Impact of Not Measuring Residual Gastric Volume on Nosocomial Pneumonia Rates in Mechanically Ventilated Patients Receiving Early Enteral Feeding: a Randomized-controlled Study
Phase: NA
Conditions: Ventilation-Associated Pneumonia
Sponsor: Centre Hospitalier Departemental Vendee

Protocol « NUTRIREA 1 » - CHD069-09 
Version No. 3 dated 18 February 2010 
 
Protocole NUTRIREA 1 
 
 
 
NCT Number : NCT01137487 
 
 
 
« Study of Impact of Not Measuring Residual Gastric Volume on 
Nosocomial Pneumonia Rates » 
 
 
 
 
Principal Investigator :   
Dr. Jean REIGNIER  
Multidisciplinary Intensive Care Unit 
Departmental Hospital Centre 
Boulevard Stéphane MOREAU 
85925 LA ROCHE-SUR-YON Cedex 
 
Promoteur :  
   Departmental Hospital Centre 
Clinical Research Unit 
Boulevard Stéphane MOREAU 
85925 LA ROCHE SUR YON Cedex 
 

 
Version No. 3 dated 18 February 2010 - Page1 of 42  
 
 
CLINICAL TRIAL PROTOCOL 
 
NUTRIREA1 
 
TRIAL CODE 
PHRI2010 – JR/NUTRIREA1 
STRATEGY 
No monitoring of gastric residue 
 
FULL TITLE 
 
 
Absence of gastric residue measurement and risk of 
nosocomial pneumonia in patients undergoing 
mechanical ventilation and enteral nutrition – 
Randomised multicentre equivalence trial 
 
INDICATION(S) (TARGET) 
Patients undergoing invasive mechanical ventilation 
 
PRINCIPAL INVESTIGATOR 
 
Dr Jean REIGNIER 
 
 
Multidisciplinary Intensive Care Unit 
Departmental Hospital Centre  
La Roche -sur-Yon 
 
PROTOCOL VERSION NO. 
 
Version No. 3 
 
 
DATE OF PROTOCOL 
 
18 February 2010 
 
CPP 
POITIERS WEST III 
 
AFSSAPS 
 
 
Not applicable  
 
THIS CONFIDENTIAL DOCUMENT ISLA PROPRIETE DU CHD OFLA ROCHE 
SUR YON. NO UNPUBLISHED INFORMATION CONTAINED IN THIS 
DOCUMENT MAY BE DISCLOSED WITHOUT THE PRIOR WRITTEN 
PERMISSION OF THE CHD OF LA ROCHE SUR YON. 
 
 
 
 
Subscribe to DeepL Pro to edit this document. 
Visit www.DeepL.com/pro for more information. 

 
 
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Version No. 3 dated 18 February 2010 - Page2 of 42  
 
SUMMARY 
 
1. 
GENERAL ................................................................................................................................................... 9 
1.1. 
TITLE .................................................................................................................................................... 9 
1.2. 
STUDY COORDINATION AND MONITORING ............................................................................................ 9 
1.3. 
INVESTIGATORS .................................................................................................................................... 9 
1.3.1. 
Coordinating investigator ............................................................................................................... 9 
1.3.2. 
Associate investigators .................................................................................................................... 9 
1.4. 
METHODOLOGISTS – BIOSTATISTICIANS ............................................................................................... 9 
2. 
SCIENTIFIC RATIONALE AND GENERAL DESCRIPTION OF THE RESEARCH ................... 11 
2.1. 
SUMMARY OF THE BENEFITS, IF ANY, AND THE FORESEEABLE AND KNOWN RISKS FOR PERSONS 
PARTICIPATING IN THE RESEARCH ..................................................................................................................... 13 
2.2. 
STATEMENT INDICATING THAT THE RESEARCH WILL BE CONDUCTED IN ACCORDANCE WITH THE 
PROTOCOL AND GOOD CLINICAL PRACTICE........................................................................................................ 14 
2.3. 
DESCRIPTION OF THE POPULATION TO BE STUDIED ............................................................................. 14 
3. 
RESEARCH OBJECTIVES ..................................................................................................................... 14 
3.1. 
PRIMARY OBJECTIVE ........................................................................................................................... 14 
3.2. 
SECONDARY OBJECTIVES .................................................................................................................... 14 
4. 
IMPACT ..................................................................................................................................................... 15 
5. 
RESEARCH DESIGN ............................................................................................................................... 15 
5.1. 
PRECISE STATEMENT OF THE PRIMARY EVALUATION CRITERIA AND, WHERE APPLICABLE, SECONDARY 
EVALUATION CRITERIA ...................................................................................................................................... 15 
5.1.1. 
Primary evaluation criterion ......................................................................................................... 15 
5.1.2. 
Secondary evaluation criteria ....................................................................................................... 16 
5.2. 
DESCRIPTION OF THE RESEARCH METHODOLOGY, ACCOMPANIED BY A SCHEMATIC PRESENTATION 
SPECIFYING, IN PARTICULAR, THE PLANNED VISITS AND EXAMINATIONS .......................................................... 17 
5.2.1. 
Experimental design ...................................................................................................................... 17 
5.2.2. 
Study procedure ............................................................................................................................ 17 
5.2.2.1. 
Inclusion .............................................................................................................................................. 17 
5.2.2.2. 
Enteral nutrition protocol..................................................................................................................... 18 
5.2.2.3. 
Study-specific intervention: monitoring or non-monitoring of gastric residue .................................... 19 
5.2.2.4. 
Treatment of intolerance ...................................................................................................................... 20 
5.2.2.5. 
Patient follow-up ................................................................................................................................. 24 
5.3. 
DESCRIPTION OF MEASURES TAKEN TO REDUCE AND AVOID BIAS ....................................................... 25 
5.3.1. 
Randomisati  .................................................................................................................................. 25 
5.3.2. 
Blinding methods ........................................................................................................................... 25 
5.4. 
EXPECTED DURATION OF PARTICIPATION AND DESCRIPTION OF THE TIMING AND DURATION OF ALL 
TRIAL PERIODS, INCLUDING FOLLOW-UP, IF APPLICABLE ................................................................................... 25 
5.5. 
DESCRIPTION OF RULES FOR PERMANENT OR TEMPORARY DISCONTINUATION .................................... 25 
5.5.1. 
Discontinuation of a subject's participation in the research ......................................................... 25 
5.5.2. 
Discontinuation of part or all of the research ............................................................................... 26 
5.6. 
DATA COLLECTED ............................................................................................................................... 26 
6. 
SELECTION AND EXCLUSION OF SUBJECTS FROM THE RESEARCH................................... 27 
6.1. 
INCLUSION CRITERIA FOR INDIVIDUALS PARTICIPATING IN THE RESEARCH ......................................... 27 
6.2. 
CRITERIA FOR NON-INCLUSION OF INDIVIDUALS IN THE RESEARCH .................................................... 28 
6.3. 
RECRUITMENT PROCEDURES ............................................................................................................... 28 
7. 
PRODUCTS ADMINISTERED TO RESEARCH PARTICIPANTS……...30  
7.1. 
AUTHORISED TREATMENTS ................................................................................................................. 30  
7.2. 
UNAUTHORISED TREATMENTS ............................................................................................................ 30 
8. 
STATISTICS.............................................................................................................................................. 29 
8.1. 
DESCRIPTION OF PLANNED STATISTICAL METHODS, INCLUDING THE SCHEDULE FOR PLANNED INTERIM 
ANALYSES ......................................................................................................................................................... 29 

 
 
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8.2. 
PLANNED NUMBER OF SUBJECTS TO BE INCLUDED IN THE RESEARCH, AND PLANNED NUMBER OF 
SUBJECTS AT EACH RESEARCH SITE WITH STATISTICAL JUSTIFICATION ............................................................. 32  
8.3. 
PLANNED LEVEL OF STATISTICAL SIGNIFICANCE ................................................................................. 32  
8.4. 
STATISTICAL CRITERIA FOR STOPPING THE RESEARCH ........................................................................ 31 
8.5. 
METHOD FOR HANDLING MISSING, UNUSED OR INVALID DATA ........................................................... 31 
8.6. 
MANAGEMENT OF CHANGES TO THE INITIAL STRATEGY ANALYSIS PLAN ............................................ 31 
8.7. 
SELECTION OF INDIVIDUALS TO BE INCLUDED IN THE ANALYSES ........................................................ 33  
9. 
JUSTIFICATION FOR THE REQUEST FOR VALIDATION OF ROUTINE CARE RESEARCH
 
33 
10. 
RIGHT OF ACCESS TO SOURCE DATA AND DOCUMENTS ........................................................ 34  
10.1. 
ACCESS TO DATA ................................................................................................................................ 34  
10.2. 
SOURCE DOCUMENTS .......................................................................................................................... 34 
10.3. 
DATA CONFIDENTIALITY ..................................................................................................................... 33 
11. 
QUALITY ASSURANCE ......................................................................................................................... 33 
12. 
ETHICAL EVALUATIONS OF SPECIFIC MONITORING PROCEDURES SET OUT IN THE 
PROTOCOL ........................................................................................................................................................ 35  
12.1. 
COMMITTEE FOR THE PROTECTION OF INDIVIDUALS........................................................................... 35 
12.2. 
SUBSTANTIAL MODIFICATIONS ........................................................................................................... 34 
12.3. 
INFORMATION LETTER AND LETTER OF NON-OBJECTION ..................................................................... 34 
13. 
DATA PROCESSING AND DOCUMENT AND DATA RETENTION .............................................. 34 
13.1. 
OBSERVATION LOG ............................................................................................................................. 34 
13.2. 
DATA ENTRY AND OUTPUT .................................................................................................................. 36  
13.3. 
CNIL .................................................................................................................................................. 35 
14. 
FINANCING AND INSURANCE ............................................................................................................ 35 
14.1. 
STUDY BUDGET ................................................................................................................................... 35 
14.2. 
INSURANCE ......................................................................................................................................... 37  
15. 
FEASIBILITY OF THE STUDY ............................................................................................................. 35 
16. 
PUBLICATION RULES ........................................................................................................................... 36 
17. 
REFERENCES TO SCIENTIFIC LITERATURE AND RELEVANT DATA USED AS 
REFERENCES FOR THE RESEARCH .......................................................................................................... 39  

 
 
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SIGNATURE OF INVESTIGATOR COORDINATOR 
 
 
 
 
 
 
 
I have read all the pages of the clinical trial protocol. I confirm that it contains all the 
information necessary to conduct the trial. I undertake to conduct the trial in accordance 
with the protocol and the terms and conditions set out therein.  
 
 
I also undertake to ensure that the investigators and other qualified members of my team 
have access to copies of this protocol and the documents relating to the conduct of the trial 
so that they can work in accordance with the provisions contained in these documents.  
 
 
 
 
NAME: Dr Reignier 
 
 
Signature: …………………………………………….. 
 
 
 
 
 
 
Date: ___________________ 
 
 
 

 
 
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Version No. 3 dated 18 February 2010 - Page5 of 42  
 
SUMMARY 
 
TITLE 
Absence of gastric residue measurement and risk of nosocomial 
pneumonia in patients on mechanical ventilation and enteral nutrition: 
Randomised multicentre equivalence trial - NUTRIREA1 
COORDINATING 
INVESTIGATOR  
Dr Jean REIGNIER 
Multidisciplinary Intensive Care Unit 
Departmental Hospital Centre  
La Roche -sur-Yon 
Tel: 02.51.44.62.12 
Fax: 02.51.44.62.94 
jean.reignier@chd-vendee.fr 
PROTOCOL VERSION  
Version no. 3 
JUSTIFICATION/CONTEXT  
Early enteral nutrition is part of the basic treatment for patients on 
mechanical ventilation. However, despite its established benefits and 
widely disseminated professional recommendations, studies show that 
the use of enteral nutrition is far from systematic and that the 
achievement of nutritional goals is unpredictable. These difficulties are 
mainly attributable to the intolerance experienced by around 50% of 
patients and the associated risks of nosocomial pneumonia and 
malnutrition. This intolerance is attributed to gastric hypokinesia, which 
causes poor gastric emptying and increased gastric residue, with a high 
risk of gastro-oesophageal reflux and nosocomial pneumonia. These 
affect 8 to 27% of ventilated patients and are associated with high 
mortality (25 to 50%). In order to reduce these risks, regular monitoring 
of gastric residual volume is a key measure in the monitoring of enteral 
nutrition. However, the validity of this measurement is increasingly 
being questioned: the technique is not standardised; its "normal" value 
is unknown; increasing its threshold value does not affect the occurrence 
of signs of intolerance, the frequency of regurgitation, or the frequency 
of gastric content inhalation. No limit value for gastric residue has been 
set above which the risk of regurgitation and pneumonia increases.  
Measuring gastric residue therefore appears to be of little relevance in 
reducing the risk of nosocomial pneumonia. By leading to unjustified 
interruptions in nutrition, it may also result in poorer enteral nutrition 
delivery. 
MAIN OBJECTIVE  
To verify that the rates of patients with at least one case of ventilator-
associated pneumonia (VAP) are equivalent regardless of whether 
gastric residue is monitored or not. 
SECONDARY OBJECTIVES  
The secondary objectives are to compare the following between the two 
groups: 
▪ 
the incidence density of VAP. 
▪ 
the VAP rate. 
▪ 
the rate of patients who vomited at least once. 
▪ 
the rate of patients who experienced diarrhoea. 
▪ 
the rate of patients who achieved daily calorie goals during the 
first week. 
▪ 
The number of calories administered enterally. 
▪ 
Mortality in intensive care, at 28 days, 90 days, and in hospital. 
▪ 
Albumin levels at the end of mechanical ventilation, on day 7 
(if mechanical ventilation continued beyond 7 days), and upon 
discharge from intensive care. 
▪ 
The frequency of other nosocomial infections:  
o Bacteremia. 

 
 
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o Central venous catheter infections. 
o Urinary tract infections. 
▪ 
Descriptive bacteriological data. 
▪ 
Length of stay in intensive care 
▪ 
Duration of mechanical ventilation 
 
PRIMARY ENDPOINT  
Percentage of patients who developed at least one VAP 
SECONDARY ENDPOINTS  
▪ 
Incidence density of nosocomial pneumonia per 1,000 days of 
mechanical ventilation  
▪ 
Rate of VAP per 100 patients  
▪ 
Rate of patients who vomited at least once per 100 patients  
▪ 
Rate of patients who experienced diarrhoea per 100 patients  
▪ 
Rate of patients who achieved daily caloric goals during the first 
week per 100 patients 
▪ 
Number of calories administered enterally  
▪ 
Mortality in intensive care, at 28 days, 90 days, in hospital. 
▪ 
Albumin levels at the end of mechanical ventilation, on day 7 (if 
mechanical ventilation continued beyond 7 days), and on 
discharge from intensive care. 
▪ 
Percentage of patients who developed at least one bacteraemia 
and incidence rate per 1,000 days of hospitalisation in intensive 
care. 
▪ 
Percentage of patients with at least one central venous catheter 
infection and incidence rate per 1,000 days of catheterisation. 
▪ 
Percentage of patients who developed at least one urinary tract 
infection 
and 
incidence 
density 
per 
1,000 
days 
of 
catheterisation. 
▪ 
Descriptive bacteriological data 
▪ 
Length of stay in intensive care 
▪ 
Duration of mechanical ventilation 
▪ 
Rate of intolerant patients in the "residual monitoring" group 
METHODOLOGY/STUDY 
DESIGN  
Randomised, multicentre, open-label equivalence trial 
SUBJECT INCLUSION 
CRITERIA  
▪ 
Patients undergoing invasive mechanical ventilation 
▪ 
All patients requiring nasogastric tube feeding within 36 hours 
of intubation and for a foreseeable period of at least 2 days 
▪ 
Aged over 18 
▪ 
Who have received information and do not object to 
participating in the study 
▪ 
Affiliated with a social security scheme 
SUBJECT EXCLUSION 
CRITERIA 
▪ 
Invasive mechanical ventilation started more than 36 hours ago 
▪ 
Expected duration of intubation less than 48 hours 
▪ 
Patients treated with prone positioning at the time of inclusion 
(prone positioning after inclusion in the study will not be a 
reason for exclusion from the study) 
▪ 
Recent digestive surgery (<1 month) 
▪ 
History of gastrectomy, oesophagectomy, 
duodenopancreatectomy 
▪ 
Presence of gastrostomy or jejunostomy 
▪ 
Active digestive haemorrhage 
▪ 
Moribund 
▪ 
Minor (<18 years old) 
▪ 
Legally incapacitated (under guardianship, curatorship) 
▪ 
Pregnant, labouring or breastfeeding woman. 

 
 
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▪ 
Patient hospitalised without consent. 
▪ 
Patient deprived of liberty by court order. 
▪ 
Patients admitted to a health or social care facility. 
▪ 
Prior inclusion in a randomised research protocol, the primary 
endpoint of which is the tolerance of enteral nutrition or the 
prevention of nosocomial pneumonia. 
▪ 
Contraindication to the administration of prokinetics 
(hypersensitivity to metoclopramide or erythromycin, heart 
rhythm disorders such as QT prolongation or torsades de 
pointes). 
 
STRATEGIES/PROCEDURES 
In both groups, intolerance to enteral nutrition will be monitored based 
on the presence or absence of vomiting. In the "residue" group, it will 
also be monitored by checking gastric residue every 6 hours according 
to a well-established protocol.  
 
NUMBER OF PATIENTS  
420 patients in total, i.e. 210 in each arm 
DURATION OFLA 
RECHERCHE  
Duration of the inclusion period: 18 months 
Duration of participation for each patient: duration of mechanical 
ventilation. 
Total duration of the study: 24 months. 
EXPECTED OUTCOMES  
If the hypothesis is confirmed, this study will make it possible to 
discontinue gastric residue measurements during enteral nutrition in 
ventilated patients. The nursing workload will be reduced. Strategies for 
preventing ventilator-associated pneumonia can be refocused on 
measures that have been proven effective. Patients will also likely be 
better nourished.  
 
 

 
 
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List of abbreviations 
 
 
 
AFSSaPS 
French Health Products Safety Agency 
AMM 
Marketing Authorisation 
ARC 
Clinical Research Associate 
BPC 
Good Clinical Practice 
CPP 
Committee for the Protection of Individuals  
CNIL 
French Data Protection Authority 
CRF 
Case Report Form 
EvIG  
Serious Adverse Event 
EIG  
Serious Adverse Effect 
EIGI  
Unexpected Serious Adverse Effect 
ICH 
International Conference on Harmonisation 
IDE 
State-registered nurse 
INSERM 
la SantéNational Institute of Health and Medical Research 
MR 
Reference Methodology 
RCP 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEC 
Clinical Research Technician 
  
 

 
 
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1. General information  
1.1. Title 
Absence of gastric residue measurement and risk of nosocomial pneumonia in patients 
undergoing mechanical ventilation and enteral nutrition: Randomised multicentre equivalence 
trial - Acronym: NUTRIREA1 
 
1.2. Study coordination and monitoring 
Clinical Research Unit 
Departmental Hospital Centre  
La Roche -sur-Yon, 85000 
 
1.3. Investigators 
1.3.1. Coordinating investigator 
 
Dr Jean REIGNIER 
Multidisciplinary Intensive Care Unit 
Departmental Hospital Centre  
La Roche -sur-Yon 
Tel: 02.51.44.62.12 
Fax: 02.51.44.62.94 
jean.reignier@chd-vendee.fr 
 
1.3.2. Associate investigators 
 
Poitiers: Prof. René Robert. 
Angoulême: Dr Valérie Gissot. 
Orléans: Dr Thierry Boulain. 
Limoges: Dr Bruno François. 
Tours: Dr Emmanuelle Mercier. 
 
1.4. Methodologists – biostatisticians s 
 

 
 
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Dr Jérôme DIMET 
Clinical Research Unit 
Vendée Departmental Hospital Centre 
85000La Roche sur Yon 
Tel: 02.51.44.61.61 ext. 20 12 
Fax: 02.51.44.62.98 
 
Dr Bruno Giraudeau 
INSERM Clinical Investigation Centre 0202 
Tours University Hospital - 2 Bd Tonnellé 
37044 Tours cedex 9 
Tel: 02.47.47.46.18 - Fax: 02.47.47.46.62 
 
Amélie Le Gouge 
INSERM Clinical Investigation Centre 0202 
Tours University Hospital - 2 Bd Tonnellé 
37044 Tours cedex 9 
Tel: 02.47.47.86.93 - Fax: 02.47.47.46.62 
 
  
 

 
 
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2. Scientific justification and general description of the research  
 
In everyday resuscitation practice, nutrition is part of the treatments routinely prescribed 
and administered. Enteral administration is recommended and should be preferred[1-4] . It 
appears to be associated with better preservation of the digestive mucosa, lower rates of 
bacterial translocation, fewer secondary infections and a reduction in length of stay and 
mortality[5-23] . Its beneficial effects are said to be even more noticeable when administered 
early after admission to intensive care and to critically ill patients with multiple organ 
failure[24, 25] .  
Nevertheless, despite its established benefits and widely disseminated professional 
recommendations, studies show 1) that the use of early enteral nutrition is far from systematic, 
2) that its methods of administration vary greatly from one department to another, and 3) that 
even in units with established practices, the achievement of nutritional goals is unpredictable[9, 
26-33] . A recent German multicentre study of a cohort of critically ill patients (mortality rate 
of 54%) showed that 35.1% of patients were fed exclusively by parenteral nutrition, 34.6% 
received combined enteral and parenteral nutrition, and only 20.1% received exclusive enteral 
nutrition[9] . These difficulties in generalising and using a treatment with supposed benefits 
can be attributed to several factors. Some are related to the published studies themselves: the 
benefits of enteral nutrition demonstrated primarily in surgical patients; the absence of large-
scale randomised studies; and the conclusions of the recommendations based on meta-analyses 
that are difficult to interpret[34, 35] . Others are related to the difficulties in establishing enteral 
nutrition due to intolerance in approximately 50% of patients and the associated risks of 
nosocomial pneumonia and malnutrition[26, 30, 32, 36] . This intolerance is attributed to gastric 
hypokinesia, which causes poor gastric emptying and increased gastric residue, with a high risk 
of gastro-oesophageal reflux and therefore inhalation of gastric contents and nosocomial 
pneumonia[37-44] .  
The fear of digestive intolerance and its potential consequences, primarily pulmonary 
infections, is a major obstacle to the satisfactory administration of early enteral nutrition[26, 
29-32, 36, 45-48] . The sequence of incomplete gastric emptying, gastro-oesophageal reflux, 
inhalation and nosocomial pneumonia is on everyone's mind and feared by healthcare teams. 
Nosocomial pneumonia remains a major complication of mechanical ventilation. It affects 8 to 
27% of patients and is associated with an increase in the length of stay in intensive care and a 
high risk of mortality (25 to 50%)[49] . To protect patients from these disadvantages, regular 
monitoring of residual gastric volume is a key measure in the supervision of enteral 

 
 
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nutrition[24, 47, 49-56] . An increased residual gastric volume is thought to reflect incomplete 
gastric emptying and is a warning sign of complications. For the most part, it therefore serves 
as a warning sign that enteral nutrition should be discontinued. However, repeated interruptions 
in enteral nutrition administration due to exceeding a given residual gastric volume value are a 
major obstacle to achieving nutritional goals[57] . Furthermore, the validity of residual gastric 
volume measurement is increasingly being questioned[58] . 
The "normal" residual gastric volume is unknown. It varies depending on the rate of 
administration of the nutritional solution and gastric emptying, which is itself physiologically 
regulated by the enterogastric reflex linked to the arrival of nutrients in the proximal intestine. 
Furthermore, it is likely that gastric volume is not constant and experiences peaks that are not 
necessarily taken into account when measurements are taken at regular intervals (usually every 
6 hours). Modelling of gastric emptying has shown that residual gastric volume is highly 
variable, that there is no "normal" value, and that the decision to stop administering nutritional 
solutions at an arbitrarily set residual value has no physiological basis[59] . Furthermore, 
residual gastric volume is not correlated with other clinical signs of digestive intolerance to 
nutrition (distension, pain, radiographic abnormalities)[60] . Increasing its threshold value does 
not affect the occurrence of signs of intolerance, the frequency of regurgitation, or the frequency 
of gastric content inhalation[61, 62] . Furthermore, no limit value for gastric residue has been 
set above which the risk of regurgitation and pneumonia increases[63] . Recommendations 
remain very vague on this point. The American text specifies that "enteral nutrition requires 
adequate gastric motility" and that "a residual gastric volume greater than 150 ml requires a 
reduction in the rate of administration, consideration of intravenous administration, or even 
direct administration of the solution into the small intestine", "the role of prokinetic agents such 
as cisapride or erythromycin not being established"[1] . The French consensus defines a gastric 
residue limit of 200 ml[4] . The Canadian recommendations state that the use of a prokinetic 
agent "may be considered" in order to improve enteral nutrition administration; they do not 
specify the criteria used to define enteral nutrition intolerance[2] . European recommendations 
only mention that "prokinetic administration should be considered in cases of enteral nutrition 
intolerance," specifying "in cases of increased gastric residue," but without defining the 
measurement technique, frequency of monitoring, or threshold value[2] . These data explain 
why the residual gastric volume values used to suspect digestive intolerance vary in the 
literature from 50 to 500 ml and are ultimately chosen arbitrarily by healthcare teams. 
Furthermore, the technique for measuring residual gastric volume is not standardised, and 

 
 
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gastric residue measured by aspiration through a gastric tube, a technique commonly used at 
the patient's bedside, does not necessarily reflect the actual gastric residue. For this to be the 
case, each aspiration through the gastric tube would have to remove all gastric contents. This is 
never certain and depends on factors such as the calibre of the tube and its position[58, 64] . 
The residual gastric volume may therefore be underestimated by this technique. Currently, the 
only other techniques available use the measurement of the concentration of dyes or radioactive 
markers after their dilution in the gastric contents and are not validated or applicable in routine 
bedside practice[65-70] . Finally, the causal link between regurgitation of enteral nutrition fluid 
and nosocomial pneumonia is being questioned. A recent study found no correlation between 
the risk of nosocomial pneumonia and the frequency of regurgitation or inhalation of gastric 
contents[61] . Bacterial colonisation and inhalation of pharyngo-laryngeal secretions appear to 
be more decisive factors than those of gastric contents[49] . 
In summary, measuring gastric residue appears to be irrelevant in preventing the risks of 
regurgitation and nosocomial pneumonia. It may also lead to poorer enteral nutrition delivery. 
A study conducted in the general intensive care unit atLa Roche sur Yon showed that the 
introduction of an enteral nutrition administration protocol that did not include monitoring of 
residual gastric volume allowed for the administration of more enteral nutrition without 
increasing the risk of vomiting and nosocomial pneumonia[71] . However, this study has 
methodological limitations that reduce its scope: it is a single-centre, before-and-after study 
with an insufficient number of patients to draw definitive conclusions about the absence of 
nosocomial pulmonary infection risk. 
 
The objective of this research is therefore to verify, in a prospective, multicentre, 
randomised and controlled study, the hypothesis that monitoring residual gastric volume does 
not reduce the risk of ventilator-associated pneumonia in patients receiving early enteral 
nutrition. 
 
2.1. Summary of the benefits, if any, and the foreseeable and known risks for individuals 
participating in the research 
 
This study aims to standardise the practice of enteral nutrition in patients treated with 
mechanical ventilation: patients will be fed according to specific protocols that comply with 

 
 
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current recommendations. This standardisation of enteral nutrition delivery will in itself be 
beneficial to patients participating in the study[72] . 
This study does not pose any additional risk to patients. Gastric residue monitoring is 
routinely performed in some departments, but is not standard practice in all. 
 
2.2. Statement indicating that the research will be conducted in accordance with the 
protocol and good clinical practice  
 
The investigator also undertakes to ensure that this research is conducted: 
- in accordance with the protocol, 
- in accordance with current French and international good clinical practice. 
 
 
2.3. Description of the population to be studied 
 
This study will therefore focus on adult patients admitted to intensive care who require 
nasogastric tube feeding within 36 hours of intubation and for a foreseeable period of at least 
two days. The selection criteria are described in Chapter 5.  
 
 
3. Objective s of the research 
3.1. Main objective 
 
The primary objective of this research is to test the hypothesis that the rates of patients with 
at least one case of ventilator-associated pneumonia (VAP) are equivalent regardless of whether 
gastric residue is monitored or not.  
 
3.2. Secondary objectives 
 
The secondary objectives are to compare the following between the two groups: 
▪ the incidence density of VAP. 
▪ the VAP rate. 
▪ the rate of patients who vomited or regurgitated at least once. 
▪ the rate of patients who experienced diarrhoea. 
▪ the rate of patients who achieved daily calorie goals during the first week. 

 
 
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▪ The number of calories administered enterally. 
▪ Mortality in intensive care, at 28 days, 90 days, and in hospital. 
▪ Albumin levels at the end of mechanical ventilation, on day 7 (if mechanical ventilation 
continued beyond 7 days), and upon discharge from intensive care. 
▪ the frequency of other nosocomial infections:  
o bacteremia 
o central venous catheter infections. 
o Urinary tract infections. 
▪ Descriptive bacteriological data. 
▪ length of stay in intensive care 
▪ Duration of mechanical ventilation 
 
4. Impact 
 
If the study hypothesis is confirmed, gastric residue measurement could be removed from 
protocols, which would limit interventions on patients, prioritise care proven to be effective in 
preventing nosocomial pneumonia, reduce the nursing workload and, probably, improve 
nutrition for critically ill patients. 
 
5. Research design 
 
5.1. Precise statement of the main evaluation criteria and, where applicable, secondary 
evaluation criteria 
5.1.1. Primary endpoint 
 
The primary endpoint is the proportion of patients who developed at least one VAP 
(numerator for each group: number of patients who developed at least one VAP after the start 
of mechanical ventilation and less than 2 days after extubation; denominator: total number of 
patients included in the group concerned). 
A diagnosis of VAP will be suspected when parenchymal opacity appears or persists on 
chest X-ray, associated with at least two of the following criteria: body temperature ≥38.5 or 
≤35.5ºC, hyperleukocytosis (>10,000/mm³3 ) or leukopenia (<4000/mm3 ), and purulent 
tracheobronchial aspirates. The diagnosis must be confirmed by a positive semi-quantitative 

 
 
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bacteriological examination: LBA (>10-4  cfu/ml), brush (>10-3  cfu/ml), tracheal aspiration 
(>10-6  cfu/ml) or PDP (>10-3  cfu/ml). 
This method of diagnosing VAP, which includes the requirement for a semi-quantitative 
bacteriological criterion, is part of standard resuscitation practice and is used in all six 
departments participating in the study[49, 73] . In addition, all VAP diagnoses will be 
confirmed by an adjudication committee. 
 
5.1.2. Secondary evaluation criteria 
 
▪ Incidence density of nosocomial pneumonia per 1,000 days of mechanical ventilation: 
the incidence density will be defined as the ratio between the number of patients who 
developed at least one VAP after the start of mechanical ventilation and less than 2 days 
after extubation and the risk period. The risk period will be defined as:  
o the sum of days of exposure to mechanical ventilation for patients who did not 
develop VAP  
o the days of exposure preceding infection only for patients with VAP. 
▪ Average number of VAP (numerator for each group: total number of VAP occurring 
after the start of mechanical ventilation and less than 2 days after extubation; 
denominator: total number of patients included in the group concerned). 
▪ Rate of patients who vomited or regurgitated at least once per 100 patients (numerator 
in each group: total number of patients who vomited or regurgitated; denominator: total 
number of patients included in the group concerned). 
▪ Rate of patients who experienced at least one episode of diarrhoea per 100 patients 
(numerator in each group: total number of patients who experienced diarrhoea; 
denominator: total number of patients included in the group concerned). Diarrhoea is 
defined as the occurrence of more than 300 ml of liquid stool if the patient has a faecal 
collector or more than 4 loose stools per day[72] . 
▪ Percentage of patients who achieved daily calorie goals during the first week per 100 
patients (numerator in each group: number of patients who received 100% of the 
prescribed goal each day of the first week of enteral nutrition; denominator: total 
number of patients included in the group concerned) 
▪ Number of calories administered enterally:  
o cumulative total during the first week  

 
 
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o daily average during the first week of nutrition 
o Daily average throughout the entire period of mechanical ventilation. 
▪ Mortality in intensive care, at 28 days, 90 days, and in hospital. 
▪ Albuminemia at the end of mechanical ventilation, on day 7 (if mechanical ventilation 
continued beyond 7 days), and upon discharge from intensive care. 
▪ Other nosocomial infections:  
o Bacteremia: percentage of patients who developed at least one episode of 
bacteremia and incidence rate per 1,000 days of hospitalisation in intensive care. 
o Central venous catheter infections: percentage of patients who had at least one 
central venous catheter infection and incidence rate per 1,000 days of 
catheterisation. 
o Urinary tract infections: percentage of patients who developed at least one 
urinary tract infection and incidence rate per 1,000 days of catheterisation. 
▪ Descriptive bacteriological data: germs identified as causing VAP and antibiotic 
resistance profiles. 
▪ Length of stay in intensive care 
▪ Duration of mechanical ventilation 
▪ Rate of patients intolerant to enteral nutrition per 100 patients in the "residual" group. 
Intolerance in the intervention group is defined by the occurrence of significant 
regurgitation or vomiting or a residual volume >250 ml.  
 
5.2. Description of the research methodology, accompanied by a schematic presentation 
specifying in particular the planned visits and examinations  
5.2.1. Experimental design 
 
This is a randomised, controlled, multicentre, open-label equivalence trial comparing two 
groups of patients treated with invasive mechanical ventilation and receiving early enteral 
nutrition: one where residual gastric volume is monitored, the other where it is not. 
 
5.2.2. Study procedure 
5.2.2.1.Inclusion 
 

 
 
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Patients must be included in the study within 36 hours of intubation. Information will be 
provided and consent to participate in the study will be sought from the patient if they are 
conscious or from their relatives if they are not. If the information has been provided to 
relatives, consent will be sought from the patient as soon as their level of consciousness allows. 
A table tracking patients who have been offered the study will be kept up to date, noting 
any reasons for non-inclusion and objections to participation. 
 
After verifying the inclusion and exclusion criteria and obtaining the consent of the patient 
or their relatives, the investigator may include the patient. Upon inclusion, the patient's 
demographic data, characteristics and vital signs will be collected: date of birth, sex, date of 
admission to intensive care, reason for admission to intensive care, McCabe and Knaus scores, 
previous chronic conditions, weight, height, BMI, SOFA. 
 
5.2.2.2. enteral nutrition protocol  
 
The enteral nutrition protocol and gastric residue monitoring must be standardised according to 
the elements defined below.  
 
Enteral administration should begin as soon as possible after invasive mechanical ventilation is 
initiated, and must begin within 36 hours of intubation. The prescribed solutions will be iso-
osmotic, isocaloric and normoproteic (such as Nutrison, Normoréal, Isosource) during the first 
week, then left to the discretion of the practitioner. Additional enteral water intake will be 
limited as much as possible during the first week of the study. The calorie target for each patient 
will be calculated based on weight and will be 20-25 kcal/kg/day during the acute phase (limited 
to a maximum of 7 days) and then 25-30 ml/kg/day. In obese patients (BMI> 30), it will be 
limited to the patient's theoretical weight for a BMI of30. L The actual administration of enteral 
nutrition must be monitored regularly based on the volumes administered and their adequacy 
in relation to the predefined daily targets. Nutrition will be prescribed in terms of flow rate 
(ml/hour) and started immediately at the prescribed flow rate (no gradual increase). Nutrition 
must be administered at a continuous flow rate over 24 hours, without interruption, via a 14 
French silicone gastric tube. Particular attention must be paid to the risk of tube obstruction, 
especially when administering medication: regularly flush the tube with 20 to 30 ml of water. 

 
 
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It is important not to fall behind schedule. Any interruption in feeding must be reported to the 
resuscitation physician. Unless specifically indicated, enteral nutrition should not be stopped 
during a CT scan. However, if it is absolutely necessary to stop enteral feeding (for a digestive 
examination, for example), the flow rate should not be increased to make up for the delay.  
In addition, the mid-gastric position of the tube will be verified by X-ray upon admission to 
intensive care or as soon as the tube is inserted, and whenever the tube is changed or 
repositioned. Finally, the patient should be placed in a supine position in a semi-sitting position, 
inclined between 30° and 45°. 
 
5.2.2.3.Study-specific intervention: monitoring or non-monitoring of gastric 
residue  
 
Enteral nutrition tolerance will be studied:  
▪ in the group without residue: only by monitoring significant regurgitation or vomiting 
(occurring outside of any care or mobilisation, of enteral nutrition solution in the mouth, 
outside or in the intubation tube) 
▪ in the residue group: by regularly measuring gastric residue every 6 hours and 
monitoring significant regurgitation or vomiting. The measurement of gastric residual 
volume (residue group only) will be performed:  
o by aspirating all residue through the gastric tube using a 50 ml syringe with a 
conical tip. 
o every 6 hours at fixed times: 6 a.m., 12 p.m., 6 p.m. and midnight. The value is 
recorded on the monitoring sheet. 
 
The aspirated gastric residue must be reinjected after measurement unless it is >250ml. If the 
gastric residue is > 250ml: 
o it must be measured in its entirety 
o it must not be reinjected 
o it must be deducted from the volume of enteral nutrition administered 
 
As patients will be cared for by teams that may vary from one day to the next, every effort will 
be made to ensure that caregivers know which randomisation arm the patient has been assigned 
to. In particular, a signalling system will be put in place in the patient's file in terms of 
prescriptions and monitoring signs. 

 
 
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Diarrhoea will also be monitored. It is defined as the occurrence of more than 300 ml of liquid 
stools or more than 4 loose stools per day[72] . Its observation requires a diagnostic and 
therapeutic approach (Appendix 2). 
 
5.2.2.4.Treatment of intolerance 
 
Intolerance will be defined in both groups by the patient vomiting or regurgitating significantly. 
Simple regurgitation of a minimal amount (frequent in the prone position), vomiting caused by 
tracheal aspiration, and oral care will not be considered signs of intolerance. In addition, in the 
"residue monitoring" group, a gastric residue volume > 250 ml will also be considered 
intolerance.  
 
Enteral nutrition intolerance requires two measures: 
▪ Firstly: to start treatment with a prokinetic agent after confirming that there are no 
contraindications and following a doctor's prescription. Investigating departments will 
use the prokinetic agent of their choice, according to their usual care protocol. This 
treatment will be continued until a period of 48 hours of good tolerance to the maximum 
prescribed flow rate has been achieved. It must then be discontinued. 
▪ Secondly, if the patient remains intolerant, the flow rate will be reduced by 25 ml/h 
every 6 hours for as long as the patient remains intolerant. Enteral feeding will therefore 
only be stopped (and the gastric tube placed in suction) if poor tolerance is observed at 
a flow rate ≤ 25 ml/h. 
 
The doctor must be notified of any interruption in feeding. This precaution must be particularly 
observed for patients treated with insulin. Enteral feeding is resumed at the prescribed flow rate 
(in accordance with the patient's needs) after 6 hours without any new signs of digestive 
intolerance. 
 

 
 
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CAUTION: 
Patients on DV 
 
Systematic 
PROKINETICS 
from day 1 ER  DV 
NE group WITH VGR: DECISION TREE 
MEDICAL PRESCRIPTION 
OF LA NUTRITION 
ENTERALE 
START OF ENTERAL NUTRITION  
As early as possible (<36 hours after intubation) 
Maximum flow rate from the outset according 
to the prescribed objective
LA TOLERANCE DIGESTIVE 
MONITORING  
➔GASTRIC RESIDUE 
Measured every 6 hours 
➔VOMITING/REGURGITATION 
RESIDUE G 
≤ 250 ml 
Reinject 
The residue 
Continue enteral nutrition at 
maximum flow rate or increase it 
back to maximum flow rate if 
Ière  start PROKINETIC on 
P.M.  up to 48 hours of 
tolerance 
at the maximum prescribed 
flow rate 
REGURGITATION 
VOMITING 
Or 
RESIDUE G > 250 ml 
Aspirate all residue 
DO NOT REINJECT 
Subtract the 
If Flow rate ≤ 25 
ml/h
If flow rate > 25 
ml/h 
DECREASE the 
IF INSULIN THERAPY 
Capillary blood glucose 
monitoring every hour 
Until resumption 
Resume maximum 
flow rate after 6 
hours unless 
otherwise prescribed 
Notify the doctor 
IMPERATIVE: 
Radiological control of the mediogastric position of the tube 
before each start of enteral feeding, then systematically at 
each change or repositioning of the tube. 
IInd 
Modification of 
enteral nutrition 
flow rate 
REGURGITATION 
VOMITING 
Or 
RESIDUE G > 250 ml 
Aspirate all residue 
DO NOT REINJECT 
Subtract the 
discarded volume
YES 
NO 

 
 
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Version No. 3 dated 18 February 2010 - Page22 of 42  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
YES 
Ist  start PROKINETIC on 
P.M.   
up to 48 hours of tolerance 
at the prescribed flow rate 
DECREASE the 
flow rate by 25 ml/h 
Dextro/h 
For 2 hours 
Notify the 
Doctor 
Resume at 
prescribed flow 
Vomiting 
REGURGITATION 
YES 
NO
REGURGITATION 
VOMITING 
IMPERATIVE: 
 
Radiological check of the mediogastric position of the tube before 
each start of enteral feeding, then systematically at each change or 
repositioning of the tube 
START OF ENTERAL NUTRITION  
As early as possible (<36 hours after intubation) 
Maximum flow rate from the outset according 
STOP Feeding 
For 6 hours 
SNG suction 
If Flow rate 
≤25 ml/h 
NE group without residue: DECISION TREE 
CAUTION 
PATIENTS IN DV 
Systematic PROKINETIC 
treatment from the first DV 
on medical prescription 
Stop 6 hours after last 
vomiting
LA TOLERANCE DIGESTIVE 
MONITORING  
➔VOMITING/REGURGITATION 
Significant outside of care and  mobilisation 
IIème  Modification 
of enteral 
nutrition flow rate 
IF INSULIN THERAPY 
Capillary blood glucose 
monitoring/hour 
Until resumption 
NO
MEDICAL PRESCRIPTION 
OF LA NUTRITION 
ENTERALE 

 
 
 
 
 
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Version No. 3 dated 18 February 2010 - Page23 of 42  
 
 
Special situations 
 
▪ Patients in the prone position: intolerance to enteral nutrition, which is particularly 
common in these patients, should be prevented by prophylactic treatment with 
prokinetics from the first session in the prone position[74, 75] . 
▪ Patients treated with insulin: They must be closely monitored and it is important to 
adhere strictly to the insulin therapy protocol. In addition: 
o in the event of a decrease in enteral nutrition flow due to poor tolerance of enteral 
nutrition (residue >250 ml and/or regurgitation), blood glucose levels should be 
monitored hourly for 2 hours following the decrease in flow. If blood glucose 
levels remain stable, monitoring should resume at the rate established by the 
insulin therapy protocol. 
o during any period of feeding cessation, blood glucose levels must be monitored 
hourly throughout the entire period of enteral nutrition cessation. 
▪ Re-intubated patients: management during the second intubation will be identical to that 
allocated for the first intubation. Thus, a patient randomised to the "residual" group will 
be managed in this way throughout their hospitalisation in intensive care. 
 
 

 
 
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5.2.2.5. Patient follow-up  
 
Vital signs, nutrition monitoring data, biology and nosocomial infections will be recorded 
until the patient is extubated. The patient will be followed up until discharge from hospital, on 
day 28 and day 90, when their status (alive or deceased) will be recorded according to the 
following flow chart:   
 
FLOW CHART (NUTRIREA 1) 
  
Inclusion 
JO* 
D1 to 
Dn 
D28 
End of 
study 
Eligibility: check criteria I and E 
X 
  
  
  
  
Information note 
X 
  
  
  
  
Demographic data 
X 
  
  
  
  
Features  
  
X 
  
  
  
Ventilation 
  
X 
  
  
  
Biology 
  
X 
X ** 
  
  
SOFA 
  
X 
X 
  
  
Nutritional assessment 
  
X 
X 
  
  
Treatments administered 
  
X 
X 
  
  
Nosocomial infections 
  
 
X 
  
  
Definitive extubation 
  
  
  
  
X 
Permanent cessation of nutrition 
  
  
  
  
X 
Living / deceased 
  
  
  
X 
X 
 
 
 
 
 
 
* = from the time of inclusion until 23:59 
 
 
 
 
 
 
 

 
 
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5.3. Description of measures taken to reduce and avoid bias 
5.3.1. Randomisation 
 
Randomisation will be stratified according to the investigating centre. The patient profile (post-
operative or medical) will not be taken into account as a stratification factor given the highly 
uneven distribution between the two types of patients (based on previous studies, the expected 
proportion of surgical patients is 10%). This randomisation will be carried out directly on the 
electronic observation log provided in each centre (see Data collection). 
 
5.3.2. Blinding methods 
 
The trial will be conducted openly, as the measurement of gastric residue requires the 
intervention of a nurse and the result leads to specific management for this group of patients.  
 
This lack of blinding has therefore led us to opt for validation of the primary endpoint by an 
adjudication committee.  
 
 
5.4. Expected duration of participation and description of the timing and duration of all 
trial periods, including follow-up, if applicable  
 
The duration of patient follow-up in the study will depend on the duration of intubation. The 
patient will be followed up until extubation. Their status (alive or deceased) will be checked 
upon discharge from intensive care, from hospital, on day 28 and on day 90. For patients 
discharged before day 28 and day 90, telephone contact will be arranged. 
 
The duration of the study is estimated at 24 months (from 2 May 2010 to 2 May 2012). 
 
 
 
5.5. Description of the rules for permanent or temporary discontinuation  
5.5.1. Discontinuation of a person's participation in the research 
 
Secondary opposition from the patient or their relatives. 
 
 

 
 
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5.5.2. Discontinuation of part or all of the research 
With regard to this routine care study, there are no planned criteria for stopping the research, 
unless a consensus following a scientific publication calls into question the main hypothesis or 
the management of patients treated with mechanical ventilation. 
 
5.6. Data collected  
 
All of this data is routinely collected in intensive care units for the management of this type of 
patient:  
 
Demographic and clinical data:  
▪ at inclusion: date of birth, sex, date of admission to intensive care, reason for admission 
to intensive care, McCabe and Knaus scores, previous chronic conditions, weight, height, 
BMI, SOFA.  
▪ at H24: IGSII, SOFA 
▪ Follow-up: date of final extubation, date of discharge from intensive care, date of 
discharge from hospital (MCO), mode of discharge from intensive care (alive or 
deceased), mode of discharge from hospital. 
 
Nutrition data: Daily assessment at midnight until patient extubation: name of enteral nutrition 
solution, volume target, calorie target, volume and calories actually administered, vomiting 
(note "yes/no" every 6 hours and time of vomiting), gastric residue (/6 hours) in the group with 
gastric residue, reduction or cessation of nutrition ("yes/no"), reason for reduction or cessation 
of nutrition (vomiting, residue, diarrhoea, other acute abdominal symptoms, examination), 
diarrhoea and its presumed cause (nutritional intolerance, medication, Clostridium difficile, 
other cause). 
 
 
Treatments administered each day until the patient was extubated: prokinetic (dose 
administered/24 hours), sedation (dose administered/24 hours of Hypnovel and/or fentanyl 
and/or Diprivan), curare (dose administered/24 hours), amines (noradrenaline or adrenaline: 

 
 
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Version No. 3 dated 14 February 2010 - Page27 on 42 
 
 
 
"yes/no" regardless of duration), EER ("yes/no"), antibiotics ("yes/no"), insulin (total dose 
administered/24 hours), total IV fluid volume (/24 hours), gastric antisecretory drugs 
(sucralfate, PPIs and H2 blockers) 
 
Biological data: 
▪ D1: Haemoglobin, leukocytes, platelets, Na, K, PaO2, PaCO2, pH, arterial lactates, 
bicarbonates, urea, creatinine, bilirubin, total proteins, albumin, CRP. 
▪ Every day from D1 to D7 (if extubation: on the day of extubation, then stop): PaO2, 
bilirubinemia, glycaemia, proteinemia, Na, K, creatininaemia, SOFA.  
▪ Albumin and CRP on D1 and D7 or on the day of extubation. 
 
Nosocomial infections (one record sheet per infection): ventilator-associated pneumonia (date, 
pathogen, resistance profile), bacteraemia (date, pathogen, resistance profile), catheter-related 
infection (date of diagnosis, pathogen, resistance profile), urinary tract infection (date of 
diagnosis, pathogen, resistance profile). 
 
Invasive devices: endotracheal tube (insertion and removal dates), catheters (insertion and 
removal dates), urinary catheters (insertion and removal dates). 
 
 
6. Selection and exclusion of research participants 
6.1. Inclusion criteria for individuals participating in the research 
▪ Patients on invasive mechanical ventilation 
▪ who must be fed via nasogastric tube within 36 hours of intubation and for a 
foreseeable period of at least 2 days 
▪ Aged over 18 
▪ Having received information and not objecting to their participation in the study 
▪ Affiliated with a social security scheme 
 

 
 
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6.2. Exclusion criteria s for individuals participating in the research 
▪ Invasive mechanical ventilation started more than 36 hours ago 
▪ Expected duration of intubation less than 48 hours 
▪ Patients treated with prone positioning at the time of inclusion (prone positioning after 
inclusion in the study will not be a reason for exclusion from the study) 
▪ Recent digestive surgery (<1 month) 
▪ History of gastrectomy, oesophagectomy, duodenopancreatectomy, bypass or gastric 
banding. 
▪ Presence of gastrostomy or jejunostomy 
▪ Active digestive haemorrhage 
▪ Moribund 
▪ Minor (<18 years old) 
▪ Legally incapacitated (under guardianship or curatorship) 
▪ Pregnant, labouring or breastfeeding woman. 
▪ Patient hospitalised without consent. 
▪ Patient deprived of liberty by court order. 
▪ Patients admitted to a health or social care facility. 
▪ Prior inclusion in a randomised research protocol, the primary endpoint of which is the 
tolerance of enteral nutrition or the prevention of nosocomial pneumonia. 
▪ Contraindication to the administration of prokinetics (hypersensibilité au 
métoclopramide ou à l’érythromycine, troubles du rythme cardiaque à type 
d’allongement de QT ou de torsades de pointes, ) 
 
 
 
6.3. Recruitment procedures 
 
 
The study will be offered to all patients admitted to intensive care units and treated with 
mechanical ventilation for a foreseeable period exceeding 48 hours and requiring early enteral 
feeding. 
 
  6.4 Contraindications to participation in other research. 
 
 
 

 
 
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Patients participating in the research may be included in other research studies, except those 
whose primary endpoint is the tolerance of enteral nutrition or the prevention of nosocomial 
pneumonia, until the patient is extubated. 
 
 
7. Products administered to persons participating in research 
 
7.1. Authorised treatments 
 
All drugs commonly used for the management of intensive care patients will be used 
according to the specific needs of each patient. 
 
7.2. Unauthorised treatments 
 
As this is a routine care study, no drugs used for their indicated purpose are prohibited. 
 
 
 
8. Statistics 
 
Statistical analysis will be conducted at CIC INSERM 202 under the supervision of Bruno 
Giraudeau. Analyses will be performed using SAS 9.1 software. 
 
8.1. Description of planned statistical methods, including the schedule for planned 
interim analyses 
 
Statistical analysis will be performed according to a pre-established analysis plan. The analysis 
will be conducted according to the intention-to-treat (ITT) principle and per protocol (PP), as 
recommended for equivalence trials. No interim analysis will be performed. A statistical 
analysis report will be prepared incorporating all the elements that must be reported, as 
recommended by the CONSORT Statement, taking into account the specificities related to the 
fact that this is a non-pharmacological trial and that the objective is one of equivalence 
(http://www.consort-s t atement.org/ - Accessed on 20.11.09). 

 
 
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Version No. 3 dated 14 February 2010 - Page30 on 42 
 
 
 
 
Description of samples at inclusion 
The groups resulting from randomisation will be compared using descriptive statistics. No 
statistical tests will be performed. 
 
Analysis samples 
The analysis will be performed using ITT, with each subject remaining in the group to which 
they were randomised, regardless of what happens. 
 
With regard to thela population PP , the following will be excluded:  
▪ patients extubated before 48 hours of mechanical ventilation or  
▪ patients with a contraindication to enteral nutrition before 12 hours of enteral nutrition  
The definition of "la population PP " will be finalised before the baseline freeze as part of a 
blind review. 
 
 
Analysis of the primary endpoint 
A two-sided 90% confidence interval for the intervention effect (Julious SA. Sample sizes for 
clinical trials with normal data. Stat Med. 2004 Jun 30;23(12):1921-86. Review. PubMed 
PMID: 15195324.), i.e. the difference in PAVM rates between the "no monitoring" group and 
the "residual" group, will be estimated and the limits of this 90% CI will be compared with the 
a priori equivalence zone, as is customary for equivalence trials. The equivalence zone has been 
set at 10%. 
 
Analysis of secondary endpoints  
For binary endpoints, the analyses will be identical to the main analysis. 
For quantitative endpoints, after logarithmic transformation of the data if necessary, the effect 
of the intervention and the associated confidence interval will be estimated using linear 
regression models in which the randomisation group will be introduced as a covariate. The 
limits of these 90% CIs will then be compared with the equivalence zone (set at 10%). 
 
8.2. Expected number of people to be included in the study , and expected number of 
people at each study site with statistical justification 
 

 
 
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This is an equivalence trial designed to demonstrate that the rates of patients with ventilator-
associated pneumonia are the same whether gastric residue is monitored or not. For an expected 
rate of patients with VAP in the residue measurement group of 19%, an equivalence zone of 
10%, an alpha risk of 5% and a beta risk of 20%, the number of patients required is 191 per 
group (Newcombe. Statist Med 1998;17:873-890), giving a theoretical total of 382. Given an 
estimated frequency of 10% of patients leaving the study after inclusion (lost to follow-up or 
mechanical ventilation duration < 48 hours), it will be necessary to include 420 patients for the 
per-protocol analysis. 
 
8.3. Expected level of statistical significance 
 
As this is an equivalence trial, we will compare the upper limits of the two-sided 90% CI of the 
intervention effect with the equivalence zone defined above (i.e. 10%). 
 
8.4. Statistical criteria for stopping the research 
In the absence of an interim analysis, there are no statistical criteria for stopping the study. 
 
8.5. Method for handling missing, unused or invalid data 
In this study, patients for whom consent cannot be obtained will not be included in the analysis. 
Apart from these patients, it is unlikely that any will be lost to follow-up, as they are hospitalised 
in intensive care. However, if the endpoint is not available for certain patients, they will be 
assigned a failure value (i.e. development of VAP), regardless of the randomisation arm. 
 
8.6. Management of changes to the initial strategy analysis plan 
The statistical analysis plan will be finalised when the database is frozen. 
 
8.7. Selection of individuals to be included in the analyses 
The analysis will be performed using ITT and PP (see above). 
 
9. Justification for the request for validation of routine care research   
 

 
 
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Taking into account all the elements presented in the project, the research manager classifies 
it as routine care research, since: 
✓ all enteral nutrition procedures and protocols are performed routinely. 
✓ the research aims to evaluate combinations of procedures and medical prevention and 
diagnosis strategies (protocol for the administration and monitoring of enteral nutrition, 
diagnosis of nosocomial pneumonia) that are standard practice, i.e. subject to 
professional consensus in accordance with their indications. 
✓ This research does not focus on techniques or strategies that are either innovative or 
obsolete. 
✓ The combination of procedures (monitoring of enteral nutrition with or without 
measurement of gastric residue) is not an innovative combination.  
✓ The research focuses on comparing two medical strategies (enteral nutrition monitoring 
with or without gastric residue measurement), neither of which can, based on current 
knowledge, be considered superior to the other in terms of safety and efficacy. 
✓ Finally, the specific implementation procedures in the research must reduce risks 
(through enhanced protocolisation of enteral nutrition delivery) and represent negligible 
constraints for the person participating in the research (Article R 1121-3 of the Public 
Health Code (CSP), Decree No. 2006-477 of 26 April 2006). 
 
The research manager shall therefore submit the study protocol to the OUEST III 
Committee for the Protection of Persons for a favourable opinion and confirmation of the 
research's eligibility prior to any implementation of the research, in accordance with Article L 
1121-1 of the Public Health Code (CSP) as resulting from Laws No. 2004-806 of 9 August 
2004 and No. 2006-450 of 18 April 2006 relating to public health policy. 
 
10. Right of access to source data and documents e 
10.1. 
Access to data 
Each patient's medical data will only be transmitted to the organisation to which the person 
responsible for the research is affiliated or to any person duly authorised by that organisation 
under conditions that guarantee confidentiality.  
 

 
 
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10.2. 
Source documents 
Where applicable, the organisation to which the person responsible belongs may request direct 
access to the medical file to verify the research procedures and/or data, without violating 
confidentiality and within the limits authorised by laws and regulations. 
 
10.3. 
Data confidentiality 
Persons with direct access shall take all necessary precautions to ensure the confidentiality of 
information relating to the persons involved, in particular with regard to their identity and the 
results obtained. 
These persons, like the investigators themselves, are subject to professional secrecy (under the 
conditions defined by Articles 226-13 and 226-14 of the Penal Code). 
During or at the end of the research, the data collected on the individuals involved and 
transmitted by the participants shall be anonymised. 
Under no circumstances shall the names or addresses of the persons concerned be disclosed.  
Only the first three letters of the subject's surname and the first two letters of their first name 
will be recorded, accompanied by a coded number specific to the study indicating the order of 
inclusion of the subjects.  
 
11. Quality assurance 
In order to optimise the implementation of the study, a Clinical Research Associate (CRA) may 
be responsible for:  
- 
preparing the submission file for review by the Committee for the Protection of Persons 
(CPP) 
- 
finalising the study documents (observation log, etc.) and the channels of communication 
between the various parties involved 
- 
setting up the study in the centres associated with the study 
 
 
12. Ethical evaluations of the specific monitoring procedures provided for in the protocol 
12.1. 
Committee for the Protection of Persons 
The protocol and the study information and non-objection form will be submitted to the CPP 
for review. 

 
 
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12.2. 
Substantial modifications 
Any substantial modification to the study protocol must be notified to the Committee for the 
Protection of Persons in order to verify that the proposed modifications do not in any way alter 
the guarantees provided to the persons participating in the research. 
 
12.3. 
Information letter and non-objection form  
Patients will be fully and honestly informed, in understandable terms, of the objectives of the 
study, their rights to refuse to participate in the study, and the possibility of withdrawing at any 
time. All this information will be included in an information and non-objection form given to 
the patient.  
 
 
13. Data processing and storage of documents and data 
13.1. 
Observation log 
 
An online data collection tool will be used for this study. This electronic observation log will 
be set up in each centre. It only requires an internet connection and a browser. A help document 
for using this tool will be provided to investigators. 
Data consistency checks will be integrated into the electronic format. An audit function is 
integrated into the electronic notebook, allowing any changes to the study data to be tracked. 
This function also clearly identifies the person who made the change and the date. A 
justification can be added as a comment if necessary. 
 
13.2. 
Data entry and output 
Data will be entered electronically via a web browser. 
Data analysis will be performed by Bruno Giraudeau. 
 

 
 
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13.3. 
CNIL 
An opinion on the implementation of the data processing necessary to carry out the study will 
be requested from the Advisory Committee on the Processing of Information in Health 
Research (CCTIRS), followed by a request for authorisation from the French Data Protection 
Authority (la Commission  Nationale Informatique et Libertés, CNIL) for the processing of 
personal data for the purposes of routine healthcare research. 
 
14. Funding and insurance 
14.1. 
Study budget 
As this trial is a routine care study, medical procedures are not covered. The costs associated 
with this research are therefore as follows: 
➢ ARC time required to prepare the submission file for review by the Human Protection 
Committee and to prepare the CNIL file (1 month full-time) and study coordination 
(10% FTE over 2 years): €12,000. 
➢ Clinical study technician time for assistance with study coordination and logistics, as 
well as data entry into the e-CRF: 1 part-time position over 2 years, i.e. €40,000 
➢ Data management:  
- 
Data management time for creating the electronic observation log and 
monitoring data quality: 3 months full-time, i.e. €      15,000. 
- 
Statistical analysis: 1 month full-time, i.e. €50,000 
➢ Meetings, coordinator assignments: €40,000 
➢ Travel expenses for the clinical study technician: €6,000 
➢ Stationery for information letters and letters of non-objection to patients or their 
relatives, nutrition monitoring sheets at patients' bedsides: €4,000 
 
14.2. 
Insurance 
As the research is classified as routine care research by the CPP (Comité de Protection des 
Personnes), meaning that there is no additional risk associated with the study, the insurance will 
be provided by the institution responsible for care (Article L. 1142-2). 
 
15. Feasibility of the study 
 

 
 
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The study will be conducted in the six investigative centres that make up the Clinical 
Research in Intensive Care and Sepsis (CRICS) network. These six centres admit a total of 
5,200 patients per year on average. Approximately 70% of these patients are treated with 
mechanical ventilation, i.e. approximately 3,600 patients per year. Given the inclusion and 
exclusion criteria for the study, we estimate that we can reliably include at least 5 patients per 
month per department, i.e. 30 patients per month and therefore 360 per year. 
As the number of patients expected to be included in the study is 420, the expected duration 
of the inclusion period will therefore be a maximum of 18 months. 
 
16. Rules relating to publication 
 
Scientific communications and reports relating to this study will be produced under the 
responsibility of the principal investigator coordinating the study, with the agreement of the 
investigators in charge. The co-authors of the report and publications will be the investigators 
and clinicians involved, in proportion to their contribution to the study, as well as the 
biostatistician and associated researchers. 
The publication rules will follow international recommendations (N Engl J Med, 1997; 
336:309-315). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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17. References to scientific literature and relevant data used as references for the research 
 
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3. 
Kreymann, K.G., et al., ESPEN Guidelines on Enteral Nutrition: Intensive care. Clin 
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4. 
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7. 
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8. 
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10. 
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511-3. 

 
 
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13. 
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14. 
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15. 
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16. 
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18. 
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21. 
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22. 
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nutrition in patients with acute pancreatitis. BMJ, 2004.328 (7453): p. 1407. 
23. 
Moore, F.A., et al., Early enteral feeding, compared with parenteral, reduces 
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24. 
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outcome of critically ill mechanically ventilated medical patients. Chest, 2006.129 (4): 
p. 960-7. 
25. 
Marik, P.E. and G.P. Zaloga, Early enteral nutrition in acutely ill patients: a systematic 
review. Crit Care Med, 2001.29 (12): p. 2264-70. 
26. 
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care unit patients: what is prescribed? What is delivered? Crit Care Med, 2001.29 (1): 
p. 8-12. 
27. 
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of a questionnaire. Working Group on Metabolism and Nutrition of the European 
Society of Intensive Care Medicine. Intensive Care Med, 1999.25 (1): p. 95-101. 
28. 
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patients. Nutrition, 2005.21 (7-8): p. 786-92. 
29. 
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patients - results of a survey on German intensive care units. Eur J Anaesthesiol, 
2008.25 (1): p. 58-66. 
30. 
Adam, S. and S. Batson, A study of problems associated with the delivery of enteral feed 
in critically ill patients in five ICUs in the UK. Intensive Care Med, 1997.23 (3): p. 261-
6. 

 
 
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31. 
Binnekade, J.M., et al., Daily enteral feeding practice on the ICU: attainment of goals 
and interfering factors. Crit Care, 2005.9 (3): p. R218-25. 
32. 
Heyland, D., et al., Enteral nutrition in the critically ill patient: a prospective survey. 
Crit Care Med, 1995.23 (6): p. 1055-60. 
33. 
Heyland, D.K., et al., Nutrition support in the critical care setting: current practice in 
Canadian ICUs—opportunities for improvement? JPEN J Parenter Enteral Nutr, 
2003.27 (1): p. 74-83. 
34. 
Bistrian, B.R. and K.C. McCowen, Nutritional and metabolic support in the adult 
intensive care unit: key controversies. Crit Care Med, 2006.34 (5): p. 1525-31. 
35. 
Wernerman, J., Guidelines for nutritional support in intensive care unit patients: a 
critical analysis. Curr Opin Clin Nutr Metab Care, 2005.8 (2): pp. 171–5. 
36. 
McClave, S.A., et al., Enteral tube feeding in the intensive care unit: factors impeding 
adequate delivery. Crit Care Med, 1999.27 (7): p. 1252-6. 
37. 
Bosscha, K., et al., Gastrointestinal motility and gastric tube feeding in mechanically 
ventilated patients. Crit Care Med, 1998.26 (9): p. 1510-7. 
38. 
Chapman, M.J., et al., Gastric emptying and the organisation of antro-duodenal 
pressures in the critically ill. Neurogastroenterol Motil, 2008.20 (1): p. 27-35. 
39. 
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patients: a manometric study. Crit Care Med, 1994.22 (3): p. 441-7. 
40. 
Kolbel, C.B., et al., Esophageal motility disorders in critically ill patients: a 24-hour 
manometric study. Intensive Care Med, 2000.26 (10): p. 1421-7. 
41. 
Landzinski, J., et al., Gastric motility function in critically ill patients tolerant vs 
intolerant to gastric nutrition. JPEN J Parenter Enteral Nutr, 2008.32 (1): p. 45-50. 
42. 
McClave, S.A., et al., North American Summit on Aspiration in the Critically Ill Patient: 
consensus statement. JPEN J Parenter Enteral Nutr, 2002.26 (6 Suppl): p. S80-5. 
43. 
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44. 
Schuster-Bruce, M., Gastric emptying in the critically ill. Crit Care Med, 2001.29 (6): 
p. 1293-4. 
45. 
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46. 
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47. 
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patients: frequency, risk factors, and complications. Crit Care Med, 2001.29 (10): p. 
1955-61. 
48. 
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49. 
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50. 
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51. 
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52. 
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1998.279 (20): pp. 1605–6. 

 
 
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54. 
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55. 
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Appendix 1: Procedure for managing diarrhoea 
This procedure was described by Doig in 2008 in JAMA [72] 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinically significant 
diarrhoea 
Potentially implicated 
medications? 
No change in enteral 
nutrition 
Continue with current 
solution 
Is the patient receiving 
antibiotics? 
Test for Clostridium difficile toxin 
in stool and continue nutrition 
 
Change the nutritional 
solution 
Has the diarrhoea 
stopped? 
Reduce the solution flow 
rate until the diarrhoea has 
stopped 
Gradually increase the flow 
rate to the desired level 
NO 
NO 
YES 
Discontinue the 
medication and 
continue nutrition. 
NO 
YES 
YES 
NO 
YES