closure time, until the end of fascia closure, while the surgeon 
approximates the abdominal muscles or completes the fixation of fascial mesh insertion; 
conversely, the speed of recovery from neuromuscular blockade after the end of 
surgery is important to minimize delays to reach a steady spontaneous ventilation, 
extubation and a speedy recovery after the end of surgery. This group of patients is 
rapidly increase in number, both for the prevalence of obesity and of elderly patients, 
but also for the iatrogenic causes of multiple surgery with laparoscopy techniques 
operated in recent years, with exiting complications resulting in large abdominal 
hernias. 
There is a growing body of evidence  that postoperative residual neuromuscular 
blockade, defined as a train-of-four ratio (T4/T1) less than 0.9, places patients at higher 
perioperative risk for respiratory complications [12–14] and may increase hospital costs. 

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
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In order to reduce or avoid postoperative residual paralysis, anesthesiologists typically 
monitor intraoperative neuromuscular transmission blockade and reverse residual 
neuromuscular blockade with acetylcholinesterase inhibitors.  
A recent publication (12) reported that the intraoperative use of ND-NMBA is 
associated with postoperative respiratory failure primarily due to pulmonary edema, 
pneumonia, and atelectasis. In addition, they observed that neostigmine reversal did 
not decrease the incidence of postoperative respiratory failure but was associated with 
a higher incidence of postoperative oxygen desaturation. However, in these patients 
who received neostigmine, qualitative neuromuscular transmission monitoring 
appeared to have a protective effect against hypoxia as the incidence of oxygen 
desaturation below 90% occurred less frequently when compared with those who 
received neostigmine without qualitative neuromuscular transmission monitoring. In 
this last study (12)  it was important to define efficiency of turn-over and recovery in 
PACU or in the OR.  PACU times were determined and documented by PACU nurses not 
involved with the study. PACU length of stay until discharge readiness was defined as 
time from PACU admission to the time the patient no longer required postoperative 
monitoring in the PACU. Actual PACU length of stay was defined as time from PACU 
admission until actual departure from the PACU. The occurrences of postoperative 
respiratory complications (i.e., atelectasis, pneumonia, and pulmonary edema) and 
mortality were retrieved from hospital billing data within 30 days after the index 
surgery. Reintubation was defined as the replacement of an endotracheal tube within 7 
days of the index procedure following initial extubation in the operating room. Any 
patient who required replacement of an endotracheal tube for a second surgical 
procedure was excluded. The secondary outcomes were postoperative hospital length 
of stay, incidence of postoperative atelectasis, and unplanned postoperative intensive 
care utilization including surgical intensive care unit, reintubation, and length of PACU 
admission until discharge and discharge readiness. Exploratory outcomes were related 
to signs and symptoms of postoperative respiratory failure including pneumonia, 
pulmonary edema, reintubation, and mortality. In this study, Neostigmine reversal did 

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
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not affect oxygenation but was associated with increased atelectasis. Exploratory 
analysis revealed that high-dose neostigmine was associated with longer postoperative 
length of stay. Unwarranted use of neostigmine, and neostigmine administration 
without appropriate guidance from neuromuscular transmission monitoring, was 
associated with increased respiratory morbidity. Neostigmine is effective in reversing 
shallow and moderate nondepolarizing neuromuscular blockade [13] by inhibiting 
acetylcholinesterase [14] and increasing the amount of acetylcholine in the 
neuromuscular junction. [15] Neostigmine does not reverse deep neuromuscular 
blockade [16] and neostigmine should not be given to patients who present with deep 
neuromuscular blockade because it can result in incomplete reversal of neuromuscular 
blockade.  
We are advancing the hypothesis in this proposal,  that the administration of 
high-dose neostigmine could be associated with additional side effects in these patients 
who are reversed from deep levels of paralysis to awake, leading to greater utilization of 
hospital resources, and we believe that this association is due to the increased incidence 
of signs and symptoms of postoperative respiratory failure. We speculate that some of 
our anesthesia providers attempt to reverse deep neuromuscular blockade with a “full-
reversal” dose of neostigmine (heuristically 5 mg at our institution for a patient of 
average weight) and then transfer extubated and weak patients to the PACU. High-dose 
neostigmine was a strong predictor of atelectasis and was associated with longer 
postoperative hospital length of stay. Unwarranted use of neostigmine, and 
neostigmine administration without appropriate guidance from neuromuscular 
monitoring, was associated with increased respiratory morbidity. Our plan to administer 
Sugammadex to half of our study population to reverse neuromuscular blockade in 
these high-risk patients will allow us to determine if Sugammadex leads to better OR 
turnover, duration in PACU, and hospital utilization by inducing faster recovery and 
fewer side effects. 
 

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
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Study Paradigm: we are planning to study the neuromuscular reversal process in 
patients who need open or closed abdominal wound closure of medium to large size: 
the surgical process benefits from and requires deep neuromuscular paralysis during 
abdominal muscle apposition and fascia closure, to result in a solid abdominal wall: we 
selected abdominal hernias and possibly open or closed abdomen colectomy, both 
groups of patients experiencing rather large wound closures. After completion of the 
muscular closure the superficial skin layers are completed quickly and anesthesia 
reversal, patient awakening and extubation will benefit from rapid reversal, restoration 
of spontaneous ventilation and reappearance of upper airway reflexes and strong cough 
responses. This will facilitate rapid transfer to PACU, turn-over in the OR and increase 
efficiency in this costly hospital area. The comparison will be between Sugammadex 
reversal vs. traditional Neostigmine/Glycopyrrolate reversal. 
 
B. Objectives 
Primary Objective: 
 
To measure operating room (OR) turnover when using Sugammadex instead of 
combination of Neostigmine and Glycopyrrolate. 
 
Primary Objective Endpoint:  
Time from injection of neuromuscular block reversal medication to start of next case 
(OR Turnover) 
 
 Primary Data Points: 
1. Time of operating room (OR) admission (physical placement of subject in 
the OR); 
2. Time of initial rocuronium dose and time of maintenance dose, if any; 
3. Time of sugammadex or neostigmine/glycopyrrolate administration; 
4. Time from sugammadex or neostigmine plus glycopyrolate 
administration to TOF of 0.9  
5. Time of extubation; 
6. Time of patient first eye opening, measured after question from provider 
7. Time of headlift, also measured from questions from provider 
8. Time of the end of surgery (end of skin suturing); 
9. Time of OR-discharge ready; 
10. Time of actual OR discharge; 
11. Time of post anesthesia care unit (PACU) admit; 

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
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12. Time of PACU discharge ready 
13. Length of hospital stay 
 
   Secondary Objectives           
 
To evaluate the impact of reversal with 4.0 mg.kg-1 of Sugammadex after sustained 
deep neuromuscular blockade induced by rocuronium on patients reversal timing in 
comparison with standard reversal with Neostigmine 0.06 mg/kg and Glycopyrrolate 
0.004mg/kg iv 
 
To determine the Incidence of side effects, including postoperative nausea and 
vomiting, post-operative pain, and post-operative complications  
 
Secondary Endpoint: Time from PACU discharge to Discharge from hospital 
 
Secondary Data Points: 
1. 
Post-operative pain measured on the Visual Analog Scale (VAS) 0 – 10 
centimeter line.  
2. 
Total amount of required supplemental analgesia during the 
postoperative period for both treatment groups 
3. 
Post-operative complications 
 
Exploratory Objectives  
 To determine the Incidence of postoperative nausea and vomiting in both 
groups, to verify the superiority of Sugammadex reversal by adding  Apfel’s 
postoperative nausea and vomiting (PONV) risk factors assessment 
 
 
 
C. Methods 
 
Study Design 
This is a parallel, blinded-safety assessor, randomized, active control study.  
 
 
Inclusion/Exclusion Criteria 
Inclusion Criteria 
 
Patients scheduled for open or closed ventral hernia repair or open or 
closed colectomy 
 
ASA class I-III 
 
18 years and older 
 
Subjects with a Body Mass Index (BMI) of < 45 kg/m2 and weight less than 
150 kg 
 
Subjects who have given written informed consent 
 

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
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Consent Process 
 
 
All patients that are scheduled to have an open or closed colectomy or ventral 
hernia repair will be evaluated for study eligibility in the preoperative assessment center 
at Tampa General Hospital during their visit with the anesthesiologist. The pre-operative 
assessment takes place 3-7 days prior to the scheduled surgery. Standard pre-operative 
orders include CBC, CMP, and PT/PTT.   Patients who qualify for the study and give 
informed consent will be entered into the study during their pre-operative visit or the 
patient may take the consent form home to review and sign on the day of surgery. All 
study discussions will take place in a private exam room in the preoperative clinic. All 
subjects will be given the opportunity to ask questions. If the investigator feels that the 
subject understands the research parameters and the subject is willing to sign the 
consent form, the patient will be enrolled in the study.  On the day of the surgical 
procedure, the study subject will present to the surgical prep unit.  It is here that the 
Exclusion criteria 
 
Subjects with medical conditions and/or undergoing surgical procedures 
that are not compatible with the use of the TOF-Watch® SX (e.g., injuries to 
the thumbs/distal forearms, bilateral ulnar nerve damage or subjects with 
cardiac pacemaker 
 
Subjects known or suspected to have neuromuscular disorders impairing 
neuromuscular blockade (e.g., subjects with myasthenia gravis) 
 
Subjects known or suspected to have significant renal dysfunction (e.g. 
creatinine clearance < 30 mL.min-1 
 
Subjects known or suspected to have significant hepatic dysfunction 
 
Subjects known or suspected to have a (family)history of malignant 
hyperthermia; 
 
Subjects known or suspected to have an allergy to opiates/opioids, muscle 
relaxants or other medications used during general anesthesia; 
 
Subjects known or suspected to be hypersensitive to Sugammadex or other 
cyclodextrins or Rocuronium or any of its excipients 
 
Subjects who have a contraindication to, Rocuronium or Sugammadex 
 
Female subjects who are pregnant 
 
Morbidly obese subjects with a BMI > 45 kg/m2 or weight more than 150 
kg 

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
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subject will be re-evaluated for willingness to participate.  Any additional questions will 
be answered prior to surgery.   
 
 
Screening & Baseline Visit: 
After the patient signs the consent form, patient demographics and medical 
history will be collected from the medical record.  A clinical examination, including vital 
signs (blood pressure, heart rate, and respiratory rate); physical measurements (body 
weight and body height) and a physical examination will be completed.  Patients will be 
assessed for postoperative nausea and vomiting (PONV) risk factors using the Apfel’s 
assessment.  All laboratory results will be reviewed to ensure that the patient meets the 
study criteria.  
 
After confirming that the patient meets the study criteria, the pharmacy will be 
notified by a member of the research team to start the randomization and drug 
preparation process.   
 
Stratification: 
The randomization procedure will minimize the imbalance between treatment arms 
within each of the following stratification factors: Age; <60 years and ≥60 years 
 
 
Randomization/ Blinding/ Unblinding 
 
A 1:1 computer-generated randomization schedule will be provided by the biostatistician 
and delivered to the research pharmacist. The research pharmacist will assign the patient 
to the next available treatment on the randomization list and prepare the study drug.  
Patients will be randomized to receive Sugammadex or neostigmine plus glycopyrrolate 
using a two-block design in which patients will be assigned to one of two groups. One 
group of 25 patients will receive Sugammadex and the second group of 25 patients will 
receive a combination of Neostigmine and Glycopyrrolate. Study personnel will provide 
the pharmacy with a copy of the signed informed consent and signed physician orders as 

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
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well the patient’s actual body weight (ABW). In return, the pharmacist will prepare the 
study drug and provide the study staff with a red travel box that contains the study drug.  
The travel box is designed to maintain the blind.   The study medications will be 
delivered to the operating room by the study staff and will be administered to the 
patient by the anesthesiologist or CRNA assigned to the case.   
The operating room team, including the surgeon, nurses, anesthesiologist, nurse 
anesthetists and research coordinator will be blinded to the study drug. The research 
coordinator will be the post-operative assessor.    Each study drug will be administered 
intraoperatively as standard of care. Intraoperative notes in the electronic medical 
record (Epic) will be listed as ‘neostigmine plus glycopyrrolate/Sugammadex given so 
that the blinded assessor cannot view the study drug in the patient’s record. If 
necessary for the clinical management of the patient, the clinical team treating the 
patient can request un-blinding from the pharmacist. 
Table 2 Study Groups 
 
Preoperative Management The preoperative course will follow our standard of care 
practices  
Intraoperative Management:  The intraoperative course will follow our standard of care 
practices.  Doses/concentration of medications/agents used for the anesthetic 
management of the subjects enrolled in this trial may be adjusted when necessary to 
provide optimal subject care.  Anesthesia will be induced with propofol, intravenous 
opioids, and other medication(s)/agent(s) at a concentration range/dose(s) based on the 
clinical need of the subject. 
After induction of anesthesia but before administration of the intubation dose of 
Group Drug 
S 
Sugammadex 4mg/kg 
 
NG 
Neostigmine 0.06 mg/kg and Glycopyrrolate 0.004mg/kg iv 

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Rocuronium, continuous neuromuscular transmission monitoring will be performed 
using the TOF-Watch® SX until the end of anesthesia, at least until recovery of the T4/T1 
ratio to 0.9 and full recovery of neuromuscular function has occurred as determined by 
the anesthesiologist. The TOFWatch® SX will be affixed to the forearm/hand. 
Stabilization and calibration of the TOFWatch® SX will be done in the operating room.  
Rocuronium 0.6 mg/kg will be given intravenously to facilitate tracheal 
intubation; additional boluses of rocuronium, 0.15 mg/kg will be given to maintain 1-2 
twitches in response to supramaximal electrical stimulation of the ulnar nerve as 
determined by a TOF-Watch SX (Schering-Plough Ireland, Dublin, Ireland). In addition to 
the TOF-Watch-SX, depth of anesthesia will be measured with BIS-monitoring of all 
patients and a standard approaching 50% suppression will be maintained throughout 
the main duration of surgery. Reversal agent will be administered at a post-tetanic 
count of 1 or 2 (PTC 1,2 defined as deep block). 
Anesthesia will be maintained in both groups with intravenous opioids, propofol 
and/or medication(s)/agent(s), including inhalation anesthetic agents, at a 
concentration range/dose(s) based on the clinical need of the subject. 
Tracheal extubation will be performed at the end of anesthesia after 
administration of Sugammadex or neostigmine/glycopyrrolate and a T4/T1 ratio of 0.9 
has been measured by means of the TOF-Watch® SX.  After extubation, the investigator 
will determine when the subject is OR discharge ready (subject is extubated, wound 
dressing is in place, and vital signs are stable).   The actual time the subject was 
physically transferred from the OR to the PACU will also be recorded.  
 
Postoperative Management: Upon arrival in the PACU, the (sub)investigator (blinded 
safety-assessor), using the visual analog scale, will clinically assess post-operative pain.  
Assessment of patient pain levels involve a series of VAS testing postoperatively 
(upon arrival and every 30 minutes postoperatively until discharge from the PACU) using 
a 10 cm line.  Patients that complain of pain intensity >5 cm/10 cm, will be given a 
standardized rescue intravenous dilaudid regimen, IV dilaudid at 0.4mg  up to a max 

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
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dose of 2mg prn q 2 hours or until a VAS of <5 is obtained. If a VAS score of <5 cannot be 
obtained, the PI may withdraw the patient from the study and administer another pain 
medication. Post-operative PACU narcotic consumption will be recorded and quantified.   
Post-operative nausea and vomiting (PONV) will be assessed using a PONV rating 
scale every 30 minutes until PACU discharge.  PONV will be rated as 0, no nausea; 1, 
mild nausea ≤ 15 minutes; 2, nausea ≥ 5 minutes and 3, vomiting.  PONV will be treated 
with ondanestron 4 mg intravenously and, if persistent, with metoclopramide 10 mg 
intravenously.    
All patients will be monitored with continuous pulse-oximetry. All post-operative 
complications will be captured.   
 
Follow-up Period: All patients will have a planned hospital admission from the PACU.  
Pain and PONV will be assessed every 2 hours for the first 24 hours followed by every 4 
hours until hospital discharge using the VAS scale.   All post-operative complications will 
be captured.  Post-PACU narcotic consumption will be recorded and quantified.  
 
CLINICAL MEASUREMENTS 
 
1. Hospital Efficiency: Time delay between injection of reversal drug (Sugammadex 
or Neostigmine and Glycopyrrolate) and time of extubation. 
 
 
2.  Analgesia quality and management:  Analysis of patient outcome will involve a 
series of Visual analog scale pain assessed both preoperatively and 
postoperatively. The participant’s pain level will then be assessed every 
30minutes in the post-anesthesia care unit (PACU) until the time of discharge 
using the Visual Analog Pain Scale. If a delay in transfer is observed, the reason 
for the delay will be noted.  
 
3. Supplemental Analgesics: Data involving the time to first intravenous dilaudid 
rescue and total dilaudid requirements will be obtained and recorded.  This data 
will be reviewed upon study completion. 
 
4. Post-operative adverse events: Analysis of adverse events will be measured to 
include: postoperative nausea and vomiting, constipation, respiratory 
depression, and sedation.  All side effects will be assessed based upon physical 
symptoms and clinical assessment.  This data will be reviewed upon study 

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completion. 
 
Duration of study participation 
The entire length of surgical procedure and length of hospital stay for each patient. The 
total study duration will be approximately 6 months from the start, in order to enroll the 
planned patients. 
 
 
 
Statistical Plan 
 
Sample Size 
As reported in a study by Della Rocca et al. (2013) **time from reversal administration 
to TOFr to 0.9 is significantly faster in the Sugammadex group than in the neostigmine 
group (deep block: 2.7 vs. 16.2 min, respectively; P < 0.0001). [17]. Based on data from 
this study published in Acta Scandinavica, the standard deviation for the primary 
outcome measure is assumed to be 18 min and in order to be able to detect a difference 
of 16 min between the treatment arm and control arm using t-test with alpha of 0.05 
and power of 80%, 21 patients are needed per study arm. To account for the possibility 
of not meeting the assumptions of t-test and the need of using non-parametric tests, 
this sample size is further adjusted to 25 per arm or 50 total according to the Pitman 
Asymptotic Relative Efficiency (ARE) method.  
 
 
Statistical Methods 
All data will be analyzed using Stata 11.0 (StataCorp LP, College Station, TX). Patients will 
be randomized to receive Sugammadex or Neostigmine/Glycopyrrolate for muscle 
paralysis reversal at a 1:1 ratio (25 patients will be in each arm). Before the start of the 
study, a sample of 50 sealed envelopes will be prepared by the biostatistician: 25 for the 
Sugammadex group and 25 for the Neostigmine/Glycopyrrolate group. Patients who 
meet the criteria for inclusion will be assigned to the next available subject number and 

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corresponding treatment as defined in the randomization envelope, in ascending 
sequence of subject numbers. Each subject number was only assigned once during the 
study. Only unblinded research staff will have access to the randomization process. 
Analysis of Variance (ANOVA) or mixed effects model will be used to analysis multiple 
VAS scores from the same patient. Categorical variables will be analyzed using either 
Chi-square or Fisher Exact tests.  Results will be expressed as mean ± SD (medians for 
nonparametric) for continuous variables and as frequencies and percentages for 
categorical variables.  A p value of <0.05 will be considered statistically significant. For 
secondary data points, post-operative pain, total amount of required supplemental 
analgesia during the postoperative period for both treatment groups, and post-
operative outcomes will be analyzed for covariance where the assigned treatment group 
will be the main predictor in the model. All statistical analyses and tests will be 
performed using SAS (v 9.1.1, Cary, NC). A two-sided P-value of <0.05 was considered 
statistically significant.  
 
Data Analysis 
We will perform a cost analysis to determine how changes in OR turnover time affect 
hospital costs and efficiency.  
 
Ethical Obligations 
Investigator Responsibilities 
 
 
The investigator is responsible for ensuring that the study is performed according to 
the IRB approved protocol, the Good Clinical Practice (GCP) guidelines, as well as any 
additional regulatory requirements.  The requirement of pre-study informed consent 
and following of guidelines will provide assurance that the patients’ rights and safety are 
protected. 
 
  
 
Informed Consent Process 
 
Each subject must provide written consent with full knowledge of the procedures 
involved with our research.  The informed consent, approved by the IRB and in 

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accordance with regulatory guidelines, must be fully explained by the investigator or 
member of the study staff including the study aims, methods, benefits, and risks and 
signed by the subject before entry into the study.  The subjects will be informed that the 
study is voluntary and that they may withdraw at any time.  The subjects will be told 
that choosing against participation will not affect the care received for treatment.  The 
subjects will be informed that they will be authorizing access of investigational staff to 
confidential medical records.  The subject will be given sufficient time to read the 
consent and ask any questions.  Once the informed consent is signed, the subject will be 
given a copy of the document.  The subject will be given a second time to ask questions 
about the study on the day of their surgery while they are in the surgical prep unit and 
pre-operative area.   
 
 
Privacy of Records and Data 
 
All patients will be identified with a study number on clinical report forms provided 
by the pharmacy. Personal data of subjects used in the study will be limited to the 
necessary information needed. The collection of this data will be done in attempts to 
provide confidentiality and compliance with privacy protection regulations.  Consent will 
be obtained from the subject before the collection of data.  The data and subject 
identity will be kept confidential.  
 
 
 
 
Risk/Benefit: 
Risk to Participants 
There may be side effects to taking part in this study. 
Major side effects of sugammadex are: minor various side effects, including mild 
headache, nausea, the injection site irritation, dry mouth, fatigue, a cold sensation at 
the injection site, and oral discomfort 
 
Major side effects of neostigmine are: bradycardia, salivation, muscle twitching, bowel 
cramps, or diarrhea. 
 

Clinical Research Protocol #TGH015: Deep NMB Reversal and Hospital Turnover 
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Major side effect of glycopyrrolate are: dry mouth, vomiting; mild constipation; stuffy 
nose, sinus pain; or flushing (warmth, redness, or tingly feeling). 
 
 
Data safety monitoring plan 
All data will be monitored by the PI on a daily basis.  
 
Stopping Guidelines / Stopping Rules: Safety  
Termination may be recommended for any perceived safety concern based on clinical 
judgment, including but not limited to a higher than anticipated rate (≥1%) for any 
component resulting in an unexpected SAEs. 
 
Benefits to Participants 
 
The benefits of participating in this study may be faster recovery, less postoperative 
pain and less nausea and vomiting.  
 
Regulatory Documentation 
Documentation that must be available prior to the start of the study is as follows: 
 Copy of the IRB approval of the written protocol 
 Copy of approved protocol and amendments 
 Copy of the IRB approved informed consent 
 Regulatory correspondence and FDA IND documentation  
 Local regulatory documentation 
 Financial disclosure of investigators 
 Study and financial agreement  
 Curriculum vitae for each investigator 
 Verification of laboratory facility conducting experimental tests 
 
Data Monitoring and Records 
 
The primary investigator will monitor each individual CRF for completion and 
accuracy, as demonstrated by a provided signature following the review of each 
completed CRF. The investigator will maintain confidential individual records 
documented on CRFs for each subject.   
 
 
Case Report Form Completion 
 
CRFs must be completed for each subject.  All data collected must be collected and 
entered in a timely manner to reflect the most recent observations at any point.  
Subjective evaluations of each subject should be performed and entered by the same 
investigator when possible.   
 
 
 
 

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Study Personnel and Responsibilities 
Enrico Camporesi, MD 
PI 
Responsible for all study 
related issues 
Devanand Mangar, MD, FFCP  
Co-PI 
Data collection and analysis 
Than Tran, MMS 
Biostatistician  
Data Analysis and 
Interpretation 
Prachiti Dalvi, MS    
Research 
Coordinator 
Data collection, Addresses IRB 
issues, communicates with IRB 
 
Conflict of Interest 
None 
 
D. References 
 
 [1] Turner DA, Smith G. Evaluation of the combined effects of atropine and neostigmine 
on the lower oesophageal sphincter. Br J Anaesth 1985;57: 956-9. 
[2] Proakis AG, Harris GB. Comparative penetration of glycopyrrolate and atropine 
across the blood-brain and placental barriers in anesthetized dogs. 
Anesthesiology 1978;48: 339-44. 
[3] Chhibber AK, Lustik SJ, Thakur R, FranciscoDR, Fickling KB. Effects of anticholinergics 
on postoperative vomiting, recovery, and hospital stay in children undergoing 
tonsillectomy with or without adenoidectomy. Anesthesiology 1999;90:697-700. 
[4] Tramer MR, Fuchs-Buder T. Omitting antagonism of neuromuscular block: effect on 
postoperative nausea and vomiting and risk of residual paralysis: a systematic 
review. Br J Anaesth 1999;82:379-86. 
[5] Cheng CR, Sessler DI, Apfel CC. Does neostigmine administration produce a clinically 
important increase in postoperative nausea and vomiting? Anesth Analg 
2005;101(5):1349-55. 

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[6] Naguib M, Brull SJ. Update on neuromuscular pharmacology. Curr Opin Anaesthesiol 
2009;22:483-90. 
[7] Puhringer F, Rex C, Sielenkamper A, Claudius C, Larsen P, Prins M, Eikermann M, 
Khuenl-Brady K, Chhibber AK, Lustik SJ, Thakur R, Francisco DR, Fickling KB. 
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[8] Plaud B, Meretoja O, Hofmockel R, Raft J, Stoddart PA, van Kuijk JHM, Hermens Y, 
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[9] Hemmerling TM, Zaouter C, Geldner G, Nauheimer D. Sugammadex —a short review 
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[10]  Abad-Gurumeta AA, Ripolles-Melchor J, Casans-Frances R, Espinosa A, Martinex-
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[11] Koyuncu O, Turhanoglu S, Ozbakis Akkurt C, Karcıoglu M, Ozkan M, Ozer C, Sessler 
DI, Turan A. Comparison of sugammadex and conventional reversal on 
postoperative nausea and vomiting: a randomized, blinded trial.  J Clin Anesth. 
2014 Dec 24.  

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[12] Sasaki N et al Effects of neostigmine reversal of nondepolarizing neuromuscular 
blocking agents on postoperative respiratory outcomes: a prospective study.. 
Anesthesiology. (2014)  959-968 
[13] Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS: Residual 
neuromuscular blockade and critical respiratory events in the postanesthesia 
care unit. Anesth Analg 2008; 107:130–7 
[14] Herbstreit F, Peters J, Eikermann M: Impaired upper airway integrity by residual 
neuromuscular 
blockade: 
Increased 
airway 
collapsibility 
and 
blunted 
genioglossus muscle activity in response to negative pharyngeal pressure. Anes 
thesio log y 2009; 110:1253–60 
[15] Murphy GS, Szokol JW, Marymont JH, Greenberg SB, Avram MJ, Vender JS, Nisman 
M: Intraoperative acceleromyographic monitoring reduces the risk of residual 
neuromuscular blockade and adverse respiratory events in the postanesthesia 
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[16] Butterly A, Bittner EA, George E, Sandberg WS, Eikermann M, Schmidt U: 
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[17]  Della Rocca G, Pompei L, Pagan DE Paganis C, Tesoro S, Mendola C, Boninsegni 
P, Tempia A, Manstretta S, Zamidei L, Gratarola A, Murabito P, Fuggiano L, DI 
Marco P. Reversal of rocuronium induced neuromuscular block with 
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