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

• Sponsor: Misha D.P. Luyer (Other)
• Overall Status: Completed
• CT.gov ID: NCT02175979
• Collaborator: Danone Research (Industry), Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other), ZonMw: The Netherlands Organisation for Health Research and Development (Other), Fonds NutsOhra (Other)
• Enrollment: 280
• Locations: 5
• Arms: 2
• Duration (Months): 41
• Patients Per Site: 56
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

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).

Condition or Disease	Intervention/Treatment	Phase
Postoperative Ileus; Anastomotic Leak	Dietary Supplement: enriched enteral nutrition; Dietary Supplement: standard	N/A

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 Design

• Study Type: Interventional
• Actual Enrollment: 280 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: Aug 1, 2014
• Actual Primary Completion Date: Mar 20, 2017
• Actual Study Completion Date: Dec 31, 2017

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of Patients Developing Postoperative Ileus [up to 3 weeks after surgery]

   number of patients with absence of flatus or stool passage and inability to tolerate a regular oral diet between surgery and postoperative day 4

Secondary Outcome Measures

1. Anastomotic Leakage [up to 6 weeks after surgery]

   number of patients developing anastomotic leakage

2. Aspiration Pneumonia [up to 3 week after surgery]

   number of patients developing aspiration pneumonia

3. Gastric Motility [3 days after surgery]

   Percent change in Gastric Antral Area, assessed by Ultrasound of the Gastric Antrum Following a Standardized Meal

4. Functional Recovery [up to 6 weeks after surgery]

   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

5. C-reactive Protein (CRP) [up to 48 hours after surgery]

   the inflammatory response measured systemically (in blood): C-reactive protein (CRP)

6. Number of Patients Needing Additional Surgical, Radiological or Endoscopic Interventions [up to 6 weeks after surgery]

   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.

7. Number of Patients Needing ICU Admission [up to 6 weeks after surgery]

   number of patients needing ICU admission after surgery

8. Health-related Quality of Life [6 months after surgery]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Regionshospitalet Randers	Randers		Denmark	8930
2	Regionshospitalet Viborg	Viborg		Denmark	8800
3	Catharina Ziekenhuis	Eindhoven	Noord-Brabant	Netherlands	5623EJ
4	Maxima Medical Center	Veldhoven	Noord-Brabant	Netherlands	5504DB
5	Elkerliek Ziekenhuis	Helmond		Netherlands	5707HA

Sponsors and Collaborators

• 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

Investigators

• Principal Investigator: Misha DP Luyer, MD PhD, Catharina Ziekenhuis Eindhoven

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 4, 2015

More Information

Publications

• 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.
• 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, 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, 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, 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. Epub 2005 Oct 10.
• 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, 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.

• Responsible Party: Misha D.P. Luyer, dr. M.D.P. Luyer, Catharina Ziekenhuis Eindhoven
• ClinicalTrials.gov Identifier: NCT02175979
• Other Study ID Numbers: NL45640.060.13
• First Posted: Jun 26, 2014
• Last Update Posted: Sep 19, 2019
• Last Verified: Aug 1, 2019

• Keywords provided by Misha D.P. Luyer, dr. M.D.P. Luyer, Catharina Ziekenhuis Eindhoven: postoperative ileus; anastomotic leak; colorectal surgery; inflammation
• Additional relevant MeSH terms: Anastomotic Leak

Study Results

Participant Flow

Arm/Group Title	Standard	Enriched Enteral Nutrition
Arm/Group Description	standard of care	enriched enteral tube feeding 1.5ml/ minute perioperative
Period Title: Overall Study
STARTED	140	140
COMPLETED	133	132
NOT COMPLETED	7	8

Baseline Characteristics

Arm/Group Title	Standard	Enriched Enteral Nutrition	Total
Arm/Group Description	standard of care standard: standard of care	enriched enteral tube feeding 1.5ml/ minute perioperative enriched enteral nutrition: enriched enteral tube feeding perioperative	Total of all reporting groups
Overall Participants	133	132	265
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	68	69	68
Sex: Female, Male (Count of Participants)
Female	55 41.4%	52 39.4%	107 40.4%
Male	78 58.6%	80 60.6%	158 59.6%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Netherlands	101 75.9%	103 78%	204 77%
Denmark	32 24.1%	29 22%	61 23%
BMI (kg/m^2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg/m^2]	26	25.8	25.8
smoking currently (Count of Participants)
Count of Participants [Participants]	17 12.8%	14 10.6%	31 11.7%
use of alcohol currently (Count of Participants)
Count of Participants [Participants]	92 69.2%	100 75.8%	192 72.5%
use of neoadjuvant therapy for resection (Count of Participants)
Count of Participants [Participants]	20 15%	27 20.5%	47 17.7%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard	Enriched Enteral Nutrition
Arm/Group Description	standard of care	enriched enteral tube feeding
Measure Participants	133	132
Count of Participants [Participants]	29 21.8%	37 28%

2. Secondary Outcome

Title	Anastomotic Leakage
Description	number of patients developing anastomotic leakage
Time Frame	up to 6 weeks after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard	Enriched Enteral Nutrition
Arm/Group Description	standard of care	enriched enteral tube feeding
Measure Participants	133	132
Count of Participants [Participants]	11 8.3%	12 9.1%

3. Secondary Outcome

Title	Aspiration Pneumonia
Description	number of patients developing aspiration pneumonia
Time Frame	up to 3 week after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard	Enriched Enteral Nutrition
Arm/Group Description	standard of care	enriched enteral tube feeding
Measure Participants	133	132
Count of Participants [Participants]	0 0%	0 0%

4. Secondary Outcome

Title	Gastric Motility
Description	Percent change in Gastric Antral Area, assessed by Ultrasound of the Gastric Antrum Following a Standardized Meal
Time Frame	3 days after surgery

Outcome Measure Data

Analysis Population Description

not every patients was fit to have the standard meal or ultrasound, therefore less antral measurements were executed.

Arm/Group Title	Standard	Enriched Enteral Nutrition
Arm/Group Description	standard of care	enriched enteral tube feeding
Measure Participants	109	106
Median (Inter-Quartile Range) [percentage of decrease in antral area]	-32.7	-31.4

5. Secondary Outcome

Title	Functional Recovery
Description	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
Time Frame	up to 6 weeks after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard	Enriched Enteral Nutrition
Arm/Group Description	standard of care	enriched enteral tube feeding
Measure Participants	133	132
Median (Inter-Quartile Range) [days]	5	5

6. Secondary Outcome

Title	C-reactive Protein (CRP)
Description	the inflammatory response measured systemically (in blood): C-reactive protein (CRP)
Time Frame	up to 48 hours after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard	Enriched Enteral Nutrition
Arm/Group Description	standard of care	enriched enteral tube feeding
Measure Participants	113	114
Median (Inter-Quartile Range) [mg/L]	150	164

7. Secondary Outcome

Title	Number of Patients Needing Additional Surgical, Radiological or Endoscopic Interventions
Description	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.
Time Frame	up to 6 weeks after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard	Enriched Enteral Nutrition
Arm/Group Description	standard of care	enriched enteral tube feeding
Measure Participants	133	132
Count of Participants [Participants]	21 15.8%	15 11.4%

8. Secondary Outcome

Title	Number of Patients Needing ICU Admission
Description	number of patients needing ICU admission after surgery
Time Frame	up to 6 weeks after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard	Enriched Enteral Nutrition
Arm/Group Description	standard of care	enriched enteral tube feeding
Measure Participants	133	132
Count of Participants [Participants]	37 27.8%	31 23.5%

9. Secondary Outcome

Title	Health-related Quality of Life
Description	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
Time Frame	6 months after surgery

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Standard	Enriched Enteral Nutrition
Arm/Group Description	standard of care	enriched enteral tube feeding
Measure Participants	102	116
Median (Inter-Quartile Range) [units on a scale]	83	78

Adverse Events

Time Frame	3 months
Arm/Group Title	Standard		Enriched Enteral Nutrition
Arm/Group Description	standard of care		enriched enteral tube feeding
All Cause Mortality
	Standard		Enriched Enteral Nutrition
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	7/133 (5.3%)		4/132 (3%)
Serious Adverse Events
	Standard		Enriched Enteral Nutrition
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/133 (39.1%)		55/132 (41.7%)
Gastrointestinal disorders
anastomotic leakage	12/133 (9%)		11/132 (8.3%)
Surgical and medical procedures
remaining serious adverse events	40/133 (30.1%)		44/132 (33.3%)
Other (Not Including Serious) Adverse Events
	Standard		Enriched Enteral Nutrition
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/133 (16.5%)		16/132 (12.1%)
Surgical and medical procedures
clavien dindo grade 1	22/133 (16.5%)		16/132 (12.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.