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Sugammadex To IMprove Bowel Function

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

Status
Completed
Phases
Phase 4
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT04546672
Acronym
STIM_Bowel
Enrollment
120
Registered
2020-09-14
Start date
2021-03-16
Completion date
2023-08-13
Last updated
2024-07-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Bowel Dysfunction, Neuromuscular Blockade, Postoperative Complications

Keywords

sugammadex, neostigmine, Gastric emptying, neuromuscular blockade

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.

Interventions

DRUGSugammadex

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

DRUGNeostigmine

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

Sponsors

Merck Sharp & Dohme LLC
CollaboratorINDUSTRY
Oregon Health and Science University
Lead SponsorOTHER

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)

Intervention model description

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

Eligibility

Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No

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

Design outcomes

Primary

MeasureTime frameDescription
Gastric Emptying150 minutes after neuromuscular reversalGastric emptying as assessed by the area under the paracetamol concentration-time curve by trapezoidal approximation (AUC)

Secondary

MeasureTime frameDescription
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. 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.
Number of Participants With Gastrointestinal Complications30 days after surgeryGastrointestinal 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.
PACU Recovery Time1 dayThe time to attain pain control and stable respiratory, hemodynamic, and neurologic status after surgery.
Reversal Time to First Bowel Movementlength hospitalization, an average of 1 weekThe time from reversal of neuromuscular blockade to first bowel movement
Reversal Time to Discharge Orderlength of hospitalization, an average of 1 weekThe number of days between reversal of neuromuscular blockade and time of discharge order

Countries

United States

Participant flow

Participants by arm

ArmCount
Sugammadex
Sugammadex 2 mg/kg IV once at the end of surgery 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
60
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 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
60
Total120

Baseline characteristics

CharacteristicSugammadexTotalNeostigmine
Age, Continuous57 years
STANDARD_DEVIATION 13.2
56.4 years
STANDARD_DEVIATION 13.5
55.9 years
STANDARD_DEVIATION 14
ASA Physical Status
1-normal health
0 Participants2 Participants2 Participants
ASA Physical Status
2-mild systemic disease
22 Participants47 Participants25 Participants
ASA Physical Status
3-severe systemic disease
38 Participants70 Participants32 Participants
ASA Physical Status
4-severe systemic disease that is a constant threat to life
0 Participants1 Participants1 Participants
Body Mass Index29.2 kg/m^2
STANDARD_DEVIATION 9.6
28.6 kg/m^2
STANDARD_DEVIATION 8.2
28.1 kg/m^2
STANDARD_DEVIATION 6.4
Ethnicity (NIH/OMB)
Hispanic or Latino
1 Participants3 Participants2 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
59 Participants117 Participants58 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
0 Participants0 Participants0 Participants
Race (NIH/OMB)
American Indian or Alaska Native
1 Participants2 Participants1 Participants
Race (NIH/OMB)
Asian
0 Participants3 Participants3 Participants
Race (NIH/OMB)
Black or African American
1 Participants2 Participants1 Participants
Race (NIH/OMB)
More than one race
1 Participants1 Participants0 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants0 Participants0 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants0 Participants0 Participants
Race (NIH/OMB)
White
57 Participants112 Participants55 Participants
Region of Enrollment
United States
60 participants120 participants60 participants
Sex: Female, Male
Female
29 Participants55 Participants26 Participants
Sex: Female, Male
Male
31 Participants65 Participants34 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
0 / 600 / 60
other
Total, other adverse events
10 / 6013 / 60
serious
Total, serious adverse events
2 / 605 / 60

Outcome results

Primary

Gastric Emptying

Gastric emptying as assessed by the area under the paracetamol concentration-time curve by trapezoidal approximation (AUC)

Time frame: 150 minutes after neuromuscular reversal

ArmMeasureValue (MEAN)Dispersion
SugammadexGastric Emptying1120 log(ng*ml-1)*minStandard Deviation 122
NeostigmineGastric Emptying1130 log(ng*ml-1)*minStandard Deviation 117
p-value: 0.5895% CI: [-31.1, 55.4]t-test, 2 sided
Secondary

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.

Time frame: 30 days after surgery

ArmMeasureValue (COUNT_OF_PARTICIPANTS)
SugammadexNumber of Participants With Gastrointestinal Complications10 Participants
NeostigmineNumber of Participants With Gastrointestinal Complications19 Participants
p-value: 0.08795% CI: [0.9, 6.2]Fisher Exact
Secondary

PACU Recovery Time

The time to attain pain control and stable respiratory, hemodynamic, and neurologic status after surgery.

Time frame: 1 day

ArmMeasureValue (MEAN)Dispersion
SugammadexPACU Recovery Time115 minutesStandard Deviation 50.3
NeostigminePACU Recovery Time108 minutesStandard Deviation 56.4
p-value: 0.4895% CI: [-26.4, 12.6]t-test, 2 sided
Secondary

Reversal Time to Discharge Order

The number of days between reversal of neuromuscular blockade and time of discharge order

Time frame: length of hospitalization, an average of 1 week

ArmMeasureValue (MEAN)Dispersion
SugammadexReversal Time to Discharge Order4.8 daysStandard Deviation 4.9
NeostigmineReversal Time to Discharge Order7.82 daysStandard Deviation 19.8
p-value: 0.2795% CI: [-2.2, 8.3]t-test, 2 sided
Secondary

Reversal Time to First Bowel Movement

The time from reversal of neuromuscular blockade to first bowel movement

Time frame: length hospitalization, an average of 1 week

ArmMeasureValue (MEAN)Dispersion
SugammadexReversal Time to First Bowel Movement44.3 hoursStandard Deviation 33.8
NeostigmineReversal Time to First Bowel Movement61 hoursStandard Deviation 43
p-value: 0.0295% CI: [2.3, 31.1]t-test, 2 sided
Secondary

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.

Time frame: 30 minutes after the administration of reversal drug.

ArmMeasureValue (MEAN)Dispersion
SugammadexTime in Minutes to Reach Train of Four (TOF) Ratio ≥ 0.9 After the Administration of Reversal Drug.5.2 minutesStandard Deviation 6.3
NeostigmineTime in Minutes to Reach Train of Four (TOF) Ratio ≥ 0.9 After the Administration of Reversal Drug.17.5 minutesStandard Deviation 10.1
p-value: <0.00195% CI: [9.2, 15.4]t-test, 2 sided

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026