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
Phase: NA
Conditions: Postoperative Ileus, Anastomotic Leak
Sponsor: Misha D.P. Luyer

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SANICS II trial 
Stimulation of the autonomic nervous system in colorectal surgery by perioperative 
nutrition 
 
A multicenter prospective double blinded controlled randomized controlled trial 
 
M.D.P. Luyer MD, PhD1, E.G. Peters MD1,2, H.J.T. Rutten MD1,3, PhD, I.H.J. de Hingh MD, 
PhD1, G.A.P. Nieuwenhuijzen MD, PhD1, M. Buise MD, PhD4, W.J. de Jonge PhD2, W.A. 
Buurman PhD5. 
 
 
1 Department of Surgery, Catharina Hospital, Michelangelolaan 2, Eindhoven, 5602 ZA, The 
Netherlands. 
2 AMC, Tytgat Institute for Intestinal and Liver Research, Meibergdreef 69-71 1105 BK 
Amsterdam, The Netherlands. 
3 Institute GROW, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The 
Netherlands. 
4 Department of Anesthesiology, Catharina Hospital, Michelangelolaan 2, Eindhoven, 5602 
ZA, The Netherlands. 
5 Institute Nutrim, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands 
 
 
Correspondence to:  
Misha DP Luyer, MD, PhD, Department of Surgery,  
Catharina Medical Centre, 5623EJ Eindhoven, the Netherlands.  
Email: misha.luyer@cze.nl  
Telephone: +31-40-2399111          Fax: +31-40-2455035 

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Protocol ID 
NL45640.060.13 
Short title 
SANICSII 
EudraCT number  
not applicable 
Version 
4 
Date 
04-03-2015 
Coordinating investigator/project 
leader 
 
Emmeline Peters, MD 
Department of Surgery,  
Catharina Medical Centre,  
5623EJ Eindhoven, the Netherlands.  
T: 040-2396350 
Email: emmeline.peters@cze.nl 
Principal 
investigator(s) 
(in 
Dutch: 
hoofdonderzoeker/ 
uitvoerder) 
 
Misha DP Luyer, MD, PhD,  
Department of Surgery,  
Catharina Medical Centre,  
5623EJ Eindhoven, the Netherlands.  
T: 040-2397175 
F: 040-2455035 
Email: misha.luyer@cze.nl  
Co-investigators 
 
Multicenter research: per site 
 
W.J. de Jonge 
W.A. Buurman 
Maxima Medical Centre 
Elkerliek Hospital 
Sponsor 
(in 
Dutch: 
verrichter/opdrachtgever) 
Catharina Ziekenhuis Eindhoven 
Michelangelolaan 2 
5623 EJ Eindhoven, the Netherlands 
T: + 31 40-2399111 

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Subsidising party 
Danone/Nutricia 
ZonMw 
Fonds NutsOhra 
Independent expert (s) 
M.R.H.M. van Sambeek 
 
 
Laboratory sites  
Catharina Hospital Eindhoven 
AMC Amsterdam; Tytgat Institute for Intestinal and 
Liver Research 
 
 
 
 
 
 
Protocol version 4.   
Issue date: February 13, 2015 
Protocol amendment number: 03 
Authors: EP, ML 
 
Revision chronology:  
Nov 13, 2013: original 
Aug 12, 2014: amendment 01: 
Primary reasons for amendment: changes in exclusion criteria, patientinformation and 
execution of the study protocol, addition of a patient diary 
Oct 10 2014: amendment 02: 
Primary reasons for amendment: change in inclusion criteria, primary and secondary 
endpoints, and patientinformation, addition of questionnaires. 
Mar 04, 2015: amendment 03: 
Primary reason for amendment: addition of centers to the study to conduct the study in 
multicenter setting. Collection of two fecal samples is added to the protocol. 
 

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Table of Contents 
1. Introduction and Rationale 
2. Objectives 
3. Study Design 
4. Study Population 
 
4.1 Population 
 
4.2 Inclusion criteria 
 
4.3 Exclusion criteria 
 
4.4 Definitions 
 
4.5 Sample size calculation 
5. Treatment of Subjects 
 
5.1 Investigational product/treatment 
6. Methods: 
 
6.1 Primary endpoints 
 
6.2 Secondary endpoints 
 
6.3 Randomisation, blinding and treatment allocation 
 
6.4 Study procedures  
 
6.5 Withdrawal of individual subjects 
7. Nutrition 
 
7.1 Perioperative enteral nutrition 
8. Safety Reporting 
 
8.1 Adverse events 
 
8.2 Serious adverse events 
 
8.3 Annual safety report  
 
8.4 Follow-up of adverse events 
 
8.5 Data and safety monitoring board 
 
8.6 Premature termination of the study 

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9. Statistical Analysis 
10. Ethical Considerations 
 
10.1 Regulation statement 
 
10.2 Recruitment and consent.  
 
10.3 Compensation for injury  
11. Administrative aspects, monitoring and publication 
 
11.1 Handling and storage of data and document 
 
11.2 Monitoring and Quality Assurance 
 
11.3 Amendments 
 
11.4 Annual progress report 
 
11.5 End of study report 
 
11.6 Publication of results 
12. Structured risk analysis 
 
12.1 Potential issues of concern 
 
12.2 Synthesis  
13. References 
 
Appendix I Insurance  
 
Appendix II Data and Safety Monitoring Board   
 
Appendix III Case Report Form 
 
Appendix IV Proefpersonen informatie  
 
Appendix V Diet composition 
 
Appendix VI Quality of life questionnaire 
 
Appendix A Experimental Design 
 
Appendix B Participating Centers 
 
 
 

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1. SUMMARY  
Rationale: Postoperative ileus and anastomotic leakage are complications associated with 
short-term morbidity and mortality following colorectal surgery. Based on experimental 
studies, we hypothesize that enriched enteral nutrition shortly before, during and early after 
colorectal surgery reduces inflammation by stimulation of the autonomic nervous system and 
thereby postoperative ileus (POI) and anastomotic leakage.  
Objective: The main objective is to investigate the effects of perioperative nutrition on 
postoperative ileus and anastomotic leakage in patients undergoing colorectal surgery.  
Study design: A prospective randomized double blinded controlled trial 
Study population: Patients undergoing segmental colon/ rectum resection with a primary 
anastomosis for colorectal cancer >18 years. 
Intervention:  Perioperative nutrition via a nasojejunal tube. 
Main study parameters: Main clinical outcome parameters are postoperative ileus and 
anastomotic leakage. Risk of aspiration pneumonia is closely monitored. Before intubation, 
gastric volumes are measured and the stomach is emptied. The inflammatory response will 
be quantified by standard assays including Enzyme Linked Immunosorbent Assay (ELISA) 
and Polymerase Chain Reaction (PCR). Mediators important in the pathogenesis of POI will 
also be measured in peritoneal lavage fluid. Clinical parameters are prospectively registered 
in a database and complications are classified using the Clavien-Dindo classification of 
surgical complications. Other parameters include intestinal barrier integrity and local 
inflammation in the intestine (measured by PCR and immunohistochemistry). Long-term 
outcome parameters such as local recurrence, overall and cancer-specific survival will also 
be registered. 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: 
All patients will receive a selfmigrating nasojejunal tube (Flocare Bengmark) one day before 
surgery. The position of the tube is checked via X-ray the same day. Via a specially designed 
blinded setup (produced by ECM bv, Gemert) patients in the intervention group receive 
enriched enteral nutrition in low amounts before, during and directly after surgery until oral 
intake is started. Patients in the control group do not receive nutrition and get a standard 
preoperative fast until standard oral intake is commenced.  
Blood samples will be collected at several predefined moments in relation to the moment of 
incision. Furthermore, gastric emptying will be assessed via ultrasound before and following 
a standard meal at day 2 postoperatively. This intervention may benefit the patient by 
reducing postoperative complications and enhancement of recovery.  

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Peritoneal lavage is performed at the start of surgery and at the end of surgery. Also gastric 
content is measured during surgery. It is expected that these procedures will be no burden 
for the patient. 
 
 
1. INTRODUCTION AND RATIONALE  
Postoperative ileus and anastomotic leakage are important clinical determinants of short-
term morbidity and mortality following colorectal surgery. Importantly, anastomotic leakage is 
also a risk factor for local recurrence of colorectal cancer and has a significant impact on 
disease-free and overall survival.1 It is therefore believed that improving postoperative 
outcome following colorectal surgery will also improve long-term oncological outcomes 
regarding overall survival and tumour recurrence.2, 3  
Postoperative ileus (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. Although the underlying mechanism has been studied extensively in 
animal experiments, targeted therapeutical strategies are lacking in a clinical setting and only 
supportive arrangements are taken to optimize the patient’s condition. 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.5 In recent 
years our group has demonstrated in experimental models that administration of enteral 
nutrition modulates the inflammatory response via the autonomic nervous system by release 
of cholecystokinin (CCK).7-9 Composition of the enteral nutrition and timing of administration 
are both essential for the magnitude of effect.10 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.11  
Next, we 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.12 In this study was shown that lipid enriched nutrition reduced the 
inflammatory response upon endotoxemia in man. 
Also in a clinical setting we have shown that enteral nutrition reduces inflammation and POI. 
In a randomized controlled trial our group has 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 POI were reduced following colorectal surgery (vd 
Heijkant et al, accepted in The British Journal of Surgery).  

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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. Early inhibition of the inflammatory 
response may play a role since release of proinflammatory cytokines such as TNF-α 
modulates intestinal epithelial function and is an inhibitory factor in the wound healing 
process of intestinal anastomoses.6 Therefore, 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. In the current study we plan to investigate the effectiveness of perioperative 
nutrition compared with standard of care (nil-per-mouth) in a large-scale trial in patients 
undergoing colorectal surgery. 
 
2. OBJECTIVE 
 
2.1 Primary objective 
To investigate the effect of perioperative nutrition on postoperative ileus and anastomotic 
leakage in patients undergoing colorectal surgery with primary anastomosis compared with 
standard care. 
 
2.2 Secondary objectives 
To investigate the effect of preoperative nutrition in colorectal surgery on: 
- 
Aspiration pneumonia 
- 
Gastric volumes preoperatively 
- 
Length of functional recovery 
- 
The pro- and anti-inflammatory response both locally, systemically and in peritoneal 
lavage fluid 
- 
Damage to the intestinal barrier (I-FABP) 
- 
Need for additional surgical, radiological or endoscopic interventions 
- 
Other complications requiring treatment (i.e. urinary tract infection) 
- 
Need for ICU admission and total length of ICU stay 
- 
Cost-effectiveness ratios 
 
3. STUDY DESIGN  
A prospective randomized double blinded controlled trial performed at the Catharina Hospital 
Eindhoven. We start the trial in one centre, and continue the trial in multicentre setting. 
Participating centres can be found in Appendix B. It is expected that patients will be included 
over a period of 3 years. At our hospital it was shown in previous studies that at least 75-100 

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patients undergoing colorectal surgery each year can be included. Most included patients will 
have colorectal cancer. Due to the nationwide screening program for colon cancer, it is 
expected that the amount of colorectal operations will further increase. In the experimental 
group patients receive enriched enteral nutrition. In the control group patients receive 
standard of care (enhanced recovery after surgery protocol).  
 
4. STUDY POPULATION 
 
4.1 population (base) 
Patients undergoing segmental colon resection with primary anastomosis. 
 
4.2 inclusion criteria 
• 
patients that undergo elective surgical resection with primary anastomosis. 
• 
written informed consent 
• 
age >18 years 
 
4.3 exclusion criteria 
• 
use of medication that disrupts acetylcholine metabolism 
• 
steroid use 
• 
previous gastric or oesophageal resection 
• 
peritoneal metastases found during surgery 
• 
pre-existent or creation of an ileostomy 
 
 
4.4 Definitions 
Anastomotic leakage is defined as clinical and radiological signs of anastomotic leakage, or 
confirmed by re-operation or occurrence of an enterocutaneous fistula. Postoperative ileus 
will be assessed as time to first flatus and defaecation and by measurements of 
gastrointestinal transit times via ultrasonography (using antrum measurements). Aspiration 
pneumonia is defined as inflammation in the lungs following aspiration of material (solid or 
liquid, vomit, saliva). 
 
4.5 Sample size calculation  
Patients will be recruited at the outpatient clinic of the Catharina Hospital Eindhoven. 
Reduction of anastomotic leakage and postoperative ileus are primary outcome parameters 
for the sample size calculation. Anastomotic leakage is the most detrimental complication 

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following colorectal surgery associated with high hospital costs and also with effects on long-
term general and cancer-specific outcome. We have performed two clinical studies in 
colorectal surgery patients that can be used as basis for the power calculation. In one study 
in which we compared very early enteral nutrition with very early parenteral nutrition, we 
observed a reduction of anastomotic leakage from 12.9% in the parenteral group to 1.6% in 
the enteral group. However, this effect may be confounded by the potential detrimental effect 
of parenteral nutrition. Early postoperative ileus reduced in this study from 35% in the 
parenteral group to 16% in the enterally fed patients.  
In a second study, the effect of sham-feeding via chewing gum on postoperative ileus was 
compared with controls. In this study postoperative ileus was reduced from 47% in the 
controls to 27% in the intervention group. The effect on anastomotic leakage was also 
apparent and leak-rates reduced from 13% in the placebo group to 3% in the intervention 
group 
Based on these previous results a power calculation can be performed. For postoperative 
ileus 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 anastomotic leakage a reduction of anastomotic leakage 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, an interim analysis is performed after inclusion of 40 patients in which 
feasibility and safety of preoperative nutrition are assessed. All analyses will be done 
according to the intention-to-treat approach in which all randomised patients are included, 
regardless of adherence to 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. 
 
 
5. TREATMENT OF SUBJECTS 
 
5.1 Investigational product/treatment 
The composition of the nutrition we will use is based on previous experimental findings and 
has already been tested in a human volunteer study (NCT00468507) showing that this 
nutrition is well-tolerated in healthy individuals. The lipid- and protein-rich nutrition contains 
44 energy percent (en%) fat, 25en% protein, and 31en% carbohydrates. The protein fraction 
consists of intact casein, whey protein, and soy protein hydrolysate. The lipid fraction of the 

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feeding contains less than 5 weight percent omega-3 fatty acids. The nutrition provides 1 
kcal/ml. The specific constituents of the feeding compositions are provided as Supplement. 
 
6. METHODS 
 
6.1 Primary endpoint 
- 
Postoperative ileus  
 
6.2 Secondary endpoints 
- 
Anastomotic leakage  
- 
Aspiration pneumonia 
- 
Gastric volumes preoperatively 
- 
Length of functional recovery 
- 
The local and systemic inflammatory response  
- 
Surgical complications 
- 
Length of stay 
- 
Intestinal barrier function and local inflammation in the gut 
- 
Need for additional surgical, radiological or endoscopic interventions 
- 
Need for ICU admission and total length of ICU stay 
- 
Quality of life (EQ-5D-5L and EORTC-QLQ-C30 at baseline, after 3 and 6 months) 
- 
Cost-effectiveness ratios (iMCQ and iPCQ at baseline, after 3 and 6 months) 
- 
Composition of faecal microbiome 
 
6.3 Randomisation, blinding and treatment allocation 
After obtaining written informed consent patients will be randomly assigned to one of two 
groups by randomization software (TENALEA Clinical Trial Data Management System). The 
randomization list was generated by this computerized program using random blocks with 
maximum block size 6, stratified by operation location (colon or rectum) and operation type 
(laparoscopic or open). Blinded, study-specific enteral feeding systems are prepared and 
coded according to this list. A corresponding randomization website will be used that 
generates the sequential randomization number corresponding to the stratified randomization 
list upon randomization of a patient. All patients will receive a selfmigrating nasojejunal tube 
(Flocare Bengmark) one day before surgery. The position of the nasojejunal tube is 
controlled by abdominal X-ray at the day before surgery. Enriched enteral nutrition (Danone 
research™) is lead through a programmed Flocare enteral feeding pump. The pump is 
connected to an opaque branched enteral feeding system (produced by ECM bv, Gemert, 
the Netherlands) that is connected both to the nasojejunal tube and to a sealed container. 

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Three hours before surgery the pump is started to administer nutrition in standardized 
amounts.  
Patients are either allocated to the experimental group, in which the blinded branched enteral 
feeding system leads the enteral nutrition via the nasojenunal 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 enteral feeding 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. The 
used enteral feeding systems are stored by an independent person, to create a checkpoint 
whether allocation to intervention and control group happened correctly.  
 
The study is blinded for the patient, the surgeon and nursing staff. A protocol explaining the 
study design and blinding is attached (Appendix A) 
 
6.4 Study procedures 
Blood samples will be collected at several predefined moments in relation to the moment of 
incision. Based on previous clinical trials in which we have measured the inflammatory 
response, these time points will be at 4h, 24h and 48h after surgery. Tissue samples from 
the resected colorectal segment are collected during the surgical procedure for 
immunohistochemistry, Western Blot and PCR analysis. When collected, all samples are 
stored at -80ºC until further analysis. The inflammatory response is measured by analysing 
the blood plasma and tissue samples for inflammatory mediators (amongst which TNF-alpha 
and interleukins such as IL-6 and IL-8). This will be done for a large part using commercially 
available enzyme linked immune assays (ELISA) and by PCR. Also, the inflammatory 
response and tissue damage parameters will be monitored in peritoneal lavage fluid. For this, 
500cc saline will be installed just after opening of the abdomen and at the end of surgery.  
Intestinal tissue damage is measured by analysis of several markers for intestinal damage in 
blood and tissue samples such as Intestinal Fatty acid Binding Protein (I-FABP). Patient 
characteristics and clinical parameters are registered in an electronic database. All surgical 
complications are classified using the Clavien-Dindo classification.14  
Postoperative ileus will be measured clinically in a patient diary (Supplement) based on 
parameters such as time to first flatus and first defecation, which are the most suitable 
according to the available literature. Furthermore, gastric motility will be assessed by 
ultrasound of the gastric antrum just before and following a standardized meal after 15 
minutes and 90 minutes as previously performed (trial M11-1102, CCMO NL25588.096.08). 

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Previous studies have shown that antrum measurements are representative for determining 
gastric emptying and thereby gastric motility.15 This ultrasound measurement will be 
performed by a specifically trained M.D.  
All results of these measurements are registered in an electronic database. Patients are 
discharged according to known criteria as in ERAS/ fast-track surgery.  
Quality of life is measured via a checklist (EQ-5D-5L and EORTC QLQ C-30) for cancer 
patients pre- and postoperatively. Long-term outcome parameters such as local recurrence, 
overall and cancer-specific survival will be registered in a database. Healthcare costs, costs 
to patients and family are measured at the individual level using data from registration 
systems of the hospitals and patient questionnaires (including adapted version of the iMTA 
Medical Consumption Questionnaire (iMCQ) and the iMTA Productivity Cost Questionnaire 
(iPCQ)). 
Preoperatively and on the fourth postoperative day, a total of two fecal samples will be 
collected. Using the E-Nose, composition of the luminal microbiome will be determined. 
 
6.5 Withdrawal of individual subjects 
Subject can leave the study at any time for any reason if the wish to do so without any 
consequences. The investigator can decide to withdraw a subject from the study for urgent 
medical reasons.  
 
 
7. NUTRITION 
 
7.1 Perioperative enteral nutrition 
Perioperative administration of enteral nutrition is a new concept. Restriction of food and fluid 
intake prior to general anaesthesia has long been applied as a method to reduce the risk of 
regurgitation of gastric contents. Increasing evidence has been build over the last years that 
this insight may be out of date and not evidence-based. A Cochrane review showed that it 
was safe to apply a shortened fluid fast (of 2 hours before surgery) and that such a regimen 
did not results in an increased risk of aspiration, regurgitation or related morbidity compared 
with the standard ’nil by mouth from midnight’ fasting policy.16 Permitting patients to drink 
water preoperatively even resulted in significantly lower gastric volumes. Since perioperative 
nutrition is a new concept the risk of aspiration pneumonia needs to be monitored closely. 
For aspiration pneumonia gastric volume and acidity are important. Emergency patients with 
larger initial gastric volumes are more susceptible for pneumonia. 17 
In this trial nutrition will be administered postpylorically thereby reducing gastric volumes. All 
patients will receive a selfmigrating nasojejunal tube (Flocare Bengmark) one day before 

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surgery at the ward. The position of the nasojejunal tube will be controlled by X-ray at the 
night before surgery. Enteral nutrition will be administered postpylorically in low amounts. 
The lipid rich nutrition provides 1 kcal/ml. The rate of infusion will be determined according to 
the re-evaluated Harris and Benedict equation of Roza and Shizgal18. In this way a rate of 1,5 
ml/ minute is generally infused.  
The nutrition is administered during a timeframe of 3 hours before, until 6 hours after 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 of the nutrition by the nasojejunal 
tube. To minimize the risk of aspiration pneumonia the stomach will be emptied by a gastric 
tube before start of surgery. In a human volunteer study the nutrition was well tolerated and 
did not lead to unwanted side-effects12. Gastric volumes will be measured when the stomach 
is emptied, before start of surgery at the operating room. Based on the above, the risk of 
administering perioperative nutrition is minimized by given the nutrition postpylorically, in a 
low volume and assuring an empty stomach before intubation. 
 
8. PATIENT SAFETY, DATA MONITORING 
This prospective randomized clinical trial will be conducted according to the rules of Good 
Clinical Practice (GCP). An independent data safety monitoring board will be appointed by 
the investigators that will evaluate all complications and monitor patient safety. Specifically, 
the aspect of safety of perioperative administration of enteral nutrition will be closely 
monitored. The clinical trial will be conducted at the Catharina Hospital in Eindhoven.  
 
8.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject during the 
study, whether or not considered related to the intervention. All adverse events reported 
spontaneously by the subject or observed by the investigator or his staff will be recorded. 
 
8.2 Serious adverse events (SAEs) 
A serious adverse event is any untoward medical occurrence or effect that at any dose:  
- 
results in death; 
- 
is life threatening (at the time of the event); 
- 
requires hospitalisation or prolongation of existing inpatients’ hospitalisation; 
- 
results in persistent or significant disability or incapacity; 
- 
is a congenital anomaly or birth defect; 
- 
Any other important medical event that may not result in death, be life threatening, or 
require hospitalization, may be considered a serious adverse experience when, based upon 

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appropriate medical judgement, the event may jeopardize the subject or may require an 
intervention to prevent one of the outcomes listed above. 
 
Infectious complications and serious complications as a result of the operation that lead to 
prolongation of the patients’ stay in the hospital will be registered as a SAE 
 
The investigator will report the SAEs through the web portal ToetsingOnline to the accredited 
METC that approved the protocol, within 15 days after the sponsor has first knowledge of the 
serious adverse reactions. 
 
SAEs that result in death or are life threatening should be reported expedited. The expedited 
reporting will occur not later than 7 days after the responsible investigator has first 
knowledge of the adverse reaction. This is for a preliminary report with another 8 days for 
completion of the report.  
 
8.3 Annual safety report 
The sponsor/investigator will submit a safety report to the METC once a year. This report 
consists of a list of all suspected serious adverse reactions and a report concerning the 
safety of the subjects, consisting of a complete safety analysis and an evaluation of the 
balance between the efficacy and the harmfulness of the medicine under investigation.  
 
8.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs need to be reported till end of study within the Netherlands, as defined in the protocol  
 
8.5 Data and safety monitoring board  
An independent data and safety monitoring board (DSMB) will evaluate the progress of the 
trial and will examine safety variables. SAE’s need to be reported to the principal investigator 
within 24 hours, some SAE’s will be specified such as: re-intervention, respiratory failure, 
aspiration pneumonia, myocardial infarction, transfer to the ICU for any reason. Per 10 
patients, individualized patient data will be presented to the DSMB. After full explanation of 
the data presented, the members of the DSMB discuss the consequences of the data 
presented separately. Besides the assessment of SAE’s and AE’s a safety analysis will be 
made after inclusion of 40 patients. In this analysis there is a special focus on gastric 

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volumes which will be compared as well as incidence of aspiration pneumonia. Adverse 
events will be listed and discussed with the DSMB. The outcome of the meeting of the DSMB 
will be discussed with the research group. The outcome will also be sent to the Medical 
Ethics Committee. All possible adverse events will be reported to the Central Committee on 
Research involving Human Subjects (Centrale Commissie Mensgebonden Onderzoek 
(CCMO)) and the IRB using the online module https://toetsingonline.ccmo.nl. 
 
The DSMB includes: 
1. 
Prof P. Soeters, Emeritus Professor Clinical Nutrition 
2. 
Dr. E. Schoon, Gastroenterologist 
3. 
Dr. A. Roos, Intensive Care Medicine 
4. 
Dr. S. Houterman, Epidemiologist. 
 
8.6 Premature termination of the study 
In addition to safeguarding the safety of the patients in the study, the DSMB will check for 
early proof of efficacy during an interim-analysis for benefit which will be performed halfway 
the study. If the DSMB suspects harm there will be a meeting between the DSMB, the study 
group and an independent statistician. During this meeting there should be a discussion 
about any potential causal relation between early start of postoperative oral nutrition and 
harm. 
 
9. STATISTICAL ANALYSIS 
All analyses will be done according to the intention-to-treat approach in which all randomized 
patients are included, regardless of adherence to 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. 
 
10 ETHICAL CONSIDERATIONS 
 
10.1 Regulation statement  
Participation in the current study is on a volunteer basis and will only be possible when 
informed consent is obtained. Subjects can leave the study at any time for any reason if they 
wish to do so without any consequences. The investigator can decide to withdraw a subject 
from the study for urgent medical reasons. The study will be performed in accordance with 

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the declaration of Helsinki and the Dutch “Wet Medisch-wetenschappelijk Onderzoek met 
Mensen, WMO” (Medical Research Involving Human Subjects Act).  
Patients can withdraw from this research at any time, without reason. Furthermore, patients 
can stop the study at any time, without consequences for the quality of treatment. 
 
10.2 Recruitment and consent 
 All patients that meet the inclusion criteria and do not have exclusion criteria will be asked to 
participate in the study. After full explanation of the study protocol informed consent will be 
obtained. Informed consent will be obtained from each participating patient in oral and written 
form prior to randomization. Informed consent will be obtained by a member of the research 
group. 
 
10.3 Compensation for injury 
An insurance policy is signed with an insurance company for all patients in the study. They 
will be insured for injury or death due to participation in this study during the study period and 
for four years after termination of this study. A more detailed overview is given in appendix I.  
 
11. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
 
11.1 Handling and storage of data and documents  
After obtaining written informed consent patients will be randomly assigned to one of two 
groups by randomization software (TENALEA Clinical Trial Data Management System). The 
randomization list was generated by this computerized program using random blocks with 
maximum block size 6, stratified by operation location (colon or rectum) and operation type 
(laparoscopic or open). Blinded, study-specific enteral feeding systems are prepared and 
coded according to this list. A corresponding randomization website will be used that 
generates the sequential randomization number corresponding to the stratified randomization 
list upon randomization of a patient.  
The obtained results will be handled confidentially and will be accessible and viewed by 
study personnel, the Ethical commission, the Data Safety monitoring Board, the Health 
Inspection (Inspectie voor de Gezondheidszorg) and Danone/ Nutricia Research. Data will be 
coded so anonymity is preserved, also when data are published. The data and/or human 
material will be kept for 15 years in storage in the Catharina Ziekenhuis  
 

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11.2 Monitoring and Quality Assurance  
A Data Safety Monitoring board is installed. More information can be found in appendix II 
(DSMB)  
The DSMB includes: 
1. 
Prof P. Soeters, Emeritus Professor Clinical Nutrition 
2. 
Dr. E. Schoon, Gastroenterologist 
3. 
Dr. A. Roos, Intensive Care medicine 
4. 
Dr. S. Houterman, Epidemiologist. 
 
11.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the accredited 
METC has been given. All amendments will be notified to the METC that gave a favourable 
opinion.  
All substantial amendments will be notified to the METC and to the competent authority. 
Non-substantial amendments (for example typing errors or administrative changes) will not 
be notified to the accredited METC and the competent authority, but will be recorded and 
filed by the sponsor.  
 
11.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the trial to the accredited 
METC once a year. Information will be provided on the date of inclusion of the first subject, 
numbers of subjects included and numbers of subjects that have completed the trial, serious 
adverse events/ serious adverse reactions, other problems, and amendments.  
 
11.5 End of study report 
The investigator will notify the accredited METC of the end of the study within a period of 8 
weeks. The end of the study is defined as the last patient’s last visit. In case the study is 
ended prematurely, the investigator will notify the accredited METC within 15 days, including 
the reasons for the premature termination. Within one year after the end of the study, the 
investigator/sponsor will submit a final study report with the results of the study, including any 
publications/abstracts of the study, to the accredited METC.  
 
11.6 Publication of results 
Results will be analyzed and presented in scientific journals. The CCMO Statement 
Publication policy will be followed. 

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12. STRUCTURED RISK ANALYSIS  
 
12.1 Potential issues of concern 
The enriched enteral nutrition that is used, has been investigated before in healthy 
volunteers during endotoxemia.12 In this study there were no adverse or serious adverse 
events. Enclosed is the diet composition.  
 
a. Level of knowledge about mechanism of action: The mechanism has been extensively 
shown in experimental models. A (pre) clinical study in healthy volunteers and a prospective 
randomized controlled trial in patients undergoing colorectal surgery showed results in line 
with the found hypothesis.  
 
b. Previous exposure of human beings with the test product(s) and/or products with a similar 
biological mechanism. As mentioned before, the enteral nutrition that is used, has been 
investigated before in healthy volunteers during endotoxemia. 12 
 
c. Can the primary or secondary mechanism be induced in animals and/or in ex-vivo human 
cell material? Yes 
 
d. Selectivity of the mechanism to target tissue in animals and/or human beings. The found 
effects in previous studies is specifically targeting the inflammatory response and has shown 
to affect both anastomotic leakage and postoperative ileus, the two primary outcome 
parameters. 
 
e. Analysis of potential effect. The nutrition itself is not considered to be harmful. 
Administration of enteral nutrition during surgery is a new concept. For this reason a data 
safety monitoring board is installed. There have been no described effects at all. A potential 
complication is aspiration pneumonia.  
 
f. Pharmacokinetic considerations: not applicable 
 
g. Study population. Patients undergoing colorectal surgery with primary anastomosis. 
 
h. Interaction with other products: not applicable 
 

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i. Predictability of effect. The found effects in animal experiments were on both the 
inflammatory response and clinical parameters. The effects were consistent in various 
experimental models and in the clinical studies. 
 
j. Can effects be managed? During surgery, gastric volumes are measured and gastric 
content is aspirated to minimize risk of aspiration pneumonia.  
 
 
12.2 Synthesis 
The potential risk of this intervention is aspiration pneumonia. Several measures are taken to 
prevent this potentially increased risk.  
1. Gastric content is aspirated; the volume of gastric content has been shown to be 
related to risk of aspiration pneumonia.  
2. Nutrition is given postpylorically 
3. A Data Safety Monitoring Board is installed. 
 

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13. REFERENCES 
1.  
Mirnezami A, Mirnezami R, Chandrakumaran K, Sasapu K, Sagar P, Finan P. 
Increased local recurrence and reduced survival from colorectal cancer following 
anastomotic leak: systematic review and meta-analysis. Ann Surg 2011; 253(5):890-899. 
2.  
Janssen-Heijnen ML, Maas HA, Houterman S, Lemmens VE, Rutten HJ, Coebergh 
JW. Comorbidity in older surgical cancer patients: influence on patient care and outcome. 
Eur J Cancer 2007; 43(15):2179-2193. 
3.  
Law WL, Choi HK, Lee YM, Ho JW. The impact of postoperative complications on 
long-term outcomes following curative resection for colorectal cancer. Ann Surg Oncol 2007; 
14(9):2559-2566. 
4.  
Lubbers T, Buurman W, Luyer M. Controlling postoperative ileus by vagal activation. 
World J Gastroenterol 2010; 16(14):1683-1687. 
5.  
Boeckxstaens GE, de Jonge WJ. Neuroimmune mechanisms in postoperative ileus. 
Gut 2009; 58(9):1300-1311. 
6.  
Ishimura K, Moroguchi A, Okano K, Maeba T, Maeta H. Local expression of tumor 
necrosis factor-alpha and interleukin-10 on wound healing of intestinal anastomosis during 
endotoxemia in mice. J Surg Res 2002; 108(1):91-97. 
7.  
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; 41(3):377-383. 
8.  
Luyer MD, Buurman WA, Hadfoune M et al. Pretreatment with high-fat enteral 
nutrition reduces endotoxin and tumor necrosis factor-alpha and preserves gut barrier 
function early after hemorrhagic shock. Shock 2004; 21(1):65-71. 
9.  
Wang H, Yu M, Ochani M et al. Nicotinic acetylcholine receptor alpha7 subunit is an 
essential regulator of inflammation. Nature 2003; 421(6921):384-388. 
10.  
de Haan JJ, Lubbers T, Hadfoune M et al. Postshock intervention with high-lipid 
enteral nutrition reduces inflammation and tissue damage. Ann Surg 2008; 248(5):842-848. 
11.  
Lubbers T, de Haan JJ, Luyer MD et al. Cholecystokinin/Cholecystokinin-1 receptor-
mediated peripheral activation of the afferent vagus by enteral nutrients attenuates 
inflammation in rats. Ann Surg 2010; 252(2):376-382. 

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12.  
Lubbers T, Kox M, de Haan JJ et al. Continuous administration of enteral lipid- and 
protein-rich nutrition limits inflammation in a human endotoxemia model. Crit Care Med 2013; 
41(5):1258-1265. 
13.  
Berghmans TM, Hulsewe KW, Buurman WA, Luyer MD. Stimulation of the autonomic 
nervous system in colorectal surgery: a study protocol for a randomized controlled trial. Trials 
2012; 13:93. 
14.  
Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new 
proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg 2004; 
240(2):205-213. 
15.  
Darwiche G, Bjorgell O, Thorsson O, Almer LO. Correlation between simultaneous 
scintigraphic and ultrasonographic measurement of gastric emptying in patients with type 1 
diabetes mellitus. J Ultrasound Med 2003; 22(5):459-466. 
16.  
Brady M, Kinn S, Stuart P. Preoperative fasting for adults to prevent perioperative 
complications. Cochrane Database Syst Rev 2003;(4):CD004423. 
17.  
Yeung L, Miraflor E, Strumwasser A, Sadeghi P, Victorino GP. Does gastric volume in 
trauma patients identify a population at risk for developing pneumonia and poor outcomes? J 
Surg Res 2012; 178(2):874-878. 
 
18.  
Roza AM, Shizgal HM. The Harris Benedict equation reevaluated: resting energy 
requirements and the body cell mass. Am J Clin Nutr 1984; 40(1):168-182. 
 
 
 
 
 
 
 
 
 
 
 

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APPENDIX I: INSURANCE 
 
Voor de deelnemers aan dit onderzoek is een verzekering afgesloten. Deze verzekering dekt 
schade door dood of letsel die het gevolg is van deelname aan het onderzoek, en die zich 
gedurende de deelname aan het onderzoek openbaart, of binnen vier jaar na beëindiging 
van de deelname aan het onderzoek. De schade wordt geacht zich te hebben geopenbaard 
wanneer deze bij de verzekeraar is gemeld.  
(In geval van schade kunt u zich direct wenden tot de verzekeraar.)  
 
Centramed: 
Onderlinge Waarborgmaatschappij Centramed B.A. 
Appelgaarde 4 
2272 TK Voorburg 
 
Telefoon 070-301 70 70  – Fax 070-301 70 71 
 
De verzekeraar kan dan vragen naar aanvullende schriftelijke informatie.  
 
De verzekering biedt een maximum dekking van € 450.000 per proefpersoon en € 3.500.000 
voor het gehele onderzoek, en €  5.000.000 per jaar voor alle onderzoeken van dezelfde 
opdrachtgever. De dekking van specifieke schades en kosten is verder tot bepaalde 
bedragen beperkt. Dit is opgenomen in het Besluit verplichte verzekering bij medisch-
wetenschappelijk onderzoek met mensen. Informatie hierover kunt u vinden op de website 
van de Centrale Commissie Mensgebonden Onderzoek: www.ccmo.nl. 
 
Voor deze verzekering gelden een aantal uitsluitingen. De verzekering dekt niet: 
- 
schade waarvan op grond van de aard van het onderzoek zeker of nagenoeg zeker was 
dat deze zich zou voordoen; 
- 
schade aan de gezondheid die ook zou zijn ontstaan indien u niet aan het onderzoek had 
deelgenomen; 
- 
schade die het gevolg is van het niet of niet volledig nakomen van aanwijzingen of 
instructies; 
- 
schade aan nakomelingen, als gevolg van een nadelige inwerking van het onderzoek op 
u of uw nakomeling; 
- 
bij onderzoek naar bestaande behandelmethoden: schade die het gevolg is van één van 
deze behandelmethoden; 
- 
bij onderzoek naar de behandeling van specifieke gezondheidsproblemen: schade die 
het gevolg is van het niet verbeteren of van het verslechteren van deze 
gezondheidsproblemen. 
 
Naast de directe schadeverzekering blijven de wettelijke regels omtrent reguliere, medische- 
en (product) aansprakelijkheid van toepassing. 
 
 
In geval van schade kunt u ook contact opnemen met Bureau Patiëntenbelangen van het 
Catharina-ziekenhuis te Eindhoven, bereikbaar via telefoonnummer 040-2398410. 
 
 

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APPENDIX II: DATA AND SAFETY MONITORING BOARD 
 
Roles and responsibilities 
The Data Safety and Monitoring Board (DSMB) is an independent group of experts that 
advises the participating investigators and the Institutional Review Board. 
The members of the DSMB serve in an individual way and provide their expertise and 
recommendations. The primary responsibilities include: 
1. Periodically review and evaluate the accumulated study data for participant’s safety, 
the study conduct and progress 
2. Make a recommendation to the investigators concerning continuation, modification or 
termination of the trial. 
 
* The DSMB considers study-specific data as well as relevant background knowledge about 
the disease or patient population under study. 
 * The DSMB is responsible to define the processes, including the event triggers that would 
call for an unscheduled review, stopping guidelines and voting procedures prior to the first 
data review. 
* The DSMB is responsible for maintaining the confidentiality of its internal discussions and 
activities. 
* The DSMB should review each protocol for any major concern prior to implementation. 
During the trial, the DSMB should review cumulative study data to evaluate the safety, the 
study conduct and the scientific validity and integrity of the trial.  
It is the responsibility of the DSMB to provide a written report after each review with a 
recommendation to continue or terminate the study. 
 
Documentation 
Each member of the DSMB will receive all documents as provided to the Medical Ethics 
Committee, including study protocol, ABR-form and patient information. 
 
Membership 
The DSMB will consist of at least three members with relevant clinical expertise, clinical trial 
methodology and biostatistics. Members will be completely independent. Written 
documentation specifying the absence of any conflict of interest will be obtained. A 
chairperson will be appointed who will act as the spokesperson 
 
 

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Review and recommendation process 
It is the responsibility of the DSMB to: 
- 
review the research protocol for data safety and monitoring 
- 
evaluate the progress of the trial, including periodic assessments of data quality and 
timelines, participant recruitment, accrual and retention, participant risk versus benefit 
and other factors that can affect the study outcome. 
- 
Consider factors external tot the study when relevant information becomes available, 
such as scientific or therapeutic developments that may have an impact on the safety 
of the participants or on the ethical conduct of the trial. 
- 
Protect the safety of the study participants. 
- 
Report on the safety and progress of the trial. 
- 
Make a recommendation to the investigators concerning continuation, modification or 
termination of the trial. 
- 
Ensure the confidentiality of the trial data and the results of the monitoring. 
 
Meetings and reports 
The first meeting of the DSMB will be a face-to-face meeting before initiation of the trial to 
discuss the protocol and to establish the guidelines to monitor the study. During the course of 
the trial the DSMB will meet after inclusion of every 20 patients. These meetings may be 
convened as conference calls, as well as in person. An emergency meeting of the DSMB 
may be called at any time by the chairperson, the investigators or any other party involved in 
the trial. Meetings must be attended by all members and the DSMB may invite other parties 
involved in the trial, when necessary. The investigators will provide the DSMB with an 
overview / listing of the occurred events.  
A formal report from the DSMB chair will be prepared and sent to all members of the DSMB 
within two weeks after the meeting. Once approved by all members of the DSMB, the report 
including a written statement (no safety concern/ safety concern) will be sent to the 
investigators and the Medical Ethics Committee. 
 
Registration of events 
All Adverse Events (AE’s) and Serious Adverse Events (SAE’s) as mentioned in the protocol 
will be registered. Any SAE must be reported within 24 hours of knowledge by the 
investigator. All serious irreversible events will be reported to the DSMB on receipt. All 
reversible serious adverse events will be reported during the regular meetings. 
In case the number of events is unacceptably high, the trial will be suspended and potentially 
prematurely terminated. 
 

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Members 
Name  
 
 
 
 
 
Signature 
 
P.B. Soeters, MD, PhD (Chair) 
Emeritus Professor of Surgery 
Maastricht University Medical Center 
 
 
 
 
Maastricht, the Netherlands                                       
                                                                                               
                          
A. Roos, MD PhD 
Intensive care,  
Catharina Hospital Eindhoven, The Netherlands 
  
 
…………………………… 
 
E.J. Schoon, MD PhD 
Gastroenterologist,  
Catharina Hospital Eindhoven, The Netherlands 
 
 
…………………………… 
 
S. Houterrman, PhD 
Epidemiologist 
Catharina Hospital Eindhoven, The Netherlands 
 
 
…………………………… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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CASE REPORT FORM 
 
Patiënt identificatie nummer: c c c c c c c 
Randomisatienummer: 
 c c c c 
 
 
Patiëntgegevens 
 
Geb datum: ___ / ___/ 19__ 
Geslacht: M / V 
Lengte: _______ cm 
 
Gewicht _______ kg 
ASA klasse:   
1 / 2 / 3 / 4 / 5 
SNAQ score:  
MUST score: 
Roken: 
 
£ Nee 
£ Ja  
 
Alcohol:  
 
£ Nee 
£ Ja   
dagelijks / wekelijks / maandelijks 
Abdominale chirurgie in de voorgeschiedenis: 
 
 
 
£ Nee 
£ Ja:__________________ 
Bestaand colostoma 
£ Nee 
£ Ja:__________________ 
 
 
Huidige situatie 
 
Diabetes 
 
£ Nee 
£ Ja  
insuline £ Nee 
 
£ Ja 
Gebruik van psychofarmaca: 
 
 
 
£ Nee 
£ Ja:__________________ 
 
 
 
 
 
Dosering:_______________ 
Gebruik van statine:£ Nee 
£ Ja:__________________ 
 
 
 
 
 
Dosering:_______________ 
Gebruik van PPI: 
£ Nee 
£ Ja:__________________ 
 
 
 
 
 
Dosering:_______________ 
Gebruik van aspirine: 
 
 
 
£ Nee 
£ Ja:__________________ 
 
 
 
 
 
Dosering:_______________ 
 
Maligniteit: 
 
£ Nee 
£ Ja   
Afstand tumor tot de anus: _____ cm 
Neoadjuvante beh: £ Nee 
£ Ja   
chemo / RT / CRT ___________ 
 
Preop bloedtransfusie:  
£ Nee 
£ Ja ______________ 
Preop NSAID: 
 
£ Nee 
£ Ja 
Welke______________start ___ / ___/ 20__ 
Dosering:___________stop ___ / ___ / 20__ 
 
Dag van opname:  ___ / ___ / 20____; Tijdstip ___:___ uur 

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Operatie 
 
Datum operatie: 
___ /___ /20_____ Operateur: ___________________ 
Starttijd operatie:  ___:___ uur 
Eindtijd operatie: 
___:___ uur 
 
Aspiratie bij intubatie/OK: £ Nee £ Ja 
 
Procedure:   
£ Open    
£ Laparoscopisch 
 
 
 
£ conversie 
 
Type OK:  
 
£ Hemicolectomie links 
£ Hemicolectomie rechts  
£ Low Anterior resectie 
 
£ Ileocoecaal resectie 
£ Sigmoidresectie 
£ Rectosigmoidresectie 
£ Transversum resectie 
 
  
 
£ Overig, namelijk _______________________ 
 
iORT      
   
£ Nee 
£ Ja 
 
Stoma aangelegd:  £ Nee 
£ Ja 
 
 
 
 
 
Eindstanding / dubbelloops 
 
 
 
 
 
Ileostoma / colostoma 
Epiduraal:  
 
£ Nee 
£ Ja   
 
 
 
 
 
Start hoeveelheid: __________________ 
 
 
 
 
 
Tijdens OK hoeveelheid: _____________ 
Noradrenaline: 
£ Nee 
£ Ja  hoeveelheid: _________________ 
 
Maagvolume preoperatief: _________ml 
 
Intra-operatief bloedverlies: _________ml 
 
Vocht toegediend tijdens OK: _________ml 
 
 
Postoperatief Beloop 
 
Epiduraal:  
 
£ Nee 
£ Ja   
in datum ___ / ___ / 20____  
 
 
uit datum ___ / ___ / 20____  
Postop NSAID 
£ Nee 
£ Ja 
Welke_______________ start ___ / ___ / 20____ 
 
 
 
 
 
Dosering:_____________stop ___ / ___ / 20____ 
 
 
 
 
 
Oraal / iv 
Postop Opioid  
£ Nee 
£ Ja 
1.Welke_______________ start ___ / ___ / 20____ 
 
 
 
 
 
Dosering:_____________stop ___ / ___ / 20____ 
 
 
 
 
 
Oraal / iv / im 
Patiënt identificatie nummer c c c c c c c  

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2.Welke_______________ start ___ / ___ / 20____ 
 
 
 
 
 
Dosering:_____________stop ___ / ___ / 20____ 
Oraal / iv / im 
 
Postop antibiotica  £ Nee 
£ Ja 
Welke_______________ start ___ / ___ / 20____ 
 
 
 
 
 
Dosering:_____________stop ___ / ___ / 20____ 
 
 
 
 
 
Oraal / iv 
 
Maagsonde:  
£ Nee 
£ Ja   
in datum ___ / ___ / 20____  
 
 
uit datum ___ / ___ / 20____  
 
Orale intake, 24 uur tolerantie: 
datum ___ / ___ / 20____ Tijdstip ___:___ uur 
Eerste flatus  
 
 
datum ___ / ___ / 20____ Tijdstip ___:___ uur 
Eerste defaecatie  
 
datum ___ / ___ / 20____ Tijdstip ___:___ uur 
 
 
POI:   
 
£ Nee 
£ Ja   
Interval from surgery until both the following criteria are met: 
a. Passage of flatus OR stool 
b. Tolerance of an oral diet 
These events should occur before day four postoperatively. 
 
Prolonged POI:  
£ Nee 
£ Ja   
defined if two or more of the following five criteria are met on or after day four postoperatively without 
prior resolution of “POI” (as described above): 
£ Nausea or vomiting 
£ Inability to tolerate an oral diet over last 24 h 
£ Absence of flatus over last 24 h 
£ Abdominal distension 
£ Radiologic confirmation 
 
Opname IC:  
£ Nee 
£ Ja   
in datum ___ / ___ / 20____  
 
 
uit datum ___ / ___ / 20____  
 
 
reden IC opname:_______________ 
 
Postoperatieve complicaties: 
£ Geen complicaties 
 
Naadlekkage 
£ Nee 
£ Ja, datum vaststellen: ___ /___ / 20____  
 
 
 
 
 
£ Klinische tekenen AL 
 
 
 
 
 
£ Radiologische tekenen AL 
 
 
 
 
 
£ Bevestigd bij reoperatie 
 
 
 
 
 
£ enterocutane fisteling 
 
Aspiratiepneumonie £ Nee 
£ Ja, datum vaststellen: ___ /___ / 20____  
 
 
 
 
Patiënt identificatie nummer c c c c c c c  

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Overige postoperatieve complicaties: 
 
 
 
 
 
 
 
 
Clavien-Dindo graad: 
 
 
 
 
 
 
 
 
Clavien-Dindo graad: 
 
 
 
 
 
 
 
 
Clavien-Dindo graad: 
 
 
 
 
 
 
 
 
Clavien-Dindo graad: 
 
 
 
 
 
 
 
 
Clavien-Dindo graad: 
 
 
Reoperatie:   
 
 
£ Nee 
£ Ja, datum ___ / ___ / 20_____ 
Reden: ___________________________________________________ 
 
Overplaatsing ander ziekenhuis: £ Nee 
 £ Ja, datum ___ / ___ / 20_____ 
 
Functioneel hersteld:  
 
datum ___ / ___ / 20____  
(ADL zelfstandig, eten, drinken etc) 
 
Dag van ontslag: 
 
 
datum___ / ___ / 20_____  tijd: ____:____uur 
 
Mortaliteit: 
 
£ Nee 
£ Ja, datum: ___ / ___ / 20_____ 
 
Opmerkingen: 
___________________________________________________________________
___________________________________________________________________
___________________________________________________________________ 
 
 
 
 
 
Clavien Dindo 
Classification 
Definition 
Grade I 
Any deviation from the normal postoperative course without the need for  
pharmacological treatment or surgical, endoscopic and radiological interventions 
Allowed therapeutic regimens are: drugs as anti-emetics, antipyretics,  
analgesics, diuretics and electrolytes and physiotherapy.  
This grade also includes wound infections opened at the bedside. 
Grade II 
Requiring pharmacological treatment with drugs other than such allowed for grade I complications. 
Blood transfusions and total parenteral nutrition are also included. 
Grade III 
Requiring surgical, endoscopic or radiological intervention 
       - IIIa 
Intervention not under general anaesthesia 
       - IIIb 
Intervention under general anaesthesia 
Grade IV 
Life-threatening complication (including CNS complications)* requiring IC/ICU-management 
       - IVa 
single organ dysfunction (including dialysis) 
       - IVb 
Multi-organ dysfunction 
Grade V 
Death of a patient 
  
 
Patiënt identificatie nummer c c c c c c c