Conditions: Bowel Dysfunction Postoperative Complications Neuromuscular Blockade
Keywords: sugammadex neostigmine Gastric emptying neuromuscular blockade
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 120
Healthy volunteers: no

Brief summary:
Colon and rectal surgery is associated with high cost, long length of stay, high postoperative surgical site infection rate, high incidence of postoperative nausea and vomiting, and a high rate of hospital readmission. Return of bowel function is of utmost importance in avoiding patient discomfort, morbidity, and mortality after colorectal surgery. All patient having colorectal surgery receive neuromuscular paralysis, which is reversed at the end of surgery with either glycopyrrolate and neostigmine, or sugammadex. Glycopyrrolate and neostigmine both affect bowel function. Sugammadex has no effect on bowel function. The purpose of this study is to determine if a strategy of neuromuscular reversal with sugammadex, instead of glycopyrrolate and neostigmine, may increase gastric emptying after surgery and lead to less postoperative complications.

Detailed description:
Colon and rectal surgery is associated with high cost, long length of stay, high postoperative surgical site infection rate, high incidence of postoperative nausea and vomiting, and a high rate of hospital readmission. The 30-day mortality rate after open or laparoscopic surgery for colorectal cancer is high-between 3 and 8%. Return of bowel function is of utmost importance in avoiding patient discomfort, morbidity, and mortality after colorectal surgery. The incidence of postoperative ileus after colorectal surgery has been reported to be 10-25%. Postoperative ileus is defined as intolerance of oral intake due to a lack of coordinated bowel motility. Significant attention has been paid to the development of guidelines and programs to reduce the incidence of postoperative ileus and accelerate return of bowel function after colorectal surgery.

The American Society of Colon and Rectal Surgeons (ASCRS) and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) created an enhanced recovery after surgery (ERAS) protocol to promote the following outcomes in patients undergoing colorectal surgery: "freedom from nausea, freedom from pain at rest, early return of bowel function, improved wound healing, and early hospital discharge". An intervention that facilitates faster postoperative gastric emptying may impact many of these outcomes; in particular, nausea may be reduced, constipation-associated pain at rest may decline, return of bowel function would be accelerated, and time to hospital discharge may be shortened. While administration of medications such as Alvimopan and adjustments in anesthetic technique (providing epidural analgesia, minimizing crystalloid administration, using multimodal analgesia) are recommended, sugammadex is not currently considered in the ERAS protocol.

Neuromuscular paralysis is required for the duration of open and laparoscopic colorectal surgery to decrease patient movement, improve operating conditions, and at times facilitate ventilation. Neostigmine and glycopyrrolate are commonly used to reverse rocuronium neuromuscular blockade at the end of surgery. Both neostigmine and glycopyrrolate impact bowel function. Neostigmine promotes and glycopyrrolate slows gastrointestinal motility. Co-administration of neostigmine and glycopyrrolate can have variable effects on return of bowel function after surgery. In general, administering a higher proportion of neostigmine than glycopyrrolate is associated with faster return of bowel function. Unopposed cholinergic activity from neostigmine administration can cause morbidity including bradycardia, bronchoconstriction, hypotension, urinary incontinence, and increased salivary secretions. Thus, the ratio of neostigmine to glycopyrrolate is relatively fixed and cannot be adjusted to promote desired gastrointestinal outcomes. Sugammadex does not bind to acetylcholine receptors on bowel and is presumed not to affect bowel function.

Some investigations into the contribution of sugammadex versus acetylcholinesterase inhibitors to recovery of bowel function have been completed. In retrospective studies, sugammadex administration has been associated with faster time to first bowel movement and less ileus-related delays in hospital discharge. Conversely, two randomized, controlled clinical trials found no difference in outcomes related to gastrointestinal motility including time to first flatus, time to first bowel movement, and incidence of postoperative ileus. One randomized, controlled trial found a shorter time to first flatus, but no difference in time to first bowel movement. Lastly, one study found a trend towards faster gastric emptying with sugammadex. A limitation of the aforementioned prospective studies is they include patients having surgery on their thyroid gland, gallbladder, and other intraabdominal organs. These surgeries lack bowel handling and anastomosis, which translates to less effect on postoperative bowel function. It is hypothesized that a randomized, controlled trial involving patients having colorectal surgery will find faster gastric emptying, less nausea, and less gastrointestinal complications (including ileus) when sugammadex is administered to reverse rocuronium neuromuscular blockade, compared to neostigmine.

The purpose of this study is to determine if administering sugammadex for reversal of neuromuscular blockade instead of neostigmine and glycopyrrolate, a strategy that avoids cholinergic effects on the bowel, is associated with faster gastric emptying, faster time to achieve a TOFr \> 0.9, less post-surgical gastrointestinal complications, shorter time to first bowel movement, shorter PACU phase 1 recovery, and shorter hospital length of stay. If sugammadex is shown to improve the aforementioned outcomes, an argument can be made that sugammadex should be considered for inclusion in the ERAS protocol for Colorectal surgery.

Arms:
arm 1: Sugammadex 2 mg/kg IV once at the end of surgery arm 2: Neostigmine 0.07 mg/kg to a maximum of 5 mg (+Glycopyrrolate 0.2 mg per 1 mg of neostigmine administered) IV once at the end of surgery

Interventions: intervention 1: Sugammadex intervention 2: Neostigmine
Intervention descriptions: intervention 1: At the end of the surgical procedure at a depth of neuromuscular blockade after the reappearance of T2 on the train-of-four, Sugammadex will be dosed once at 2 mg/kg actual body weight through an intravenous line with brisk flow intervention 2: At the end of surgical procedure at a depth of neuromuscular blockade after the reappearance of T2 on the train-of-four, Neostigmine will be dosed once at 0.07 mg/kg actual body weight to a maximum of 5 mg through an intravenous line with brisk flow. Glycopyrrolate will be coadministered with Neostigmine at a dose of 0.2 mg of Glycopyrrolate per 1.0 mg of Neostigmine administered

Protocol document:
Prot_SAP_000.pdf: 
STIM Bowel Function 
IRB #21895 v07.25.2020 
 
         Page 1 of 21  
STIM BOWEL FUNCTION: Sugammadex To IMprove Bowel Function 
 
Protocol and Statistical Analysis Plan 
July 23, 2020 
 
ClinicalTrials.gov Identifier: NCT04546672 
 
Full Title: An assessor-blinded, randomized, controlled, single center, parallel design trial with patient 
masking to compare early postoperative gastric emptying associated with rocuronium neuromuscular 
reversal with sugammadex versus neostigmine in adults undergoing colon and rectal surgery 
 
Principal Investigator:  
 Brandon Togioka, MD (503) 494-4572 
 
 3181 SW Sam Jackson Park Road 
 
 Mail Code UHN-2 
 
 Portland, OR 97239 
 
 
 
 
Fax: 503-494-3092 
 
 togioka@ohsu.edu 
 
Co-investigators:  
 
Michael Aziz, MD (503) 418-8044 
3181 SW Sam Jackson Park Road 
Mail Code KPV-5A 
Portland, OR 97239 
azizm@ohsu.edu 
 
 
 
 
 
Yiyi Chen, PhD (503) 346-0790 
 
 
 
 
3181 SW Sam Jackson Park Road 
 
 
 
 
Mail Code CR-145 
 
 
 
 
Portland, OR 97239 
 
 
 
 
chenyiy@ohsu.edu  
 
 
 
 
 
Vassiliki (Liana) Tsikitis, MD (503) 494-6900 
 
 
 
 
3181 SW Sam Jackson Park Road 
 
 
 
 
 
Mail Code L223A 
 
 
 
 
Portland, OR 97239 
 
 
 
 
tsikitis@ohsu.edu  
 
Sponsor: 
 
 
Merck & Co., Inc 
 
 
 


STIM Bowel Function 
IRB #21895 v07.25.2020 
 
         Page 2 of 21  
 
1. Protocol Title 
 
An assessor-blinded, randomized, controlled, single center, parallel design trial with patient masking 
to compare early postoperative gastric emptying associated with rocuronium neuromuscular 
reversal with sugammadex versus neostigmine in adults undergoing colon and rectal surgery 
 
2. Objectives 
Primary Hypothesis: We hypothesize that compared to neostigmine and glycopyrrolate, reversal of 
rocuronium neuromuscular blockade with sugammadex will increase gastric emptying in patients 
undergoing colorectal surgery. 
 
Primary Objective: To determine if a strategy of rocuronium neuromuscular blockade reversal with 
sugammadex will increase gastric emptying as assessed by the paracetamol absorption test, 
compared to neostigmine and glycopyrrolate. 
 
Secondary Objectives:  
1. To determine if a strategy of rocuronium neuromuscular blockade reversal with sugammadex 
will reduce time to first bowel movement, compared to neostigmine. 
2. To determine if a strategy of rocuronium neuromuscular blockade reversal with sugammadex 
will reduce the proportion (percentage) of patients with a gastrointestinal complication 
(anastomotic leak, postoperative ileus, reoperation, or organ space infection), compared to 
neostigmine. 
3. To determine if a strategy of rocuronium neuromuscular blockade reversal with sugammadex 
will reduce the time between administration of reversal agent to achievement of a train-of-
four ratio > 0.9, compared to neostigmine. 
4. To determine if a strategy of rocuronium neuromuscular blockade reversal with sugammadex 
will reduce Post Anesthesia Care Unit (PACU) phase 1 recovery time, compared to 
neostigmine. 
5. To determine if a strategy of rocuronium neuromuscular blockade reversal with sugammadex 
will reduce hospital length of stay, compared to neostigmine. 
 
3. Background 
 
Colon and rectal surgery is associated with high cost, long length of stay, high postoperative surgical 
site infection rate, high incidence of postoperative nausea and vomiting, and a high rate of hospital 
readmission.1-3  The 30-day mortality rate after open or laparoscopic surgery for colorectal cancer is 
high—in many studies around 3%.1,4-6 A six year study of over 170,000 patients having colon and 
rectal resections for malignant and non-malignant disease found a 30-day mortality rate of 8.5%.7  
Return of bowel function is of utmost importance in avoiding patient discomfort, morbidity, and 
mortality after colorectal surgery.  The incidence of postoperative ileus after colorectal surgery has 
been reported to be 10-25%.3,8,9 Postoperative ileus is defined as intolerance of oral intake due to a 
lack of coordinated bowel motility.10  Significant attention has been paid to the development of 


STIM Bowel Function 
IRB #21895 v07.25.2020 
 
         Page 3 of 21  
guidelines and programs to reduce the incidence of postoperative ileus and accelerate return of 
bowel function after colorectal surgery. 
 
The American Society of Colon and Rectal Surgeons (ASCRS) and the Society of American 
Gastrointestinal and Endoscopic Surgeons (SAGES) created an enhanced recovery after surgery 
(ERAS) protocol to promote the following outcomes in patients undergoing colorectal surgery: 
“freedom from nausea, freedom from pain at rest, early return of bowel function, improved wound 
healing, and early hospital discharge”.2  An intervention that facilitates faster postoperative gastric 
emptying may impact many of these outcomes; in particular, nausea may be reduced, constipation-
associated pain at rest may decline, return of bowel function would be accelerated, and time to 
hospital discharge may be shortened.  While administration of medications such as Alvimopan and 
adjustments in anesthetic technique (providing epidural analgesia, minimizing crystalloid 
administration, using multimodal analgesia) are recommended, sugammadex is not currently 
considered in the ERAS protocol.2   
 
Neuromuscular paralysis is required for the duration of open and laparoscopic colorectal surgery to 
decrease patient movement, improve operating conditions, and at times facilitate ventilation.  
Neostigmine and glycopyrrolate are commonly used to reverse rocuronium neuromuscular blockade 
at the end of surgery.  Both neostigmine and glycopyrrolate impact bowel function.  Neostigmine 
promotes and glycopyrrolate slows gastrointestinal motility11,12.  Co-administration of neostigmine 
and glycopyrrolate can have variable effects on return of bowel function after surgery.  In general, 
administering a higher proportion of neostigmine than glycopyrrolate is associated with faster return 
of bowel function.13  Unopposed cholinergic activity from neostigmine administration can cause 
morbidity including bradycardia, bronchoconstriction, hypotension, urinary incontinence, and 
increased salivary secretions.11  Thus, the ratio of neostigmine to glycopyrrolate is relatively fixed 
and cannot be adjusted to promote desired gastrointestinal outcomes.  Sugammadex does not bind 
to acetylcholine receptors on bowel and is presumed not to affect bowel function.   
 
Some investigations into the contribution of sugammadex versus acetylcholinesterase inhibitors to 
recovery of bowel function have been completed.  In retrospective studies, sugammadex 
administration has been associated with faster time to first bowel movement14 and less ileus-related 
delays in hospital discharge15.  Conversely, two randomized, controlled clinical trials found no 
difference in outcomes related to gastrointestinal motility including time to first flatus16, time to first 
bowel movement16, and incidence of postoperative ileus17.  One randomized, controlled trial found 
a shorter time to first flatus, but no difference in time to first bowel movement.18  Lastly, one study 
found a trend towards faster gastric emptying with sugammadex.19  A limitation of the 
aforementioned prospective studies16-19 is they include patients having surgery on their thyroid 
gland, gallbladder, and other intraabdominal organs.  These surgeries lack bowel handling and 
anastomosis, which translates to less effect on postoperative bowel function.  It is hypothesized that 
a randomized, controlled trial involving patients having colorectal surgery will find faster gastric 
emptying, less nausea, and less gastrointestinal complications (including ileus) when sugammadex is 
administered to reverse rocuronium neuromuscular blockade, compared to neostigmine.  
 
The purpose of this study is to determine if administering sugammadex for reversal of neuromuscular 
blockade instead of neostigmine and glycopyrrolate, a strategy that avoids cholinergic effects on the 
bowel, is associated with faster gastric emptying, shorter time to first bowel movement, less post-


STIM Bowel Function 
IRB #21895 v07.25.2020 
 
         Page 4 of 21  
surgical gastrointestinal complications, faster time to achieve a TOFr > 0.9, shorter PACU phase 1 
recovery, and shorter hospital length of stay.  If sugammadex is shown to improve the 
aforementioned outcomes, an argument can be made that sugammadex should be considered for 
inclusion in the ERAS protocol for Colorectal surgery.  
 
4. Study Design 
 
Design: Assessor-blinded, randomized, controlled, single center, parallel design trial with patient 
masking  
 
Intervention Arm: Sugammadex for reversal of rocuronium neuromuscular blockade will be 
administered at a dose of 2 mg/kg actual body weight once T2 has reappeared on the train-of-four, 
in accordance with product labeling.1 
 
Control/Standard Arm: Neostigmine and glycopyrrolate will be administered in a dose and ratio 
consistent with product labeling and best practice2-4 once T2 has reappeared on the train-of-four (i.e. 
0.07 mg/kg neostigmine actual body weight to a maximum of 5 mg given concomitantly with 0.2 mg 
glycopyrrolate for every 1 mg neostigmine). 
 
Randomization and Assignment: Patients will be randomly assigned to either the intervention 
(sugammadex) or control (neostigmine) arm. Before initiation of the clinical portion of the study, 120 
opaque sealed envelopes will be prepared by a researcher not involved in patient recruitment or 
enrollment: 60 for the intervention arm and 60 for the control arm.  These envelopes will be 
randomized without stratification via a computer-generated random allocation sequence and 
numbered in ascending order from 1 to 120.  A block size of 6 will be used for random number 
generation to ensure balanced assignments over time. Patients enrolled in the study will be assigned 
to the next free envelope and given the corresponding treatment contained therein.  All researchers 
involved in patient recruitment, allocation, and assessment will be kept blind to the allocation 
sequence. 
 
Research Integrity: The study will be assessed for initial approval by the Institutional Review Board 
(IRB) at OHSU, Portland, OR, USA, and given a unique identifier for ongoing review. 
 
 
5. Study Population 
 
a. Number of Subjects 
 
Study Size: 60 subjects will be enrolled in the intervention (sugammadex) arm and 60 patients 
will be enrolled in the control (neostigmine and glycopyrrolate) arm at OHSU. 
 
b. Inclusion and Exclusion Criteria 
 
Inclusion Criteria: Patients ≥ 18 years of age having colorectal surgery under general endotracheal 
anesthesia in the south operating rooms of Oregon Health & Science University (OHSU).  The 
following are examples of common colorectal surgeries at OHSU that would be eligible for 


STIM Bowel Function 
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         Page 5 of 21  
inclusion: abdominal perineal resection, colostomy reversal, colostomy revision, ileostomy 
reversal, ileostomy revision, bowel resection, protocolectomy, and proctectomy. 
 
Exclusion Criteria:  
1. Prisoners 
2. Pregnant women 
3. Patients lacking capacity to consent 
4. Patients with an allergy to a study drug 
5. Patients with a medical contraindication to neuromuscular blockade 
6. Stage IV renal disease or worse (eGFR < 30 ml/min) 
7. Significant hepatic dysfunction (AST or ALT > twice the institutional normal) 
8. Patients taking the selective estrogen receptor modulator toremifene 
 
 
c. Vulnerable Populations 
The following populations will be excluded from the study  
• Prisoners 
• Decisionally impaired adults 
• Pregnant Women 
 
d. Setting 
 
Study Location: Single center study performed at OHSU in Portland, OR, USA in the South 
Operating Rooms (highest acuity operating rooms).  Subjects will be enrolled in the preoperative 
area of the South Operating Room Suite.  All study interventions will occur in the South Operating 
Room preoperative area, the operating rooms, or in the Post-Anesthesia Care Unit.  Data 
collection will continue to occur throughout the subject’s hospitalization. 
 
 
e. Recruitment Methods 
 
Patient Recruitment and Enrollment:  
 
Patients will be identified by the research staff and the general surgery team via review of the 
electronic medical record as posted in EPIC (Verona, Wisconsin) as early as two months prior to 
a potential subject’s scheduled surgery.  
 
We will review all the inclusion/exclusion criteria as early as two months prior to a potential 
subject’s scheduled surgery.  If a potential subject has been identified as meeting all inclusion 
criteria and none of the exclusion criteria, an approved study staffer will call the subject, using 
an approved phone script (included in ‘Consent Form and Recruitment Materials’ section of 
application) to introduce the study. 
 
If interested, the patient will receive a follow up email that includes the informed consent.   
 


STIM Bowel Function 
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         Page 6 of 21  
If the subject is amenable to the study, study staff will make arrangements to meet with the 
subject to provide formal consent materials and signature at their pre-op visit or day of surgery. 
If the subject is not interested in participating in the study, the inclusion/exclusion criteria and 
any other information related to this subject will be destroyed. 
 
The study will be listed on ClinicalTrials.gov to provide subjects, family members, and the public 
background information on the study. 
 
Other than posting this study on OHSU Study Participation Opportunities, we do not expect to 
create advertisements for the study.   
 
There will be no payments to subjects, we do not have funds to offer subjects payment for 
participation in the study. 
 
 
f. Consent Process 
 
 
The consent process will take place in a private and confidential area. All subjects that are 
approached for recruitment will hear a description of the study, reasons for pursuing this 
research study, options for opting out the research protocol or not completing data collection, 
and potential risks, advantages, and disadvantages from participating.    We will ask subjects to 
reiterate their understanding of how the study will affect their care and allow time for questions 
before collecting a signature for consent. Subjects that agree to participate in the study will be 
asked to sign a written informed consent that has been approved by our Institutional Review 
Board. An electronic copy of the signed consent will be scanned into the subject’s medical records 
system. A copy of the signed consent, describing the research study and providing contact 
information for the principal investigators will be given to subject. 
 
Dr. Sydney Rose will serve as medical monitor and will conduct periodic reviews to ensure that 
proper consent devoid of coercion is being collected as the study progresses.  Dr. Rose is an 
anesthesiologist at OHSU and the Associate Chief of Quality and Safety for the Department of 
Anesthesiology.  She has clinical trial experience. Dr. Rose is currently the PI for two clinical trials. 
 
Non-English speaking subjects will be enrolled with the help of an interpreter for all telephone 
communications, in-person procedures including obtaining consent, and study follow up.  The 
short consent form will be used.   
 
6. Procedures Involved 
 
This is an assessor-blinded, randomized, controlled, single center, parallel design trial with patient 
masking to compare early postoperative gastric emptying associated with rocuronium neuromuscular 
reversal with sugammadex and neostigmine at Oregon Health and Science University (Portland, OR).  
 
Recruitment, Randomization, and Blinding: 
 


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         Page 7 of 21  
Patients will be recruited at home or during presurgical clinic visits by research staff or primary surgeons 
up to 2 months prior to surgery.  Enrollment and acquisition of written informed consent will occur on 
the morning of surgery in the preoperative bay.  Once a study subject signs a consent form, a unique 
number corresponding to the opened opaque envelope will be assigned to that subject.  This subject 
number will never be reused and will remain with the subject for the entirety of the study.  No subject 
will ever be allowed to have more than one unique subject number.  All patients undergoing colorectal 
surgery will have an equal probability of being approached for the study.  
 
Patients will be randomly allocated to rocuronium neuromuscular block reversal with sugammadex or 
neostigmine based upon a computer-generated random allocation sequence with 1:1 assignment ratio.  
The allocation sequence will be created before study commencement by a member of the clinical 
research department not involved in recruitment, coordination, or data collection. Allocation will be 
concealed in sequentially numbered opaque envelopes. Anesthesia providers will be blinded until they 
are ready to prepare and administer reversal, typically when surgical closure begins.  Study personnel 
involved in recruitment, consent, and outcomes assessment will be blinded to group allocation until 
study completion. Assessors will not have access to anesthesia records. Patients will also be masked.   
 
Baseline Characteristics: 
 
The following baseline patient characteristics will be obtained on the morning of surgery: 
1. Age 
2. Sex 
3. Race 
4. Weight 
5. Height 
6. Body Mass Index 
7. American Society of Anesthesiologists classification 
8. Tobacco use/smoking (current, past, never) 
9. History of COPD or chronic lung disease 
10. Diagnosis of obstructive sleep apnea 
11. History of cardiovascular disease 
12. Diabetic status (uncomplicated, end-organ dysfunction) 
13. Diagnosis of gastroparesis 
14. Cancer (metastatic, localized, none) 
15. Impaired mobility  
16. Current home opioid use 
17. Creatinine 
18. AST and ALT 
19. Albumin 
 
Intraoperative Management: 
 
All patients will have standard ASA monitors plus five lead EKG applied.  Additional monitoring will be 
left to the discretion of the anesthesia team directing patient care. Anesthesia will be induced with 
propofol and the TwitchView electromyograph will be placed after cleaning the patient’s hand with an 
alcohol pad.  First, the TwitchView electromyograph stimulating electrodes will be placed over the ulnar 


STIM Bowel Function 
IRB #21895 v07.25.2020 
 
         Page 8 of 21  
nerve just proximal to the wrist crease.  Next, the recording electrodes will be placed over the adductor 
pollicis muscle and the first dorsal interosseous muscle. The ground electrode will be placed over the 
index finger.  The TwitchView electromyograph will then be calibrated followed by administration of 
rocuronium to facilitate intubation.  Next, a nasogastric or orogastric tube will be inserted.  The 
nasogastric or orogastric tube will be inserted until gastric contents or bile is achieved.  If gastric contents 
or bile cannot be suctioned the surgical team will help guide the gastric tube to the correct location. 
Gastric tubes are commonly used during colorectal surgery.  A large bore peripheral IV or arterial line 
will be inserted to provide safe patient care and facilitate blood sampling to measure plasma 
paracetamol concentrations after surgery. 
 
Anesthesia will be maintained with inhalational agent.  Rocuronium will be intermittently dosed to 
achieve the desired depth of neuromuscular block, as directed by the surgical team.  Decisions on when 
to dose and what quantity of rocuronium should be dosed for maintenance of neuromuscular blockade 
will be left to the discretion of the anesthesia team in the operating room.  The level of neuromuscular 
blockade will be monitored in the operating room with the TwitchView electromyograph via automatic 
train-of-four measurement every 20 seconds, which is the device default.   
 
During surgical closure the opaque envelope containing patient allocation will be opened.  The 
anesthesia provider will dispose of the allocation sequence into the sharps bin immediately after reading 
it.  This will help ensure research coordinator masking when they enter the operating room.  
Neostigmine, glycopyrrolate, sugammadex and paracetamol will be obtained from the research 
pharmacy.  Neostigmine, glycopyrrolate, and sugammadex will be delivered to the anesthesia provider 
in the original vials.  Vials containing reversal agents will be immediately disposed of in the sharps bin 
after medications are drawn up.  A 1 gram paracetamol per 200 ml sterile water solution will be created 
in the research pharmacy and dispensed to the anesthesia provider.  Prior to administering 
neuromuscular block reversal paracetamol will be administered down the orogastric or nasogastric tube. 
The gastric tube will then be rinsed with 20 ml of water.  Providers will be encouraged to administer 
paracetamol immediately before administering neuromuscular reversal.  The gastric tube will be 
removed or left in situ, per the direction of the surgical team. 
 
Providers will be told to make their best effort to reverse neuromuscular blockade at a train-of-four 
count of 2.   Neuromuscular reversal with be administered in accordance with random assignment.  
Administration of sugammadex or neostigmine will occur into a fast flowing intravenous line that is 
running wide open.  Sugammadex will be dosed at 2 mg/kg actual body weight, rounded to the nearest 
10 mg.  Neostigmine will be dosed at 0.07 mg/kg actual body weight (maximum of 5 mg), rounded to the 
nearest 0.1 mg.  Glycopyrrolate will be co-administered in the neostigmine arm at a dose of 0.2 mg of 
glycopyrrolate per 1.0 mg of neostigmine.  To maintain blinding, the study team will not be present in 
the operating room when anesthesia providers access the randomization assignment and administer 
reversal.  Anesthesia providers will page the research coordinator immediately after neuromuscular 
reversal is administered.  The page will cue the research coordinator to enter the operating room and 
inquire the time of reversal. The research coordinator will be trained not to walk into the anesthesia 
workspace so as not to inadvertently view the anesthesia record. 
 
Train-of-four ratios will be saved in the TwitchView monitor for analysis at a later time to determine time 
to achieve train-of-four ratio ≥ 0.9. Three consecutive train-of-four ratios ≥ 0.9 will be required.   
 


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Postoperative Study Procedures: 
 
Blood samples will be obtained at the following timepoints after reversal: 15 (T15), 30 (T30), 45 (T45), 
60 (T60), 90 (T90), 120 (T120), and 150 (T150) minutes.  Each sample will require a volume of 1-2 mL of 
blood.  These will be stored on ice and delivered to the pharmacokinetics laboratory to determine plasma 
paracetamol concentrations.   
 
A research coordinator at the patient’s bedside in the PACU will assess for PACU phase 1 recovery time 
and monitor for the following adverse events: 
1. Drug hypersensitivity reaction 
2. Bronchospasm  
3. Upper airway obstruction 
4. Bradycardia 
5. Tachycardia 
6. Unremitting coughing 
7. Treatment of nausea or vomiting 
8. Dysgeusia (foul, salty, or metallic taste) 
 
Thereafter, the study team will conduct in-person daily assessment to identify gastrointestinal 
complications (anastomotic leak, ileus, reoperation, or organ space infection), in hospital mortality, 
determine time to first bowel movement, and determine hospital length of stay.   
 
A phone call and screen of the electronic medical record will be completed 30-60 days after hospital 
discharge to assess for gastrointestinal complications. A standard pro forma will be used for the daily in-
person hospital assessment and the post-discharge phone call. 
 
Electronic Medical Record Data Extraction: 
 
The following variables will be extracted from the electronic medical record after patient discharge.   
1. Categorized surgical procedure 
2. Laparoscopic versus open procedure 
3. Surgical wound classification (clean, clean-contaminated, contaminated, dirty or infected) 
4. Cumulative rocuronium dose 
5. Intraoperative opioid dose in parenteral morphine equivalents 
6. Train-of-four count at time of reversal 
7. Volume of crystalloid administered intraoperatively 
8. Volume of blood transfused intraoperatively 
9. Estimated blood loss 
10. PACU opioid dose in parenteral morphine equivalents 
11. Use of epidural for postoperative analgesia 
12. Duration of anesthesia 
13. Duration of surgery 
14. Time from paracetamol administration to arrival to PACU 
15. Time from reversal to arrival to PACU 


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         Page 10 of 21  
16. Presence of nasogastric tube in the PACU 
17. Initial PACU glucose 
 
Subjects enrolled that do not receive neuromuscular relaxant during surgery, for any reason, may be 
withdrawn from the study without their consent.  In addition, a subject may be removed from the study 
if the investigator or funder stops the study, the subject’s clinical status changes, or if the subject does 
not follow study instructions. In the event that such a situation occurs the subject would be informed at 
the earliest reasonable time. 
 
The subject’s status in the research project will show up clearly in their electronic medical record 
problem list, until the subject’s participation is complete.  A progress note will be placed in the subject’s 
chart to allow other providers to easily contact study investigators.   
 
Subjects that enroll in the study and then decide to withdraw before randomization and assignment 
occur will be excluded from further data collection and analysis.  
 
An example of how the study would affect a single patient is shown in the diagram on the following page. 
 
 


STIM Bowel Function 
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         Page 11 of 21  
 
 
•Patient identification by electronic medical record review
•Call to introduce the study
•If the patient expresses interest, a follow up email is sent that contains 
the consent
1-2 weeks 
before 
surgery
•Enrollment and acquisition of written informed consent
•Collection of baseline characteristics
Morning of 
surgery
•Induction of anesthesia followed by calibration of the TwitchView 
electromyograph
•Administration of rocuronium to facilitate intubation
•Insertion of orogastric or nasogastric tube
Anesthesia 
preparation 
for surgery in 
the operating 
room (pre-
incision)
•Maintenance of anesthesia
•Intermittent dosing of rocuronium to maintain desired plane of 
neuromuscular paralysis
Middle of 
surgery
•Opening of opaque envelope to reveal patient allocation
•Administration of paracetamol
•Reversal of neuromuscular blockade
End of 
surgery
•Primary Outcome Data Collection: Obtaining blood samples to measure 
paracetamol plasma concentrations
•Secondary Outcome Data Collection: Measuring train-of-four ratio
•Secondary Outcome Data Collection: PACU phase 1 recovery time
Post-
Anesthesia 
Care Unit
•Secondary Outcome Data Collection: Time to first bowel movement
•Secondary Outcome Data Collection: Hospital length of stay
•Secondary Outcome Data Collection: Gastrointestinal complications will 
be monitored for 30 days
Postoperative 
day 1 to 30 
days post-
discharge


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7. Data and Specimens 
a. Handling of Data and Specimens 
 
Study subjects will be assigned a unique study number after enrollment in the study.  All data 
points, procedure related data, and electronic files for data analysis will be linked only to this 
unique study number.  This study number will not contain any of the 18 HIPAA identifiers such 
as: geographic location, dates related to the individual, medical record number, account 
numbers, etc.  The key linking study subjects to study code will be kept in a cloud location with 
special protection for confidential and restricted health information (the OHSU Box).  Only the 
principal investigator and other study staff will have access to this key. 
 
Data collected in the course of the study will be stored in Qualtrics on an OHSU server.  Data will 
be managed by Praveen Tekkali, an analyst within the Anesthesiology and Perioperative Medicine 
Research Division.  Again, this data tool will be only be made available to study personnel though 
a secure online log-in.  Secure data will be stored in Qualtrics for indefinite use.  Data in Qualtrics 
will be linked only to subject study code, not to any of the 18 HIPAA identifiers.   
 
Any data that is shared will be transmitted in an encrypted manner over a secure network.  
Transmitted data will be labeled only with the study code, none of the 18 HIPAA identifiers.  
When data is transmitted, the transmitter (research personnel with access to Qualtrics) will be 
responsible for sending the data in a protected manner.   Any person receiving data will then 
assume responsibility for patient confidentiality and data integrity.   
 
Seven blood samples will be drawn after surgery.  Samples will be kept on ice in a cooler in the 
PACU until all samples for a given subject have been collected. The cooler will be kept by the 
research coordinator at all times and will never be left unattended.  Specimens will be labeled 
with subject study number and time the sample was drawn. For example, the blood sample for 
study subject #1 drawn 15 minutes after reversal will be labeled “1-T15”. Samples will then be 
prepared by centrifuge at 2000xg at 4C for 15 minutes.  Samples will be stored in a freezer at -
80C in the Anesthesia Research Refrigerator, Mackenzie Hall Room #2148.  This is a secure locked 
area used for research.  Samples will be stored in this room for 1 to 4 weeks.  Samples will be 
batched and taken to the Bioanalytical Shared Resource/Pharmacokinetics Core at OHSU where 
they will be analyzed and discarded in accordance with blood waste guidelines in the 
Bioanalytical Shared Resource/Pharmacokinetics Core at OHSU. There will be no long term 
storing of plasma samples in the Bioanalytical Shared Resource/Pharmacokinetics Core.   
 
b. Sharing of Results with Subjects 
 
Study results will not be available to subjects at the time of participation.  All subjects will be 
given the contact information of the principal investigator (Brandon Togioka) and told that they 
may contact him to obtain conglomerated de-identified data at the conclusion of the study.  
Patients will also be able to obtain a free copy of any published data should they indicate interest.  
The study will not generate any genetic information or imaging studies.   
 


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The laboratory data obtained will be plasma paracetamol concentrations.  These values have not 
been linked to disease states and do not carry a risk of incidental findings. Individual laboratory 
results will not be shared with subjects or their healthcare providers. 
 
c. Data and Specimen Banking 
 
Data will  be stored in Qualtrics for indefinite use. There is no plan to conduct additional research 
on this data set or to send data to a separate repository.  Should an additional study be conceived 
IRB approval would be obtained before proceeding with data analysis.  Requests for release of 
data would be addressed to the principal investigator.  Release of data would need to be 
approved by the principal investigator, Director of Research, and Chair of the Department of 
Anesthesiology.  No groups are excluded from requesting data access.  All de-identified data 
within the Qualtrics database would be available for release.  A data sharing agreement would 
be required before the principal investigator would allow researchers access to the data 
contained in Qualtrics.  
 
 
 
8. Data Analysis 
Data Analysis: 
 
The database will be created and managed by Praveen Tekkali, a computer scientist within the Clinical 
Research Division of Anesthesiology and Perioperative Medicine.  Dr. Yiyi Chen, an associate professor 
in biostatistics, will be responsible for performing the statistical analysis described herein.  The research 
team led by Dr. Brandon Togioka will be responsible for interpreting the data.   
 
 
Blinding of Data: 
 
The statistician will be responsible for generating the random assignment list. Study subjects will be 
assigned a unique study number after enrollment. The key linking subject study numbers to the 
allocation sequence will be kept in an OHSU approved cloud location with special protection for 
confidential and restricted health information (the OHSU Box).  The data manager, Praveen Tekkali, will 
guard this key.  The outcome assessor will not be in the operating room when allocation is revealed or 
when neuromuscular reversal is administered.  Variables that need to be retrieved from the electronic 
medical record will be pulled by the data manager to avoid unblinding the outcome assessor.  After data 
collection is complete for the final patient the key linking the subject study numbers to the allocation 
sequence will be given to the statistician.  At this point the remainder of the research team will be kept 
blinded in case data cleaning is necessary.  For the purpose of the final analysis, the official clinical 
database will not be unblinded to the rest of the research team until medical/scientific review has been 
completed, protocol violators have been identified (if appropriate), data has been declared complete, 
and statistical analysis is finished. 
 
Variables/Time Points of Interest 
 


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Primary Endpoint: Gastric emptying to be assessed by the area under the paracetamol concentration 
versus time curve will be determined at 150 minutes by trapezoidal approximation.  In addition, the 
individual paracetamol plasma concentrations will be compared between study arms at the following 
timepoints after neuromuscular reversal: 15 (T15), 30 (T30), 45 (T45), 60 (T60), 90 (T90), 120 (T120), and 
150 (T150) minutes. 
 
The paracetamol absorption test is a validated test for assessment of gastric emptying that is more 
feasible in the perioperative setting than the gold standard of scintigraphy.1-3 Scintigraphy is a test 
performed with nuclear medicine. It is a costly outpatient procedure that exposes patients to radiation.  
Paracetamol is poorly absorbed in the stomach, but is rapidly absorbed through the small intestine.4  
Thus, gastric emptying is the rate limiting step to allowing paracetamol to be absorbed into the blood 
stream.4  Accordingly, higher plasma concentrations of paracetamol are associated with faster gastric 
emptying. 
 
Please note, we realize Merck & Co. has experts in the field of pharmacokinetics.  We would be more 
than happy to work with these experts to optimize our paracetamol absorption test. 
 
Secondary Endpoint: Time to first bowel movement.  This variable will be monitored on an ongoing daily 
basis until hospital discharge.   
 
Secondary Endpoint: The proportion (percentage) of patients with a gastrointestinal complication.  
Gastrointestinal complications will include the following: anastomotic leak, postoperative ileus, 
reoperation, and organ space infection.  National Surgical Quality Improvement Project definitions will 
be used.5  Active monitoring for these outcomes will occur on an ongoing daily basis until hospital 
discharge.  In addition, chart review and patient phone call will occur 30-60 days after discharge to assess 
for complications that occur after discharge.   
1. Anastomotic leak will be defined as visualized leak of endoluminal contents through an 
anastomosis or presence of infection or abscess thought related to the anastomosis within 30 
days of the index operation. 
2. Postoperative ileus will be defined as prolonged NPO status or gastric tube for decompression 
for more than 3 postoperative days or reinserting a gastric tube or reinitiating NPO status at any 
time between postoperative day 4 and postoperative day 30. 
3. Reoperation will include any surgery performed to correct a complication related to the index 
operation within 30 postoperative days.6 
4. Organ space infection will include infections within 30 days of the index operation that involve a 
structure, other than the skin, that was manipulated. 
 
Secondary Endpoint: The time between injection of sugammadex or neostigmine and achievement of 
train-of-four ratio ≥ 0.9.  The TwitchView electromyograph will set to automatically check a train-of-four 
ratio every 20 seconds.  These data points will be saved in the TwitchView monitor for download and 
analysis at a later time.  A research coordinator in the PACU will turn off the TwitchView device once 
three consecutive ratios are ≥ 0.9.  If a train-of-four ratio ≥ 0.9 is not achieved within 30 minutes after 
study drug injection the patient will be considered to have incomplete reversal and train-of-four counts 
will cease to be measured. 


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Secondary Endpoint: Phase 1 PACU recovery time.  PACU phase 1 recovery time is defined as the time 
required to attain pain control and stable respiratory, hemodynamic, and neurologic status.  This variable 
will be assessed by a research coordinator in the PACU on postoperative day zero. 
 
Secondary Endpoint: Hospital length of stay.  This variable will be monitored on an ongoing daily basis 
until hospital discharge. 
 
Safety Endpoints: 
1. In hospital mortality will be defined by a death in the hospital.  This variable will be monitored 
on an ongoing daily basis until hospital discharge. 
2. Drug hypersensitivity reaction will be defined by flushing, urticaria, new edema, sudden 
hypotension or tachycardia, or wheezing within 5 minutes of administration of study drug.  This 
variable will be assessed by the research coordinator at the time the patient arrives to the PACU. 
3. Bronchospasm will be defined by the need to administer a bronchodilator, such as albuterol, in 
the PACU.  This variable will be assessed on an ongoing basis by the research coordinator in the 
PACU. 
4. Upper airway obstruction will be defined by the requirement to place a nasal airway, or airway, 
or initiation of continuous positive airway pressure in the PACU. This variable will be assessed on 
an ongoing basis by the research coordinator in the PACU. 
5. Bradycardia will be defined by a heart rate < 60 beats per minute at any time while the patient 
is in the PACU.  This variable will be assessed on an ongoing basis by the research coordinator in 
the PACU. 
6. Tachycardia will be defined by a heart rate > 100 beats per minute at any time while the patient 
is in the PACU. This variable will be assessed on an ongoing basis by the research coordinator in 
the PACU. 
7. Unremitting coughing will be defined as ≥ 3 consecutive coughs at any time while the patient is 
in the PACU.  This variable will be assessed on an ongoing basis by the research coordinator in 
the PACU. 
8. Nausea or vomiting will be defined by nurse administration of an antiemetic or witnessed 
vomiting in the PACU.  This variable will be assessed on an ongoing basis by the research 
coordinator in the PACU. 
9. Foul, salty or metallic taste will be assessed by asking the patient if they have any unpleasant 
taste.  This variable will be assessed on an ongoing basis by the research coordinator in the PACU. 
 
Statistical Methods 
 
Descriptive summaries will be presented as mean, standard deviation, median and range for continuous 
characteristics and frequencies and percentages for categorical characteristics, overall as well as by 
group.  
 
All statistical analysis will use intent-to-treat patient population.  
 
Primary analysis: Welch’s t-test will be used to test for a treatment effect for the primary endpoint of 
area under the curve at 150 minutes. Log transformation will be applied to the AUC when necessary.  
The Welch’s t-test will also be used to test for a treatment effect for paracetamol plasma concentration 


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at T15, T30, T45, T60, T90, T120, and T150. Mixed effect model will be used to compare the treatment 
effects over time (from T15 to T150) for the two groups. 
 
Secondary analysis: Welch’s t-test will be used to test for a treatment effect for the secondary endpoints 
time to first bowel movement, time to achieve a train-of-four ratio ≥ 0.9, PACU phase 1 recovery time, 
and hospital length of stay.  The chi-square statistic or Fisher’s exact test will be used to test for a 
treatment effect for postoperative gastrointestinal complications.   
 
We will not conduct an interim analysis since we will need the full sample to evaluate efficacy.  A two-
sided alpha level of 5% will be required for statistical significance.  The statistical software STATA (Stat 
Corporation, College Station, TX) will be used for analyses.   
 
Multiplicity 
 
This study consists of two treatment groups, no planned interim analysis, a single primary endpoint, and 
includes a statistical strategy in which a single pre-specified null hypothesis will be tested. Accordingly, 
adjustment for type I error is not required.  
 
Power/Sample Size: 
 
An abstract was published that compared sugammadex with neostigmine for the primary outcome of 
gastric emptying by paracetamol absorption.7  The data generated from that abstract was used for 
sample size calculations.  Assuming a pooled standard deviation of 140 and an area under the curve of 
627 mcg*min/ml in the sugammadex group and 548 mcg*min/ml in the neostigmine group, the study 
requires a sample size of 50 in each group to achieve 80% power at 5% significance level using two-sided 
two-sample t-test.  Ten subjects were added to each group to account for possible dropouts. 
 
Timeline: 
 
A review of colorectal surgeries at OHSU in the South Operating Rooms in 2019 found 179 surgeries.  Our 
rate of enrollment in our last Merck sponsored sugammadex study was 56% (200/358).  Assuming we 
have a similar enrollment rate we should be able to enroll 120 subjects in 18 months, with a projected 
enrollment of 1-2 patients per week. 
 
9. Privacy, Confidentiality, and Data Security 
 
The results of the study as well as all other information collected on the data collection sheet will be 
stored on site at OHSU in the office of the research coordinator.  This office requires a key for entry and 
the corridor to the office requires a passcode for entry.  The office is not shared with any other 
individuals.  No protected health information or other data collected during the completion of this 
randomized controlled trial will be taken off campus.  All data gathered for this study will be coded 
before any analysis or publication occurs. 
 
This study number will not contain any of the 18 HIPAA identifiers such as: geographic location, dates 
related to the individual, medical record number, account numbers, etc.  The key linking study subjects 
to study code will be kept in a cloud location with special protection for confidential and restricted health 


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information (the OHSU Box).  Only the principal investigator and other study staff will have access to this 
key. 
 
Data collected in the course of the study will be stored using OHSU’s preferred secure database platform 
(Qualtrics).  Again, this data tool will be only be made available to study personnel though a secure online 
log-in.  Secure data will be stored in Qualtrics for indefinite use.  Data in Qualtrics will be linked only to 
subject study code, not to any of the 18 HIPAA identifiers 
 
In order to maintain patient privacy, data capture tools, study drug accountability records, study reports, 
and communications will identify the patient only by initials and the assigned patient number. The 
investigator will grant monitor(s) and auditor(s) from the Sponsor or its designee and regulatory 
authorities access to the patient’s original medical records, including medical history, laboratory studies, 
and medication administrations, for verification of data gathered and to audit the data collection 
process. This information will be accessed for the duration of the research study, including the follow-
up period, for the purpose of data reconciliation. The patient’s confidentiality will be maintained and will 
not be made publicly available to the extent permitted by the applicable laws and regulations. 
 
 
10. Provisions to Monitor the Data to Ensure the Safety of Subjects 
 
DSMP submitted as a separate document. 
 
11. Risks and Benefits 
a. Risks to Subjects 
 
As with all studies, breach of confidentiality is a common risk.  In addition, there is the possibility 
of slightly increased anxiety on the day of surgery for patients approached for inclusion in the 
study.  There is also likely to be a loss of free time in the preoperative area as consent will likely 
take 15 minutes to complete.  TOF ratios will also be obtained in the Post-Anesthesia Care Unit 
(PACU), which is not currently standard of care at OHSU.  This TOF ratio may result in a slight 
discomfort.  Based upon our experience with our previous study involving sugammadex, patients 
do not remember having their TOF ratio measured.  The TOF ratio will be measured while the 
patient is still under a significant depth of anesthesia.  As data collection will continue to occur 
throughout the patient’s hospitalization inconvenience is possible. 
 
The orogastric or nasogastric tube is part of the standard anesthesia pathway for colorectal 
surgery. Accordingly, no additional risk is incurred by study participation.  The decision regarding 
removing the gastric tube or leaving it in after surgery will be left to the discretion of the surgical 
team.   
 
Large bore peripheral IV access and arterial line insertion are common procedures in the South 
Operating Rooms (High Risk Surgical Suite).  For most patients having colorectal surgery in the 
South Operating Rooms the lines placed to ensure safe delivery of anesthetic care will suffice for 
postoperative blood sampling. If blood sampling cannot occur through the lines placed for surgery 
the least invasive method of obtaining blood samples will be used.  This will typically mean the 
insertion of a new large bore peripheral IV.  


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Sugammadex is a novel method of reversing neuromuscular relaxant in the operating room 
approved by the FDA on December 15, 2015.  There is a history of safe Sugammadex use in 
Europe since its initial approval by the European Union on July 29, 2008. As Sugammadex is a 
newer drug in the United States there is a possibility of unknown or understated adverse events 
associated with its use.  To this extent adverse experience reporting will include monitoring for 
and publishing the occurrence of any of the following adverse events associated with 
sugammadex or neostigmine administration:  
 
Adverse experience reporting will include monitoring for and publishing the occurrence of any of 
the following adverse events associated with sugammadex or neostigmine administration:  
 
 
1. In hospital mortality 
2. Drug hypersensitivity reaction defined by flushing, urticaria, new edema, sudden hypotension 
or tachycardia, or wheezing within 5 minutes of administration of neuromuscular blockade 
reversal   
3. Bronchospasm in the PACU 
4. Upper airway obstruction in the PACU 
5. Bradycardia in the PACU 
6. Tachycardia in the PACU 
7. Unremitting coughing in the PACU 
8. Nausea or vomiting in the PACU 
9. Foul, salty, or metallic taste in the PACU 
 
Participants will not incur any additional cost for participating in this study. 
 
Sugammadex, acetaminophen, neostigmine, and glycopyrrolate are regularly handled by 
anesthesia providers.  There is no additional risk to anesthesia providers that participate 
in this trial.   
 
There is no risk to family of patients that participate in this trial. 
 
 
b. Potential Benefits to Subjects 
 
 
We are performing this study because the incidence of postoperative ileus after colorectal 
surgery has been reported to be 10-25%.  Return of bowel function is of utmost importance in 
avoiding patient discomfort, morbidity, and mortality after colorectal surgery.  Whether the 
study drug is better than the current standard of care at promoting return of bowel function is 
unknown.  We anticipate that patients that receive Sugammadex will have faster gastric 
emptying, shorter phase 1 recovery length of stay, shorter length of hospitalization, and lower 
incidence of postoperative gastrointestinal complications including: anastomotic leak, 
postoperative ileus, reoperation, and organ space infection—compared to glycopyrrolate and 
neostigmine. 


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12. Drugs or Devices (delete if not applicable) 
 
 
We request that sugammadex be provided by Merck & Co. as it was for our last trial. We request 80 vials 
of open label 200 mg/2 mL sugammadex solution for administration to 60 patients.  We are requesting 
a surplus in case there are packaging or manufacturing defects or in case there are spills.  In addition, 
some patients will require two vials because of their weight. 
 
Vials of sugammadex can be sent to the research pharmacy at OHSU. The address and designated contact 
person can be shared at a future date.  Individual vials can be sent, i.e. bulk supplies are not needed. The 
research pharmacy will be responsible for maintaining the inventory of sugammadex, safely and properly 
storing sugammadex in a secure location, and dispensing sugammadex solely for the purpose of 
completing the study protocol. Accurate records of sugammadex quantities drawn up, administered, 
wasted, and disposed of at the end of the study will be kept by the research pharmacy.  Any unused 
sugammadex (either left over after patient administration or at the conclusion of the study) will be 
destroyed at OHSU pursuant to ICH/GCP guidelines, city of Portland regulations, state of Oregon 
regulations, federal policy, and OHSU institutional policy. 
 
Blinding of sugammadex will not be necessary because the anesthesia provider will not be masked.  The 
vials of sugammadex will be delivered unchanged to the anesthesia provider with the exception of a 
bright orange circular label that will identify the drug for research purposes only.  The anesthesia 
provider will be responsible for checking, drawing up, labeling and administering sugammadex safely.  
 
Paracetamol is available at our institution and we intend to purchase it for the study.  The research 
pharmacy will similarly be responsible for maintaining paracetamol inventory, safely and properly 
storing paracetamol in a secure location, and dispensing paracetamol solely for the purpose of 
completing the study protocol. Accurate records of paracetamol quantities drawn up, administered, 
wasted, and disposed of at the end of the study will be kept by the research pharmacy.  Any unused 
paracetamol (either left over after patient administration or at the conclusion of the study) will be 
destroyed at OHSU pursuant to ICH/GCP guidelines, city of Portland regulations, state of Oregon 
regulations, federal policy, and OHSU institutional policy. 
 
Blinding of paracetamol will not be necessary.  Paracetamol will be prepared for administration in the 
research pharmacy.  One gram of paracetamol will be dissolved in 200 mL of water.  This solution will be 
identified as a research drug by a bright orange circular label.  The anesthesia provider will be responsible 
for checking, drawing up, labeling and administering paracetamol safely.   
 
To avoid patient charges, sugammadex and paracetamol administered to study participants will be 
ordered and identified as a research medication in the electronic medical record.  
 
The TwitchView electromyography is a device for measuring degree of neuromuscular blockade during 
surgery and in the acute postoperative period.  The TwitchView allows for a more accurate assessment 
of neuromuscular function than the clinical observation of muscle function when using a peripheral 
nerve stimulator. A price quote has been obtained from the company that produces the TwitchView and 


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the sponsor has agreed to pay for the purchase of this equipment. The TwitchView is approved for clinical 
use in the operating room. 
 
 
13. Study Duration 
 
It is expected that this study can be completed within 30 months.  The first 6 months would be 
used for the following: obtaining IRB approval, obtaining study drugs, setting up the research 
pharmacy account, developing the paracetamol assay and performing instrument validation, 
training research assistants on use of the TwitchView electromyograph, educating anesthesia 
providers, educating surgery providers, educating PACU nursing staff, and setting up a database.  
The next 18 months would be used for patient recruitment, patient enrollment, study 
implementation, data collection, and database creation.  The final 6 months would be spent on 
data synthesis, statistical analysis, interpretation, writing, and revising the study for publication. 
 
14. References 
1. 
Alves A, Panis Y, Mathieu P, et al. Postoperative mortality and morbidity in French patients undergoing 
colorectal surgery: results of a prospective multicenter study. Arch Surg. 2005;140(3):278-283, discussion 
284. 
2. 
Carmichael JC, Keller DS, Baldini G, et al. Clinical Practice Guidelines for Enhanced Recovery After Colon 
and Rectal Surgery From the American Society of Colon and Rectal Surgeons and Society of American 
Gastrointestinal and Endoscopic Surgeons. Dis Colon Rectum. 2017;60(8):761-784. 
3. 
Tevis SE, Kennedy GD. Postoperative Complications: Looking Forward to a Safer Future. Clin Colon Rectal 
Surg. 2016;29(3):246-252. 
4. 
Adam MA, Turner MC, Sun Z, et al. The appropriateness of 30-day mortality as a quality metric in colorectal 
cancer surgery. Am J Surg. 2018;215(1):66-70. 
5. 
Iversen LH, Ingeholm P, Gogenur I, Laurberg S. Major reduction in 30-day mortality after elective 
colorectal cancer surgery: a nationwide population-based study in Denmark 2001-2011. Ann Surg Oncol. 
2014;21(7):2267-2273. 
6. 
Osler M, Iversen LH, Borglykke A, et al. Hospital variation in 30-day mortality after colorectal cancer 
surgery in denmark: the contribution of hospital volume and patient characteristics. Ann Surg. 
2011;253(4):733-738. 
7. 
Byrne BE, Mamidanna R, Vincent CA, Faiz O. Population-based cohort study comparing 30- and 90-day 
institutional mortality rates after colorectal surgery. Br J Surg. 2013;100(13):1810-1817. 
8. 
Asgeirsson T, El-Badawi KI, Mahmood A, Barletta J, Luchtefeld M, Senagore AJ. Postoperative ileus: it costs 
more than you expect. J Am Coll Surg. 2010;210(2):228-231. 
9. 
Wolthuis AM, Bislenghi G, Fieuws S, de Buck van Overstraeten A, Boeckxstaens G, D'Hoore A. Incidence 
of prolonged postoperative ileus after colorectal surgery: a systematic review and meta-analysis. 
Colorectal Dis. 2016;18(1):O1-9. 
10. 
Keller D, Stein SL. Facilitating return of bowel function after colorectal surgery: alvimopan and gum 
chewing. Clin Colon Rectal Surg. 2013;26(3):186-190. 
11. 
Neely GA, Kohli A. Neostigmine. In: StatPearls. Treasure Island (FL)2020. 
12. 
Gallanosa A, Quick J. Glycopyrrolate. In: StatPearls. Treasure Island (FL)2020. 
13. 
Deljou A, Schroeder DR, Ballinger BA, Sprung J, Weingarten TN. Effects of Sugammadex on Time of First 
Postoperative Bowel Movement: A Retrospective Analysis. Mayo Clin Proc Innov Qual Outcomes. 
2019;3(3):294-301. 
14. 
Delijou A, Schroeder D, Ballinger B, Sprung J, Weingarten T. Effects of sugammadex on time of first 
postoperative bowel movement: A retrospective analysis. Mayo Clin Proc Inn Qual Out. 2019;3(3):294-
301. 


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15. 
Chae YJ, Joe HB, Oh J, Lee E, Yi IK. Thirty-Day Postoperative Outcomes Following Sugammadex Use in 
Colorectal Surgery Patients; Retrospective Study. J Clin Med. 2019;8(1). 
16. 
Sen A, Erdivanli B, Tomak Y, Pergel A. Reversal of neuromuscular blockade with sugammadex or 
neostigmine/atropine: Effect on postoperative gastrointestinal motility. J Clin Anesth. 2016;32:208-213. 
17. 
Brueckmann B, Sasaki N, Grobara P, et al. Effects of sugammadex on incidence of postoperative residual 
neuromuscular blockade: a randomized, controlled study. Br J Anaesth. 2015;115(5):743-751. 
18. 
An J, Noh H, Kim E, Lee J, Woo K, Kim H. Neuromuscular blockade reversal with sugammadex versus 
pyridostigmine/glycopyrrolate in laparoscopic cholecystectomy: a randomized trial of effects on 
postoperative gastrointestinal motility. Korean J Anesthesiol. 2020;73(2):137-144. 
19. 
Sustic A, Dijana D. Early postoperative gastric emptying in patients undergoing laparoscopic 
cholecystectomy: sugammadex vs. neostigmine/atropine neuromuscular blockade reversal agents. Eur J 
Anaesthesiol. 2012;29:140.