Impact of Ambulatory Physiological Stimulation of the Efferent Limb Prior to Ileostomy Closure on Colorectal Microbiota Composition and Histopathological Findings

Official title

The STIMIC Trial: A Multicenter Randomized Control Trial Evaluating the Impact of Ambulatory Physiological Stimulation of the Efferent Limb Prior to Ileostomy Closure on Colorectal Microbiota Composition and Histopathological Findings

Overview

BACKGROUND Loop ileostomies are a type of stoma frequently used to protect high-risk colorectal anastomoses (surgical reconnection of the intestines), for example following rectal cancer resection. Temporary diversion of intestinal transit does not reduce the risk of anastomotic failure, but it does lower the morbidity and mortality associated with potential pelvic sepsis. Unfortunately, a second surgical procedure is required to restore intestinal continuity, and this carries its own risk of complications, the most common being postoperative ileus (temporary paralysis of bowel motility associated with abdominal distension, absence of bowel movements, nausea, and vomiting), which occurs in up to 20% of cases. Several strategies have been proposed to reduce this problem, including stimulation of the efferent limb of the ileostomy (the part that is connected to the unused colon). This intervention consists of instilling a substance through the efferent limb of the ileostomy into the colon, simulating natural intestinal transit. It emerged as a harmless alternative aimed at reversing changes in the excluded colon in preparation for restoration of intestinal continuity. Several Spanish studies have investigated this technique, concluding that it is safe and significantly reduces the rate of postoperative ileus, thereby shortening hospital stay. Regarding the mechanism by which this intervention may be effective, there are studies investigating the changes that occur during diversion of intestinal transit: 1. Histopathology: reduced muscular contractility and the presence of intestinal villi in the efferent intestinal limb and excluded colon, which improve once intestinal flow is restored. 2. Microbiome: significant loss of microbiota in the defunctionalized colon, which progressively recovers with natural intestinal transit and reintroduction of a fiber-rich diet. Structural and microbiota-related changes favor the development of diversion colitis, a condition associated with erratic bowel habits once intestinal transit is restored. In an attempt to reverse this condition, several products have been tested for stimulation of the efferent limb of the ileostomy: probiotics, short chain fatty acids, saline solution with a thickening agent, and the patient's own intestinal contents, a well-tolerated and effective technique, in some cases superior to saline-based alternatives. Overall, the available evidence is of low quality due to the limited number of patients studied and protocol variability. For this reason, we propose the implementation of a protocol for stimulation of the distal ileostomy limb prior to ileostomy closure, either with saline solution and thickening agent (the most widely described technique in the literature) or physiological stimulation using the patient's own intestinal contents. The protocol consists of several sessions in which the instilled volume is progressively increased. This intervention will be performed on an outpatient basis, once daily, during the two weeks prior to surgery. This process promotes the onset of bowel movements through the anus, which progressively become more formed and less frequent, approaching a more normal bowel habit. Only minor adverse effects have been described with this technique, including cramp-like abdominal pain in 27.6% of sessions. Recently, a nationwide study confirmed the favorable clinical outcomes following distal ileostomy limb stimulation before ileostomy closure. However, to our knowledge, no studies have evaluated its effect on intestinal microbiota. HYPOTHESIS Distal limb stimulation of the ileostomy before its closure helps in the recovery of the colorectal microbiome and tissue. This associates with lower postoperative complications, specially postoperative ileus. OBJECTIVES To gain knowledge regarding changes in intestinal microbiota composition before and after stimulation, in order to better understand recovery of intestinal function following this procedure. We will also analyze outcomes after ileostomy closure following efferent limb stimulation, determining the incidence of postoperative complications, particularly postoperative ileus. METHODOLOGY Patients will be randomly assigned to one of three groups: 1. Control (no intervention other than the usual preoperative protocol) 2. Stimulation with serum and thickener 3. Stimulation with own stoma output Samples will be collected in all patients: 1. Stoma output 2. Stool, before stimulation, if performed 3. Stool, after stimulation, if performed 4. Stool, a month after surgery For a group of patients, the ones recruited at Hospital Clínic, rectal biopsies will also be collected before and after stimulation, to compare the effect of the treatment in the colonic tissue. We will collect clinical data during the whole process regarding postoperative complications.

Interventions

• Other Serum stimulation
  The intervention has been described in previous studies, but the investigation of the microbiome changes associated with the obtained clinical results hasn't been described to date. Also, a study with three arms hasn't been published to date.
• Other Physiological stimulation
  The intervention has been described in previous studies, but the investigation of the microbiome changes associated with the obtained clinical results hasn't been described to date. Also, a study with three arms hasn't been published to date.

Primary outcome measures

• Changes in colorectal microbiome before and after efferent limb stimulation prior to stoma closure. [Time frame: From enrollment to the end of follow-up at 3 months.]
• Changes in colorectal tissue before and after efferent limb stimulation prior to stoma closure. [Time frame: From the time of first biopsy (before stimulation) to the second one (surgery day).]

Secondary outcome measures (3)

• Postoperative complications after stoma closure. [Time frame: From the surgery (ileostomy closure) to 30 days follow-up.]
• Functional outcomes after efferent limb stimulation (LARS score) [Time frame: From enrollment to the end of follow-up a 3 months.]
• Functional outcomes after efferent limb stimulation (Vaizey score) [Time frame: From enrollment to the end of follow-up at 3 months.]

Eligibility criteria

Inclusion criteria

• Patients 18 yo and older, with a loop ileostomy after colorectal surgery for malignant or benign disease and a barium enema that rules out colorectal anastomotic leak or stenosis.
• Patients must be self-sufficient in their stoma care or dispose of assistance by a family member or healthcare provider.
• Patients must reside no further than 50km from the hospital and dispose of postoperative home-assistance by a family member or healthcare provider.

Exclusion criteria

• Patients with a terminal ileostomy or a closed distal limb, inaccesible to preoperative stimulation.
• Patients with the diagnosis of inflammatory bowel disease.
• Patients incapable of comprehending or signing the informed consent.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Double blind

Primary purpose

Basic science

Study locations

Center list to be confirmed — check the primary protocol.

Publications

• Charbonneau J, Morin G, Pare XG, Frigault J, Drolet S, Bouchard A, Rouleau-Fournier F, Bouchard P, Thibault C, Letarte F. Loop Ileostomy Closure as a 23-Hour Stay Procedure With Preoperative Efferent Limb Enteral Stimulation: A Randomized Controlled Trial. Dis Colon Rectum. 2024 Mar 1;67(3):466-475. doi: 10.1097/DCR.0000000000003111. Epub 2023 Nov 16. PMID 37994456
• Bracey E, Chave H, Agombar A, Sleight S, Dukes S, Bryan S, Branagan G. Ileostomy closure in an enhanced recovery setting. Colorectal Dis. 2015 Oct;17(10):917-21. doi: 10.1111/codi.12989. PMID 25950922
• Kim MJ, Park JW, Lee MA, Lim HK, Kwon YH, Ryoo SB, Park KJ, Jeong SY. Two dominant patterns of low anterior resection syndrome and their effects on patients' quality of life. Sci Rep. 2021 Feb 11;11(1):3538. doi: 10.1038/s41598-021-82149-9. PMID 33574345
• Matthiessen P, Hallbook O, Rutegard J, Simert G, Sjodahl R. Defunctioning stoma reduces symptomatic anastomotic leakage after low anterior resection of the rectum for cancer: a randomized multicenter trial. Ann Surg. 2007 Aug;246(2):207-14. doi: 10.1097/SLA.0b013e3180603024. PMID 17667498
• Arredondo J, Uriz A, Oliva I, Martin JI, Iglesias CN, Choolani E, Valle A, Rivera J, Jeri-McFarlane S, Romero JM, Gonzalez C, Alvarellos A, Tasende M, Gomez L, Lazaro L, Montcusi B, Tejedor P, Trujillo-Diaz J, de la Hermosa AR, Baixauli J, Nunez-Cordoba JM, Aliseda D; ILEOSTIM Trial Group. The ILEOSTIM trial: A multicentre randomised controlled trial evaluating the impact of efferent loop stimulat PMID 42092745
• Liu Z, Fang L, Lv L, Niu Z, Hou L, Chen D, Zhou Y, Guo D. Self-administered succus entericus reinfusion before ileostomy closure improves short-term outcomes. BMC Surg. 2021 Dec 28;21(1):440. doi: 10.1186/s12893-021-01444-4. PMID 34961502
• Xia F, Zou Y, Zhang Q, Wu J, Sun Z. A novel nomogram to predict low anterior resection syndrome (LARS) after ileostomy reversal for rectal cancer patients. Eur J Surg Oncol. 2023 Feb;49(2):452-460. doi: 10.1016/j.ejso.2022.10.015. Epub 2022 Oct 23. PMID 37406079
• Vogel I, Reeves N, Tanis PJ, Bemelman WA, Torkington J, Hompes R, Cornish JA. Impact of a defunctioning ileostomy and time to stoma closure on bowel function after low anterior resection for rectal cancer: a systematic review and meta-analysis. Tech Coloproctol. 2021 Jul;25(7):751-760. doi: 10.1007/s10151-021-02436-5. Epub 2021 Apr 1. PMID 33792822

Identifiers

NCT: NCT07640113 · HCB/2026/0615

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗