SANICS II Trial: Stimulation of the Autonomic Nervous System in Colorectal Surgery by Perioperative Nutrition

Study Overview
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Brief Summary
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The main objective is to investigate the effects of perioperative nutrition on postoperative ileus and anastomotic leakage in patients undergoing colorectal surgery. Perioperative enteral nutrition is compared to the standard of care (fasting perioperatively).

Detailed Description
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Postoperative ileus (POI) and anastomotic leakage (AL) are important clinical determinants of short-term morbidity and mortality following colorectal surgery. Importantly, AL is also a risk factor for local recurrence of colorectal cancer and has a significant impact on disease-free and overall survival. It is therefore believed that improving postoperative outcome following colorectal surgery will also improve long-term oncological outcomes regarding overall survival and tumour recurrence. POI is a common complication after colorectal surgery that causes discomfort for the patient but also leads to a prolonged hospital length of stay and increasing health care costs. For POI it is believed that formation of an inflammatory infiltrate in the muscular layers of the intestine following bowel manipulation during surgery leads to a decreased gastrointestinal motility. In recent years the investigators have demonstrated in experimental models that administration of enteral nutrition modulates the inflammatory response via the autonomic nervous system by release of cholecystokinin (CCK). Composition of the enteral nutrition and timing of administration are both essential for the magnitude of effect. For the most optimal effect, nutrition is given with a higher fraction of lipids and protein and is administered just before, during and directly after the inciting event. In this way, the inflammatory response is optimally dampened via release of CCK. In an experimental study has been shown that such a lipid-enriched enteral nutrition reduces systemic inflammation and postoperative ileus in a CCK-dependent manner when given just before and directly after bowel manipulation. Next, the investigators performed a study in healthy volunteers in which the effect of continuous low volume enteral nutrition was investigated on inflammatory parameters in a human endotoxemia model. In this study was shown that lipid enriched nutrition reduced the inflammatory response upon endotoxemia in man. Also in a clinical setting the investigators have shown that enteral nutrition reduces inflammation and postoperative ileus. In a randomized controlled trial the investigators have shown that enteral nutrition early after colorectal surgery reduced POI. Furthermore, in a model of sham-feeding using chewing gum was shown that inflammation and postoperative ileus were reduced following colorectal surgery. Interestingly, both clinical studies with sham feeding and early enteral nutrition revealed a yet unaccountable effect on anastomotic leakage. Evidence on the relation between POI and anastomotic leakage is scarce but has great impact. It seems that an early intervention with enteral nutrition shortly before, during and early after colorectal surgery may reduce inflammation and reduce important determinants in postoperative morbidity as POI and anastomotic leakage. All patients will receive a self-migrating nasojejunal tube one day before surgery. The position of the nasojejunal tube is verified by means of an X-ray at the night before surgery. Preoperatively, patients receive standard of care with a fast for solid (oral) food of 6 hours and a (oral) fluid fast for 2 hours before administration. Three hours before surgery the pump is started to administer nutrition in standardized amounts. Enriched enteral nutrition (produced by Danone research) is administered via a programmed Flocare enteral feeding pump. The pump is connected to the opaque branched system that is connected both to the nasojejunal tube and to a sealed container. Patients are either allocated to the experimental group, in which the blinded branched system leads the enteral nutrition via the nasojejunal tube to the patient. Via this route, the patients in the experimental group will receive the enteral nutrition just before, during and directly after surgery. In patients allocated to the control group, the blinded branched system leads the enteral nutrition to the container. Consequently, when the feeding pump starts just before surgery, patients in the control group do not receive the nutrition. In both groups, the pump with enteral nutrition is stopped 6 hours after surgery and normal intake is resumed. Based on previous results a power calculation is performed. For POI a sample size of at least 91 patients per group is needed based on a power of 0.8 and an alpha of 0.05. For AL a reduction of AL of at least 75% was observed in the previous clinical studies. Using a power of 0.8 and a drop-out percentage of 5% a total of 140 patients are needed per group. Since perioperative nutrition is a new concept, a safety analysis is performed after inclusion of 40 patients in which feasibility and safety of preoperative nutrition are assessed. The effect size is determined based on previous studies and is substantial. Considering the size of the effect, an interim-analysis will be performed after inclusion of 140 patients. All analyses will be done according to the intention-to-treat approach in which all randomized patients are included, regardless of adherence to the study protocol. Occurrences of the primary and secondary endpoints are compared between the treatment groups. Results are presented as risk ratios with corresponding 95% confidence intervals. A two-tailed P < 0.05 is considered statistically significant. To compare the groups, the data will be tested for normal distribution and an unpaired T-test will be performed when appropriate, otherwise the Mann-Whitney U or Chi-square tests. SPSS (Statistical Package for the Social Sciences version 20) will be used to analyze the data. The investigators respect the Dutch Scientific Code of conduct with regard to collection and storage of our data. The investigators hereby mind the criteria of retrievability, accessibility and interchangeability of the data. The investigators will obtain written informed consent from all patients, in which is stated that their records will be used and saved for research purposes for a minimum of 15 years. Anonymity and confidentiality of data will be guaranteed compliant with CBP (Commission Protection of Personal Data) guidelines. Thus, all variables will be registered anonymously, but via a secured code, personally identifiable information can be retrieved. The investigators verified completeness of patient Data Management Strategy via the Data Archiving and Networked Services checklist. Rough data will be stored in a digital archive, with appended description, to interpret the data.

Official Title
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SANICS II Trial: A Multicenter Prospective Double-blind Randomized Controlled Trial Investigating the Effect of Stimulation of the Autonomic Nervous System in Colorectal Surgery by Perioperative Nutrition

Conditions
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Postoperative Ileus, Anastomotic Leak

Intervention / Treatment
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* Dietary Supplement: enriched enteral nutrition
* Dietary Supplement: standard


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients that undergo elective surgical resection of the colon or rectum with primary anastomosis. written informed consent age >18 years Exclusion Criteria: use of medication that disrupts acetylcholine metabolism steroid use previous gastric or esophageal resection peritoneal metastases found during surgery ileostomy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: standard<br>standard of care | Dietary Supplement: standard<br>* standard of care<br>|
| Experimental: enriched enteral nutrition<br>enriched enteral tube feeding 1.5ml/ minute perioperative | Dietary Supplement: enriched enteral nutrition<br>* enriched enteral tube feeding perioperative<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Developing Postoperative Ileus | number of patients with absence of flatus or stool passage and inability to tolerate a regular oral diet between surgery and postoperative day 4 | up to 3 weeks after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anastomotic Leakage | number of patients developing anastomotic leakage | up to 6 weeks after surgery | 
| Aspiration Pneumonia | number of patients developing aspiration pneumonia | up to 3 week after surgery | 
| Gastric Motility | Percent change in Gastric Antral Area, assessed by Ultrasound of the Gastric Antrum Following a Standardized Meal | 3 days after surgery | 
| Functional Recovery | Length of functional recovery in days, Functional recovery was defined as postoperative patients not receiving intravenous fluid who have adequate pain control, restoration ofindependent mobility, sufficient caloric intake, and no signs of active infection | up to 6 weeks after surgery | 
| C-reactive Protein (CRP) | the inflammatory response measured systemically (in blood): C-reactive protein (CRP) | up to 48 hours after surgery | 
| Number of Patients Needing Additional Surgical, Radiological or Endoscopic Interventions | number of patients needing additional surgical, radiological or endoscopic interventions: All surgical complications are classified using the Clavien-Dindo classification. patients with a Clavien Dindo grade IIIa, IIIb, IVa, IVb, V complication had a surgical, radiological or endoscopic intervention. | up to 6 weeks after surgery | 
| Number of Patients Needing ICU Admission | number of patients needing ICU admission after surgery | up to 6 weeks after surgery | 
| Health-related Quality of Life | Global Quality of life on a scale ranging from 0 to 100, with higher scores indicating higher level of functioning. The EORTC QLQ C-30 questionnaires are used | 6 months after surgery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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postoperative ileus, anastomotic leak, colorectal surgery, inflammation