STIM_Bowel: Sugammadex To IMprove Bowel Function

Sponsor

Oregon Health and Science University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04546672

Collaborator

Merck Sharp & Dohme LLC (Industry)

120

Enrollment

Location

Arms

21.5

Anticipated Duration (Months)

5.6

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Bowel Dysfunction Postoperative Complications Neuromuscular Blockade	Drug: Sugammadex Drug: Neostigmine	Phase 4

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 Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Assessor-blinded, randomized, controlled, single center, parallel design trial with patient maskingAssessor-blinded, randomized, controlled, single center, parallel design trial with patient masking

Masking:

Triple (Participant, Investigator, Outcomes Assessor)

Primary Purpose:

Prevention

Official 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

Actual Study Start Date :

Mar 16, 2021

Anticipated Primary Completion Date :

Jun 30, 2022

Anticipated Study Completion Date :

Dec 31, 2022

Arms and Interventions

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: Org 25969 Bridion
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: Prostigmin Vagostigmin

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:

Org 25969

Bridion

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:

Prostigmin

Vagostigmin

Outcome Measures

Primary Outcome Measures

Gastric emptying [0, 15, 30, 45, 60, 90, 120, and 150 minutes after neuromuscular reversal]
Gastric emptying as assessed by the area under the paracetamol concentration-time curve by trapezoidal approximation (AUC)

Secondary Outcome Measures

Time in minutes to reach train of four (TOF) ratio ≥ 0.9 after the administration of reversal drug. [30 minutes 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.

Other Outcome Measures

Gastrointestinal complications [60 days after surgery]
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.
Bowel movement [length hospitalization, an average of 1 week]
The time to first bowel movement after surgery
PACU phase 1 recovery time [1 day]
The time to attain pain control and stable respiratory, hemodynamic, and neurologic status after surgery.
Hospital length of stay [length of hospitalization, an average of 1 week]
The number of days between hospital admission and hospital discharge

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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