Sugammadex To IMprove Bowel Function (STIM_Bowel)

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

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.

Study Overview

• Status: Completed
• Conditions: Postoperative Complications; Neuromuscular Blockade; Bowel Dysfunction
• Intervention / Treatment: Drug: Sugammadex; Drug: Neostigmine

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.

• Study Type: Interventional
• Enrollment (Actual): 120
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health & Science University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years
• Having surgery in the South Operating Rooms at Oregon Health & Science University
• Surgery scheduled Monday through Friday
• Having colorectal surgery
• Planned general endotracheal anesthesia

Exclusion Criteria:

• Prisoners
• Pregnant women
• An inability to consent for surgery or anesthesia
• Allergy to a study drug
• Medical contraindication to neuromuscular blockade
• Stage 4 kidney disease or worse (glomerular filtration rate < 30 ml/min)
• Significant liver dysfunction (Aspartate transaminase or Alanine transaminase > twice the OHSU normal)
• Taking Toremifene

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sugammadex; Sugammadex 2 mg/kg IV once at the end of surgery	Drug: Sugammadex; 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; Other Names: Bridion; Org 25969
Active Comparator: Neostigmine; 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	Drug: Neostigmine; 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; Other Names: Vagostigmin; Prostigmin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gastric Emptying	Gastric emptying as assessed by the area under the paracetamol concentration-time curve by trapezoidal approximation (AUC)	150 minutes after neuromuscular reversal

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time in Minutes to Reach Train of Four (TOF) Ratio ≥ 0.9 After the Administration of Reversal Drug.	The TOF ratio will be measured in continuous manner every 15 seconds after the administration of reversal drug. The TOF ratio will be measured by the TwitchView electromyograph. The TOF ratio was measured in this study by stimulating the ulnar nerve with four equal stimuli at a frequency of 2 hertz. The TOF ratio is calculated by dividing the amplitude of the muscle response from the fourth stimuli by the amplitude of the muscle response from the first stimuli.	30 minutes after the administration of reversal drug.
Number of Participants With Gastrointestinal Complications	Gastrointestinal complications will include all of the following: anastomotic leak, postoperative ileus, reoperation, and organ space infection. National Surgical Quality Improvement Project definitions will be used. 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 days after discharge to assess for complications after discharge.	30 days after surgery
PACU Recovery Time	The time to attain pain control and stable respiratory, hemodynamic, and neurologic status after surgery.	1 day
Reversal Time to First Bowel Movement	The time from reversal of neuromuscular blockade to first bowel movement	length hospitalization, an average of 1 week
Reversal Time to Discharge Order	The number of days between reversal of neuromuscular blockade and time of discharge order	length of hospitalization, an average of 1 week

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Gastrointestinal complications	Gastrointestinal complications will include all of the following: anastomotic leak, postoperative ileus, reoperation, and organ space infection. National Surgical Quality Improvement Project definitions will be used. 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 after discharge.	60 days after surgery
Bowel movement	The time to first bowel movement after surgery	length hospitalization, an average of 1 week
PACU phase 1 recovery time	The time to attain pain control and stable respiratory, hemodynamic, and neurologic status after surgery.	1 day
Hospital length of stay	The number of days between hospital admission and hospital discharge	length of hospitalization, an average of 1 week

Collaborators and Investigators

• Sponsor: Oregon Health and Science University
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Brandon M Togioka, MD, Oregon Health and Science University

Study record dates

Study Major Dates

• Study Start (Actual): March 16, 2021
• Primary Completion (Actual): June 14, 2023
• Study Completion (Actual): August 13, 2023

Study Registration Dates

• First Submitted: September 5, 2020
• First Submitted That Met QC Criteria: September 5, 2020
• First Posted (Actual): September 14, 2020

Study Record Updates

• Last Update Posted (Actual): July 29, 2024
• Last Update Submitted That Met QC Criteria: July 25, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Keywords: Gastric emptying; neuromuscular blockade; sugammadex; neostigmine
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Intestinal Diseases; Postoperative Complications; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Cholinergic Agents; Enzyme Inhibitors; Cholinesterase Inhibitors; Parasympathomimetics; Neostigmine
• Other Study ID Numbers: 21895; MISP #60224 (Other Grant/Funding Number: Merck & Co., INC.)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes