SANICS II Trial: Stimulation of the Autonomic Nervous System in Colorectal Surgery by Perioperative Nutrition
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
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
Postoperative Ileus, Anastomotic Leak
postoperative ileus, anastomotic leak, colorectal surgery, inflammation
Catharina Ziekenhuis Eindhoven
Misha D.P. Luyer, Danone Research, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA), ZonMw: The Netherlands Organisation for Health Research and Development, Fonds NutsOhra
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.
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.
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.
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.