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

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

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).

Study Overview

• Status: Completed
• Conditions: Anastomotic Leak; Postoperative Ileus
• Intervention / Treatment: Dietary supplement: standard; Dietary supplement: enriched enteral nutrition

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 280
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Denmark
  • Randers, Denmark, 8930
    • Regionshospitalet Randers
  • Viborg, Denmark, 8800
    • Regionshospitalet Viborg
• Netherlands
  • Helmond, Netherlands, 5707HA
    • Elkerliek Ziekenhuis
  • Noord-Brabant
    • Eindhoven, Noord-Brabant, Netherlands, 5623EJ
      • Catharina Ziekenhuis
    • Veldhoven, Noord-Brabant, Netherlands, 5504DB
      • Maxima Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: standard; standard of care	Dietary supplement: standard; standard of care
Experimental: enriched enteral nutrition; enriched enteral tube feeding 1.5ml/ minute perioperative	Dietary supplement: enriched enteral nutrition; enriched enteral tube feeding perioperative

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Misha D.P. Luyer
• Collaborators: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA); ZonMw: The Netherlands Organisation for Health Research and Development; Danone Research; Fonds NutsOhra
• Investigators: Principal Investigator: Misha DP Luyer, MD PhD, Catharina Ziekenhuis Eindhoven

Publications and helpful links

General Publications

• Lubbers T, Luyer MD, de Haan JJ, Hadfoune M, Buurman WA, Greve JW. Lipid-rich enteral nutrition reduces postoperative ileus in rats via activation of cholecystokinin-receptors. Ann Surg. 2009 Mar;249(3):481-7. doi: 10.1097/SLA.0b013e318194d187.
• Luyer MD, Greve JW, Hadfoune M, Jacobs JA, Dejong CH, Buurman WA. Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve. J Exp Med. 2005 Oct 17;202(8):1023-9. doi: 10.1084/jem.20042397. Epub 2005 Oct 10.
• Boelens PG, Heesakkers FF, Luyer MD, van Barneveld KW, de Hingh IH, Nieuwenhuijzen GA, Roos AN, Rutten HJ. Reduction of postoperative ileus by early enteral nutrition in patients undergoing major rectal surgery: prospective, randomized, controlled trial. Ann Surg. 2014 Apr;259(4):649-55. doi: 10.1097/SLA.0000000000000288.
• Lubbers T, Kox M, de Haan JJ, Greve JW, Pompe JC, Ramakers BP, Pickkers P, Buurman WA. Continuous administration of enteral lipid- and protein-rich nutrition limits inflammation in a human endotoxemia model. Crit Care Med. 2013 May;41(5):1258-65. doi: 10.1097/CCM.0b013e31827c0a17.
• Luyer MD, Habes Q, van Hak R, Buurman W. Nutritional stimulation of the autonomic nervous system. World J Gastroenterol. 2011 Sep 14;17(34):3859-63. doi: 10.3748/wjg.v17.i34.3859.
• Luyer MD, Derikx JP, Beyaert R, Hadfoune M, van Kuppevelt TH, Dejong CH, Heineman E, Buurman WA, Greve JW. High-fat nutrition reduces hepatic damage following exposure to bacterial DNA and hemorrhagic shock. J Hepatol. 2009 Feb;50(2):342-50. doi: 10.1016/j.jhep.2008.08.025. Epub 2008 Nov 8.
• Luyer MD, Buurman WA, Hadfoune M, Jacobs JA, Dejong CH, Greve JW. High-fat enteral nutrition reduces endotoxin, tumor necrosis factor-alpha and gut permeability in bile duct-ligated rats subjected to hemorrhagic shock. J Hepatol. 2004 Sep;41(3):377-83. doi: 10.1016/j.jhep.2004.04.026.
• Luyer MD, Jacobs JA, Vreugdenhil AC, Hadfoune M, Dejong CH, Buurman WA, Greve JW. Enteral administration of high-fat nutrition before and directly after hemorrhagic shock reduces endotoxemia and bacterial translocation. Ann Surg. 2004 Feb;239(2):257-64. doi: 10.1097/01.sla.0000108695.60059.80.
• Peters EG, Smeets BJJ, Nors J, Back CM, Funder JA, Sommer T, Laurberg S, Love US, Leclercq WKG, Slooter GD, de Vries Reilingh TS, Wegdam JA, Nieuwenhuijzen GAP, Hiligsmann M, Buise MP, Buurman WA, de Jonge WJ, Rutten HJT, Luyer MDP. Perioperative lipid-enriched enteral nutrition versus standard care in patients undergoing elective colorectal surgery (SANICS II): a multicentre, double-blind, randomised controlled trial. Lancet Gastroenterol Hepatol. 2018 Apr;3(4):242-251. doi: 10.1016/S2468-1253(18)30031-1. Epub 2018 Feb 14.
• Peters EG, De Jonge WJ, Smeets BJ, Luyer MD. The contribution of mast cells to postoperative ileus in experimental and clinical studies. Neurogastroenterol Motil. 2015 Jun;27(6):743-9. doi: 10.1111/nmo.12579.
• Peters EG, Smeets BJ, Dekkers M, Buise MD, de Jonge WJ, Slooter GD, Reilingh TS, Wegdam JA, Nieuwenhuijzen GA, Rutten HJ, de Hingh IH, Hiligsmann M, Buurman WA, Luyer MD. The effects of stimulation of the autonomic nervous system via perioperative nutrition on postoperative ileus and anastomotic leakage following colorectal surgery (SANICS II trial): a study protocol for a double-blind randomized controlled trial. Trials. 2015 Jan 27;16:20. doi: 10.1186/s13063-014-0532-x.

Study record dates

Study Major Dates

• Study Start: August 1, 2014
• Primary Completion (Actual): March 20, 2017
• Study Completion (Actual): December 31, 2017

Study Registration Dates

• First Submitted: June 25, 2014
• First Submitted That Met QC Criteria: June 25, 2014
• First Posted (Estimate): June 26, 2014

Study Record Updates

• Last Update Posted (Actual): September 19, 2019
• Last Update Submitted That Met QC Criteria: August 14, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: anastomotic leak; colorectal surgery; inflammation; postoperative ileus
• Additional Relevant MeSH Terms: Pathologic Processes; Postoperative Complications; Anastomotic Leak
• Other Study ID Numbers: NL45640.060.13

Drug and device information, study documents

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