Impact of Early Enteral vs. Parenteral Nutrition on Mortality in Patients Requiring Mechanical Ventilation and Catecholamines: Multicenter, Randomized Controlled Trial (NUTRIREA-2)
Phase: NA
Conditions: Acute Respiratory Failure, Shock
Sponsor: Centre Hospitalier Departemental Vendee

 
 
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CLINICAL TRIAL PROTOCOL 
 
NUTRIREA-2 
 
TRIAL IDENTIFIER 
–  
STRATEGY 
Early nutritional support in mechanically ventilated 
patients: enteral vs. parenteral 
FULL TITLE  
Impact of Early Enteral vs. Parenteral Nutrition on 
Mortality 
in 
Patients 
Requiring 
Mechanical 
Ventilation 
and 
Catecholamines: 
Multicenter 
Randomized Controlled Trial (NUTRIREA-2) 
TARGET POPULATION 
Patients 
receiving 
endotracheal 
mechanical 
ventilation and one or more vasoactive agents 
CHIEF INVESTIGATOR  
Dr Jean REIGNIER 
 
Service de Réanimation Polyvalente 
Centre Hospitalier Départemental  
85000 La Roche-sur-Yon, FRANCE 
jean.reignier@chd-vendee.fr 
VERSION OF THE PROTOCOL 
Version 5.1 
DATE OF THE PROTOCOL 
December 12, 2014 
ETHICS COMMITTEE (Comité de 
Protection des Personnes, CPP) 
Poitiers - Ouest III (Approved on Dec. 21, 2014) 
FRENCH HEALTHCARE 
PRODUCT SAFETY AGENCY 
(AFSSAPS) 
Not applicable 
THIS CONFIDENTIAL DOCUMENT IS THE PROPERTY OF THE LA ROCHE-
SUR-YON DISTRICT HOSPITAL CENTER. NO UNPUBLISHED INFORMATION 
SUPPLIED IN THIS DOCUMENT CAN BE DISCLOSED WITHOUT PRIOR 
WRITTEN AUTHORIZATION FROM THE LA ROCHE-SUR-YON DISTRICT 
HOSPITAL CENTER. 
 
 
 
 

 
 
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TABLE OF CONTENTS 
SYNOPSIS ............................................................................................................................................................. 5 
LIST OF ABBREVIATIONS ..............................................................................................................................11 
1) 
BACKGROUND ..........................................................................................................................................12 
1.1. 
TITLE .......................................................................................................................................................12 
1.2. 
COORDINATION AND MONITORING OF THE STUDY ...................................................................................12 
1.3. 
INVESTIGATORS .......................................................................................................................................12 
1.3.1. 
Chief Investigator .......................................................................................................................... 12 
1.3.2. 
Associate Chief Investigator .......................................................................................................... 12 
1.3.3. 
Co-investigators ............................................................................................................................. 13 
1.4. 
METHODOLOGISTS – BIOSTATISTICIANS ..................................................................................................15 
2) 
SCIENTIFIC RATIONALE FOR THE STUDY ......................................................................................16 
2.1. 
OVERVIEW OF THE RESEARCH PROJECT ...................................................................................................16 
2.2. 
OVERVIEW OF POTENTIAL BENEFITS AND, WHERE APPLICABLE, OF PREDICTABLE AND KNOWN RISKS FOR 
THE PATIENTS PARTICIPATING IN THE RESEARCH PROJECT .................................................................................21 
2.3. 
STATEMENT THAT THE RESEARCH PROJECT WILL BE CONDUCTED IN COMPLIANCE WITH THE STUDY 
PROTOCOL AND WITH GOOD CLINICAL PRACTICE GUIDELINES ............................................................................22 
2.4. 
DESCRIPTION OF THE STUDY POPULATION ...............................................................................................22 
3) 
STUDY OBJECTIVES ................................................................................................................................24 
3.1. 
PRIMARY OBJECTIVE ...............................................................................................................................24 
3.2. 
SECONDARY OBJECTIVES .........................................................................................................................24 
3.3. 
IMPACT ....................................................................................................................................................25 
4) 
STUDY CONCEPTS ...................................................................................................................................27 
4.1. 
DETAILED DESCRIPTIONS OF THE PRIMARY ENDPOINT AND, WHERE APPLICABLE, OF THE SECONDARY 
ENDPOINTS .........................................................................................................................................................27 
4.1.1. 
Primary endpoint ........................................................................................................................... 27 
4.1.2. 
Secondary endpoints .............................................................................. Erreur ! Signet non défini. 
4.2. 
DESCRIPTION OF THE RESEARCH PROJECT METHODOLOGY WITH A STUDY DIAGRAM INCLUDING 
SCHEDULED VISITS AND INVESTIGATIONS ..........................................................................................................30 
4.2.1. 
Study design ................................................................................................................................... 30 
4.2.2. 
Conduct of the study ...................................................................................................................... 30 
4.2.2.1 
Inclusion .............................................................................................. Erreur ! Signet non défini. 
4.2.2.2 
Nutritional support protocol ........................................................................................................ 31 
a. 
General principles ............................................................................................................................... 31 
b. 
Enteral nutrition .................................................................................................................................. 31 
c. 
Parenteral nutrition ............................................................................................................................. 32 
d. 
Additional intakes (water, electrolytes, trace elements, and vitamins) ................................................ 33 
4.2.2.3 
Study intervention: first-line enteral or parenteral nutrition ....................................................... 33 
4.2.2.4 
Monitoring of intestinal transit .................................................................................................... 36 
4.2.2.5 
Special situations ......................................................................................................................... 36 
4.2.3. 
Patient follow-up ................................................................................... Erreur ! Signet non défini. 
4.3. 
DESCRIPTION OF MEASURES TAKEN TO MINIMIZE AND AVOID BIASES .....................................................38 
4.3.1. 
Random allocation ......................................................................................................................... 40 
4.3.2. 
Blinding methods ........................................................................................................................... 40 
4.4. 
EXPECTED DURATION OF STUDY PATIENT PARTICIPATION AND DESCRIPTION OF THE TIME SEQUENCE AND 
DURATION OF ALL TRIAL PERIODS, INCLUDING FOLLOW-UP, WHERE APPLICABLE ..............................................40 
4.5. 
REASONS FOR PERMANENT OR TEMPORARY STUDY DISCONTINUATION ...................................................40 
4.5.1. 
Patient withdrawal from the study ................................................................................................. 41 
4.5.2. 
Discontinuation of all or part of the study ..................................................................................... 41 
4.6. 
DATA COLLECTION ..................................................................................................................................41 
5) 
SELECTION AND EXCLUSION OF PATIENTS FOR THE STUDY .................................................44 

 
 
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5.1. 
INCLUSION CRITERIA TO BE MET BY STUDY PARTICIPANTS ......................................................................44 
5.2. 
NONINCLUSION CRITERIA TO BE ABSENT IN STUDY PARTICIPANTS ..........................................................44 
5.3. 
RECRUITMENT MODALITIES .....................................................................................................................45 
5.4. 
CONTRAINDICATION TO PARTICIPATION IN ANOTHER RESEARCH PROJECT ..............................................45 
6) 
PRODUCTS ADMINISTERED TO THE STUDY PARTICIPANTS ....................................................46 
6.1. 
STUDY INTERVENTION .............................................................................................................................46 
6.2. 
TREATMENTS THAT MAY BE USED ...........................................................................................................47 
6.3. 
TREATMENTS THAT MAY NOT BE USED ....................................................................................................47 
7) 
STATISTICS ................................................................................................................................................48 
7.1. 
DESCRIPTION OF PLANNED STATISTICAL METHODS, WITH THE SCHEDULE OF PLANNED INTERIM 
ANALYSES ..........................................................................................................................................................48 
7.1.1. 
Description of the groups at baseline ............................................................................................ 48 
7.1.2. 
Analysis populations ...................................................................................................................... 48 
7.1.3. 
Analysis of the primary endpoint ................................................................................................... 48 
7.1.4. 
Analysis of secondary endpoints .................................................................................................... 49 
7.2. 
ESTIMATED SAMPLE SIZE, AND ESTIMATED NUMBERS OF PATIENTS RECRUITED AT EACH STUDY CENTER, 
WITH SUPPORTING STATISTICAL INFORMATION ..................................................................................................52 
7.3. 
DEGREE OF STATISTICAL SIGNIFICANCE PLANNED FOR THE STUDY .........................................................52 
7.4. 
STATISTICAL RULES FOR STUDY DISCONTINUATION ................................................................................53 
7.5. 
HANDLING OF MISSING, UNUSED, OR INVALID DATA ...............................................................................53 
7.6. 
HANDLING OF CHANGES TO THE INITIAL STATISTICAL ANALYSIS PLAN ...................................................53 
7.7. 
SELECTION OF PATIENTS TO BE INCLUDED IN THE ANALYSES ..................................................................53 
8) 
RATIONALE FOR REQUESTING CATEGORIZATION OF THE TRIAL AS A STUDY OF 
STANDARD CARE .............................................................................................................................................53 
9) 
RIGHT OF ACCESS TO THE STUDY DATA AND SOURCE DOCUMENTS ..................................56 
9.1. 
ACCESS TO THE STUDY DATA ..................................................................................................................56 
9.2. 
SOURCE DOCUMENTS ..............................................................................................................................56 
9.3. 
DATA CONFIDENTIALITY .........................................................................................................................56 
10) 
QUALITY ASSURANCE ..........................................................................................................................57 
11) 
ETHICAL EVALUATION OF THE SPECIFIC MONITORING MODALITIES DEFINED IN 
THE RESEARCH PROTOCOL ..........................................................................................................................57 
11.1. ETHICS COMMITTEE (COMITE DE PROTECTION DES PERSONNES, CPP) ....................................................57 
11.2. SUBSTANTIAL MODIFICATIONS ...............................................................................................................57 
11.3. PATIENT INFORMATION SHEET AND INFORMED CONSENT FORM ..............................................................57 
12) 
HANDLING OF THE STUDY DATA AND STORAGE OF THE STUDY DOCUMENTS AND 
DATA ....................................................................................................................................................................59 
12.1. CASE-REPORT FORM ...............................................................................................................................59 
12.2. DATA ENTRY AND ANALYSIS ..................................................................................................................59 
12.3. FRENCH DATA PROTECTION AUTHORITY (CNIL)...................................................................................59 
13) 
FUNDING AND INSURANCE .................................................................................................................59 
13.1. STUDY BUDGET.......................................................................................................................................60 
13.2. INSURANCE .............................................................................................................................................61 
14) 
STUDY FEASIBILITY .............................................................................................................................62 
15) 
PUBLICATION POLICY .........................................................................................................................63 
16) 
APPENDICES ............................................................................................................................................64 
17) 
REFERENCES ...........................................................................................................................................67 

 
 
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SIGNATURE OF THE CHIEF INVESTIGATOR 
 
 
 
 
 
 
 
I have read all the pages of the clinical trial protocol. I confirm that this protocol contains 
all the information needed to conduct the trial. I undertake to conduct the trial in 
compliance with the protocol and with the terms and conditions defined in the protocol.  
 
 
I also undertake that the investigators and other qualified members of my team will have 
access to copies of this protocol and to the documents relevant to the conduct of the trial, 
in order to ensure that they can work in compliance with the rules set forth in this 
protocol.  
 
 
 
 
NAME: Dr Reignier 
 
 
Signature: …………………………………………….. 
 
 
 
 
 
 
Date: ___________________ 
 
 
 
 
 

 
 
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SYNOPSIS 
 
TITLE 
Impact of Early Enteral vs. Parenteral Nutrition on Mortality in 
Patients Requiring Mechanical Ventilation and Catecholamines: 
Multicenter Randomized Controlled Trial (NUTRIREA-2) 
KEYWORDS 
Nutritional support. Intensive care. Intensive care units. Enteral 
nutrition. Parenteral nutrition. Shock. 
CHIEF INVESTIGATOR  
Dr Jean REIGNIER 
Service de Réanimation Polyvalente 
Centre Hospitalier Départemental  
85000 La Roche-sur-Yon, FRANCE 
Tel.: +33 251 446 212  
Fax: +33 251 446 294 
E-mail: jean.reignier@chd-vendee.fr 
VERSION OF THE PROTOCOL 
Version #3 
METHODOLOGY / STUDY 
DESIGN 
Multicenter randomized controlled trial without blinding 
STUDY TYPE 
Evaluation of standard care  
RATIONALE / SETTING 
Nutritional support is a mainstay of the management of patients 
receiving invasive mechanical ventilation and the most commonly 
prescribed treatment in intensive care units (ICUs). Malnutrition in 
critically ill patients is associated with an increased risk of infection, 
delayed wound healing, longer times on mechanical ventilation, longer 
ICU stays and, probably, a higher risk of death. Recommendations 
issued by international professional organizations consistently indicate 
that enteral nutrition should be preferred over parenteral nutrition 
whenever possible and that nutritional support should be started as 
early as possible after the initiation of mechanical ventilation. 
Numerous studies suggest that early enteral nutrition may be associated 
with lower nosocomial infection rates, a decreased risk of progression 
to multiorgan failure, shorter hospital stays, and decreased hospital 
costs, compared to parenteral nutrition. Furthermore, evidence from 
observational studies suggests lower mortality rates with the enteral 
route compared to the parenteral route. However, recent studies 
showed chronic suboptimal use of enteral nutrition, as well as 
considerable variability in nutritional management across ICUs and 
across patients in a given unit. Failure to initiate early nutritional 
support via any modality is common, the calorie targets are frequently 
inconsistent, and routine use of first-line enteral nutrition is far from 
being the rule. As a result, malnutrition remains common among ICU 
patients receiving invasive mechanical ventilation. This fact is 
ascribable both to the difficulty of initiating early enteral nutrition in 
mechanically ventilated patients and to the conflicting results of studies 
comparing the enteral and parenteral routes. Manifestations of 
gastrointestinal intolerance occur in about 50% of patients. More 
specifically, regurgitation affects 8% to 27% of patients and may be 
associated with an increased risk of ventilator-associated pneumonia. 

 
 
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In addition, the safety of enteral nutrition in patients with circulatory 
failure, particularly those with low splanchnic blood flow, remains in 
doubt. In healthy individuals, enteral nutrition increases blood flow in 
the superior mesenteric artery by over 50%. As a result, in patients 
with circulatory failure, enteral nutrition may induce nonocclusive 
mesenteric ischemia, a condition associated with mortality rates of 
70% to 100%. Although these potential complications have not been 
convincingly linked to enteral nutrition, they lead many physicians to 
delay the initiation of nutritional support by several days or to prefer 
parenteral nutrition at the acute phase of the management of critically 
ill patients and/or of patients with shock. This attitude is strengthened 
by the absence of a vast multicenter randomized trial evaluating the 
impact of early enteral nutrition on outcomes of patients receiving 
mechanical ventilation. Current recommendations are based on 
observational or retrospective data and on studies that have inadequate 
statistical power. Thus, several recent editorials have emphasized the 
need for well-designed clinical trials capable of resolving current 
uncertainties about the nutritional management of mechanically 
ventilated patients. A recent randomized controlled trial found that 
parenteral nutrition added to inadequate enteral nutrition was 
associated with longer stays and higher infection rates while failing to 
affect mortality when started early instead of at the end of the first 
week in the ICU. An as yet unpublished study from Switzerland 
investigated the same topic and found contrary results. These studies 
fail to establish that the enteral route is superior over the parenteral 
route at the acute phase. Choosing between these two routes is among 
the crucial unresolved issues in the management of mechanically 
ventilated patients in the ICU. The working hypothesis for the present 
study is that, compared to early parenteral nutrition, early enteral 
nutrition is associated with lower mortality rates in patients receiving 
invasive mechanical ventilation and vasoactive agents for shock. 
Ancillary studies: 
The NUTRIREA2 trial provides the opportunity to answer two 
additional questions, via an ancillary study for each.  
− 
Ancillary study 1. Is enteral nutrition associated with better 
preservation of gut mucosa integrity compared to parenteral nutrition? 
Published data suggest that enteral nutrition may be associated with 
improved preservation of the gut lymphoid tissues and gut immune 
function, as well as with decreased gut mucosa permeability, thereby 
diminishing the risk of organ failure. Citrulline is an amino acid 
produced from glutamine by small-bowel enterocytes. Plasma citrulline 
levels reflect functional enterocyte mass. Intestinal fatty acid-binding 
protein (I-FABP, also known as FABP2) is a small protein found in the 
cytosol of small-bowel enterocytes. Plasma I-FABP is normally 
undetectable and, when elevated, constitutes a reliable marker for 
enterocyte damage. The hypothesis underlying this ancillary study is 
that first-line enteral nutrition is associated with improved gut mucosa 
integrity and function compared to parenteral nutrition.  
− 
Ancillary study 2. Is enteral nutrition associated with a higher 
risk of gastric-content aspiration compared to parenteral nutrition? As 
indicated above, a common obstacle to enteral nutrition is 
gastrointestinal intolerance, with regurgitations potentially responsible 
for gastric-content aspiration. Several studies involving technetium 
99m (99mTc) labeling of gastric contents have established that gastric-

 
 
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fluid microaspiration is common in critically ill patients receiving both 
endotracheal ventilation and enteral nutrition. However, to our 
knowledge, no studies have specifically addressed the role for enteral 
nutrition in the occurrence of microaspiration. The objective of this 
ancillary study is to compare the frequency of gastric-content 
microaspiration in patients given enteral versus parenteral nutrition 
during the NUTRIREA2 trial. The new knowledge of risk factors for 
microaspiration provided by this study may help to improve strategies 
for preventing microaspiration and ventilator-associated pneumonia 
(VAP). 
PRIMARY OBJECTIVE 
To investigate whether a strategy involving early first-line enteral 
nutrition decreases day-28 all-cause mortality in patients receiving 
mechanical ventilation and vasoactive agents for shock, compared to a 
strategy of early first-line parenteral nutrition. 
SECONDARY OBJECTIVES  
The secondary objectives are to compare the following in the two 
groups: 
▪ 
proportion of patients with at least one VAP episode  
▪ 
VAP incidence density  
▪ 
number of VAP episodes  
▪ 
rates and incidence densities of other nosocomial infections: 
o bloodstream infections (BSI): proportion of patients with 
at least one BSI episode, BSI incidence density  
o central 
venous 
catheter 
(CVC)-related 
infections: 
proportion of patients with at least one CVC-related 
infection, incidence density of CVC-related infections 
o urinary tract infections: proportion of patients with at least 
one urinary tract infection, incidence density of urinary 
tract infections 
▪ 
proportion of patients with at least one nosocomial infection 
▪ 
descriptive bacteriological data (organisms recovered and 
antibiotic resistance profile for each nosocomial infection) 
▪ 
proportion of patients with at least one episode of regurgitation or 
vomiting 
▪ 
proportion of patients with diarrhea 
▪ 
proportion of patients with constipation 
▪ 
proportion of patients with a documented episode of bowel 
ischemia 
▪ 
number of calories administered per day by the enteral and 
parenteral routes 
▪ 
volume of enteral and parenteral feeds administered per day  
▪ 
ratio of prescribed versus delivered calories 
▪ 
ICU mortality, hospital  mortality, and day-90 mortality 
▪ 
time-course of nutritional markers during follow-up (measured at 
discontinuation of mechanical ventilation, on day 7 in patients 
receiving mechanical ventilation for more than 7 days, and at ICU 
discharge) 
▪ 
proportion of patients with at least one episode of liver dysfunction 
(evaluated at discontinuation of mechanical ventilation, on day 7 in 
patients receiving mechanical ventilation for more than 7 days, and 
at ICU discharge) 
▪ 
ICU stay length 
▪ 
hospital stay length  
▪ 
total time spent on mechanical ventilation 
▪ 
change in body weight from admission to day 7 and to ICU 

 
 
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discharge  
OBJECTIVES OF THE 
ANCILLARY STUDIES  
− 
Ancillary study 1. To demonstrate that a strategy involving 
early first-line enteral nutrition is associated with improved 
preservation of gut mucosa integrity, as assessed based on the plasma 
citrulline level at H72, compared to a strategy involving early first-line 
parenteral nutrition 
− 
Ancillary study 2. To evaluate the impact of enteral nutrition 
on microaspiration of gastric content and pharyngeal secretions 
PRIMARY OUTCOME 
MEASURE  
All cause day-28 mortality 
SECONDARY OUTCOME 
MEASURES  
▪ 
proportion of patients with at least one episode of ventilator-
associated pneumonia (VAP) 
▪ 
VAP incidence density per 1000 days of mechanical ventilation 
▪ 
number of VAP episodes per patient 
▪ 
proportion of patients with at least one bloodstream infection (BSI) 
and incidence density per 1000 ICU days  
▪ 
proportion of patients with at least one central venous catheter 
(CVC)-related infection and incidence density per 1000 CVC days  
▪ 
proportion of patients with at least one urinary tract infection and 
incidence density per 1000 urinary-catheter days  
▪ 
proportion of patients with at least one soft tissue infection and 
incidence density per 1000 ICU days 
▪ 
proportion of patients with at least one nosocomial infection 
▪ 
descriptive bacteriological data (organisms recovered and 
antibiotic resistance profile for each nosocomial infection) 
▪ 
proportion of patients with at least one episode of vomiting 
▪ 
proportion of patients with at least one episode of diarrhea 
▪ 
proportion of patients with an episode of acute colonic 
pseudoobstruction 
▪ 
proportion of patients with a documented episode of bowel 
ischemia 
▪ 
number of calories (in Kcal) given enterally and parenterally:  
o time-course of mean daily values over the first week 
o time-course of mean daily values throughout the time 
spent on mechanical ventilation 
▪ 
ratio of prescribed calories over calories delivered enterally and 
parenterally (as percentages):  
o time-course of mean daily values over the first week 
o time-course of mean daily values throughout the time 
spent on mechanical ventilation 
o proportion of patients in whom the calorie target was 
achieved on each day 
▪ 
volume of feed (in mL) administered: 
o time-course of mean daily values over the first week 
o time-course of mean daily values throughout the time 
spent on mechanical ventilation 
▪ 
ICU mortality, hospital mortality, 90-day mortality 
▪ 
mean changes in serum albumin, prealbumin, transthyretin, and C-
reactive protein between study inclusion and mechanical 
ventilation discontinuation, day 7 (in patients on mechanical 
ventilation for more than 7 days), and ICU discharge  
▪ 
proportion of patients with at least one episode of liver dysfunction 
at mechanical ventilation discontinuation, on day 7 (in patients on 
mechanical ventilation for more than 7 days), and at ICU discharge  

 
 
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▪ 
ICU stay length  
▪ 
hospital stay length  
▪ 
total time spent on mechanical ventilation 
▪ 
mean change in body weight from admission to day 7 and to ICU 
discharge  
OUTCOME MEASURES FOR 
THE ANCILLARY STUDIES 
▪ 
Ancillary study 1  
Primary outcome measure: Plasma citrulline level at H72 
Secondary outcome measures: SOFA score; plasma levels of citrulline 
and I-FABP on D0, D3, and D8; proportion of patients whose plasma 
I-FABP is ≥100 pg/mL on D0, D3, and D8; proportion of patients 
whose plasma citrulline is ≤10 μL/L on D0, D3, and D8; mean plasma 
I-FABP; mean plasma citrulline; proportion of patients with at least 
one episode of bacteremia; proportion of patients with at least one 
episode of gastrointestinal intolerance; proportion of patients with at 
least one episode of diarrhea; in the enteral-nutrition group, cumulative 
calorie intake over the first 3 days and on D7; impossibility of 
administering enteral nutrition. 
 
▪ 
Ancillary study 2  
Primary outcome measure: proportion of patients with abundant 
microaspiration (defined as a pepsin level >200 ng/mL in at least 30% 
of tracheal aspirates). 
Secondary outcome measures: Salivary amylase levels in tracheal 
aspirates. 
INCLUSION CRITERIA FOR 
STUDY PARTICIPANTS 
▪ 
invasive mechanical ventilation for an expected duration of at least 
48 hours 
▪ 
nutritional support started within 24 hours after intubation, or after 
ICU admission in patients intubated before ICU admission 
▪ 
administration of a vasoactive agent (adrenaline, dobutamine, or 
noradrenaline) via a central venous catheter 
▪ 
age older than 18 years 
▪ 
informed consent to study participation 
▪ 
coverage by one of the French statutory health insurance agencies 
NONINCLUSION CRITERIA 
FOR STUDY PARTICIPANTS  
▪ 
invasive mechanical ventilation started more than 24 hours earlier 
▪ 
surgery on the gastrointestinal tract within the past month 
▪ 
history of gastrectomy, esophagectomy, duodenopancreatectomy, 
gastric bypass or banding, or short bowel syndrome 
▪ 
gastrostomy or jejunostomy 
▪ 
specific diet 
▪ 
active bleeding from the gastrointestinal tract 
▪ 
dying patient – not-to-be-resuscitated order or other treatment 
limitation decision at ICU admission  
▪ 
adult under guardianship 
▪ 
pregnancy, recent delivery, or lactation 
▪ 
patient admitted without his or her consent 
▪ 
department of corrections inmate 
▪ 
institutionalized patient 
▪ 
prior inclusion in a randomized trial comparing early enteral 
nutrition to early parenteral nutrition and having mortality as the 
primary outcome measure  
▪ 
contraindication to parenteral nutrition: known hypersensitivity to 
egg protein, soybean protein, or another component; inborn error in 

 
 
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amino acid metabolism; severe familial dyslipidemia manifesting 
as hypertriglyceridemia 
STRATEGIES / PROCEDURES 
In both groups, nutritional support will be started within 24 hours after 
the initiation of mechanical ventilation. Calorie targets will be 20-25 
Kcal/Kg/day during the first week then 25-30 Kcal/Kg/day starting on 
day 8. In the parenteral nutrition group, a switch to the enteral route 
will be possible after at least 72 hours of parenteral nutrition, provided 
the vasoactive agent(s) were stopped at least 24 hours earlier and the 
arterial lactic acid level is lower than 2 mmol/L; on day 7, all patients 
will be switched to enteral nutrition in the absence of an absolute 
contraindication to use of the enteral route. In the enteral nutrition 
group, supplemental parenteral nutrition may be added, starting on day 
8, in patients with intolerance to enteral nutrition and inadequate 
calorie intakes. A written protocol for prescribing and delivering 
nutritional support will be available to ensure standardization across 
study centers. 
STRATEGIES / PROCEDURES 
SPECIFIC OF THE ANCILLARY 
STUDIES 
− 
Ancillary study 1  
The assays on D0, D3, and D8 will be performed on part of the blood 
samples drawn for the standard care of these critically ill patients. 
− 
Ancillary study 2  
All tracheal aspirates (obtained routinely in patients receiving invasive 
mechanical ventilation) will be collected over the first 48 hours 
following randomization and stored at -20°. The aspirates will then be 
centralized at the Biology and Pathology Center of the Lille Teaching 
Hospital (Lille, France), where they will be used for quantitative assays 
of pepsin and salivary amylase. 
NUMBER OF PATIENTS 
1427 in each group, i.e., 2854 patients in all 
NUMBER OF PATIENTS IN THE 
ANCILLARY STUDIES 
− 
Ancillary study 1  
85 patients per group, i.e., 170 patients in all 
− 
Ancillary study 2  
94 patients per group, i.e., 188 patients in all 
DURATION OF THE STUDY 
Inclusion period duration: 30 months 
Duration of participation for each patient: duration of mechanical 
ventilation (final extubation), follow-up until hospital discharge 
Total study duration: 36 months (30 months for inclusion plus 6 
months for follow-up and data checking). 
PLANNED TRIAL START DATE September 3, 2012 
EXPECTED IMPACT 
If the study hypothesis is confirmed, early enteral nutrition will 
become the reference standard for initial nutritional support in 
mechanically ventilated patients with shock, and the result will be 
decreased morbidity and mortality rates and improved overall patient 
outcomes. 
 
 
 

 
 
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LIST OF ABBREVIATIONS 
 
AFSSaPS 
Agence Française de Sécurité Sanitaire des Produits de Santé 
(French Healthcare Product Safety Agency) 
APACHE 
Acute Physiology And Chronic Health Evaluation 
BMI 
Body mass index 
CCTIRS  
Comité Consultatif sur le Traitement de l’Information en 
matière de Recherche (French Advisory Committee on Data 
Handling in Healthcare Research) 
CepiDc 
Centre d’épidémiologie sur les causes médicales de décès 
(Epidemiology center for medical causes of death) 
CFU 
Colony-forming unit 
CIRCI 
Critical illness-related colonic ileus 
CNIL 
Commission Nationale de l’Informatique et des Libertés 
(French Data Protection Authority) 
CRA 
Clinical research assistant 
CRF 
Case-report form 
CRN 
Clinical research nurse 
CRP 
C-reactive protein 
CRT 
Clinical research technician 
CT 
Computed tomography 
CTA 
Computed tomography angiography 
CVC 
Central venous catheter 
D 
Day 
GCP 
Good clinical practice 
H 
Hour 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
I-FABP 
Intestinal Fatty Acid-Binding Protein 
INSERM 
Institut National de la Santé et de la Recherche Médicale, 
(French National Institute for Health and Medical Research) 
ITT 
Intention to treat 
IV 
Intravenous 
MPM-0 
Mortality Prediction Model at admission 
MRA 
Magnetic resonance angiography 
NOMI 
Nonocclusive mesenteric ischemia 
NRS 
Nutritional Risk Screening 
NTBR 
Not to be resuscitated 
REE 
Resting energy expenditure 
RN 
Registered nurse 
RRT 
Renal replacement therapy 
SAE 
Serious adverse event 
SAPSII 
Simplified Acute Physiology Score version II 
SOFA 
Sequential Organ Failure Assessment 
SPC 
Summary of product characteristics 
SUSAR 
Suspected unexpected serious adverse reaction 
TEI 
Total energy intake 
USAE 
Unexpected serious adverse event 
VAP  
 
 
Ventilator-associated pneumonia 

 
 
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1) BACKGROUND 
 
5.1  Title 
Impact of Early Enteral vs. Parenteral Nutrition on Mortality in Patients Requiring 
Mechanical Ventilation and Catecholamines: Multicenter Randomized Controlled Trial 
(NUTRIREA-2) 
 
5.2  Coordination and monitoring of the study 
Unité de Recherche Clinique 
Centre Hospitalier Départemental  
85000 La Roche sur Yon, FRANCE 
 
5.3  Investigators 
Chief Investigator 
Dr Jean REIGNIER 
Service de Réanimation Polyvalente 
Centre Hospitalier Départemental 
85000 La Roche sur Yon, FRANCE 
Tel.: +33 251 446 212 
Fax: +33 251 446 294 
jean.reignier@chd-vendee.fr 
 
Associate Chief Investigator 
Laurent BRISARD 
Service Anesthésie-Réanimation – Chirurgie-Thoracique et Cardio-Vasculaire (C.T.C.V.). 
Centre Hospitalier Universitaire – H.G.R.L. 
44093 Nantes, FRANCE 
Tel.: +33 240 165 304 
Fax: +33 240 165 294 
laurent.brisard@chu-nantes.fr 

 
 
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Co-investigators: 
− Amiens, CHU: Pr Hervé Dupont 
− Angers, CHU: Pr Pierre Asfar 
− Annecy, CH: Dr Michel Sirodot 
− Beauvais, CH: Dr Jack Richecoeur 
− Besançon, CHU: Dr Gael Piton 
− Bordeaux, CHU: Dr Hoang-Nam Bui 
− Chartres, CH: Dr Olivier Gontier 
− Clermont-Ferrand, CHU: Dr Ali Ait Hssain 
− Colombes, CHU Louis Mourier: Dr Stéphane Gaudry 
− Dieppe, CH: Dr Jean-Philippe Rigaud 
− Dijon, CHU: Dr Jean-Pierre Quenot 
− Garches, CHU: Pr Djillali Annane 
− Grenoble, CHU: Dr Carole Schwebel 
− Kremlin-Bicêtre, CHU: Dr Nadia Anguel 
− Lens, CH, Dr Didier Thévenin 
− Lille, CHRU: Pr Saad Nseir, Dr Saint Léger, Dr Parmentier, Pr Jourdain 
− Lyon Medical ICU, CHU, Dr Véronique Leray 
− Lyon E.Herriot, CHU, Dr Laurent Argaud 
− Melun, CH: Dr Mehran Monchi 
− Montauban, CH: Dr Frédéric Bellec 
− Montreuil, CH: Dr Vincent Das 
− Mulhouse, CH: Dr Frédérique Ganster 
− Nantes Surgical ICU, CHU, Dr Antoine Roquilly 
− Nantes Medical ICU, CHU, Dr Christophe Guitton 
− Nantes Surgical ICU, Nord, CHU, Dr Raphael Cinotti 
− Orléans, CHR: Dr Thierry Boulain 
− Paris, CHU Cochin: Pr Jean-Paul Mira 
− Paris, CHU Saint-Louis: Dr Emmanuel Canet 
− Paris, CHU Saint-Antoine: Pr Bertrand Guidet 
− Paris, CHU Tenon: Dr Michel Djibre 

 
 
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− Paris, Hôpital Saint-Joseph: Pr Benoit Misset 
− Pointe à Pitre, CHU: Dr Guillaume Thiery 
− Poitiers, CHU: Pr René Robert 
− Rodez, CH: Dr Philippe Letocard 
− Saint Denis, CH: Dr Daniel Silva 
− Saint-Etienne, CHU: Pr Michael Darmon 
− Saint-Malo, CH: Dr François Collet 
− Strasbourg (NHC), CHRU: Pr Ferhat Meziani 
− Strasbourg Hautepierre, CHRU: Dr Etienne Herbrecht 
− Suresnes, Hôpital Foch: Dr Jérôme Devaquet 
− Tours Medical ICU, CHU: Dr Emmanuelle Mercier 
 
 
 

 
 
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5.4  Methodologists – biostatisticians 
Amélie Le Gouge 
Centre d'Investigation Clinique INSERM 0202 
CHRU de Tours - 2 Bd Tonnellé 
37044 Tours cedex 9, FRANCE 
Tel.: +33 247 478 693 - Fax: +33 247 474 662 
 
Dr Bruno Giraudeau 
Centre d'Investigation Clinique INSERM 0202 
CHRU de Tours - 2 Bd Tonnellé 
37044 Tours cedex 9, FRANCE 
Tel.: +33 247 474 618 - Fax: +33 247 474 662 
 
Dr Jérôme DIMET 
Unité de Recherche Clinique 
Centre Hospitalier Départemental Vendée 
85000 La Roche sur Yon, FRANCE 
Tel.: +33 251 446 161 ext. 20 12 
Fax: +33 251 446 298 
 
 

 
 
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2) SCIENTIFIC RATIONALE FOR THE STUDY 
 
5.5  Overview of the research project 
In everyday ICU practice, nutritional support is an integral part of the life-sustaining 
strategies used to combat the impact of critical insults (1). The enteral route, as opposed to the 
parenteral route, is the recommended first-line route of administration in the most recent 
French and international guidelines (2-7). Enteral nutrition has well-documented beneficial 
effects on gastrointestinal mucosa integrity, wound healing, immune function, and responses 
to tissue damage; these benefits may preserve the physical and functional integrity of the 
gastrointestinal tract (8-11). Enteral nutrition may produce optimal benefits when started early 
and in patients with multiple organ failures (12, 13). Most authors and professional 
organizations define “early nutrition” as nutritional support started within 24 to 48 hours after 
ICU admission (5, 14, 15). Early nutrition may contribute to diminish nosocomial infection 
rates, stay lengths, and healthcare costs (2, 11, 16-29).  
Despite the scientific evidence of benefits from nutritional support via the enteral route, 
substantial gaps persist between everyday practice in many ICUs and widely disseminated 
clinical practice guidelines. In a 2010 multicenter observational study that included nearly 
3000 patients, almost 40% of patients were still without nutritional support 48 hours after ICU 
admission, 35% of patients eligible for enteral nutrition were receiving parenteral nutrition, 
and mean calorie and protein intakes amounted to only 60% of recommended targets (30). 
Inadequacies were more marked among surgical patients than among medical patients (31). 
Although delayed initiation of early enteral nutrition thus appears to be a common contributor 
to malnutrition, variability in administration modalities combined with calorie deficiencies 
also emerge as key factors in poor patient outcomes (19, 32-39). Before 2011, a multicenter 
study from Germany in a cohort of patients with very severe critical illnesses (54% mortality 
rate) showed that 35.1% of patients received parenteral nutrition only, 34.6% received 
combined enteral and parenteral nutrition, and only  20.1% received enteral nutrition only 
(19). This inadequate use of enteral nutrition can be ascribed to at least two factors: legitimate 
or exaggerated concern about complications related to the enteral route and the absence of 
sound scientific evidence demonstrating that one route is superior over the other.  
The most common complication of early enteral nutrition is upper gastrointestinal 
intolerance, which occurs in 50% of patients. Concern about nosocomial pneumonia and 
undernutrition related to this complication remains a major deterrent to the use of early enteral 

 
 
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nutrition (32-35, 38, 40-44). Upper gastrointestinal intolerance manifests as gastric 
hypokinesia responsible for an increase in the residual gastric volume, which in turn is 
believed to increase the risk of gastroesophageal reflux, aspiration, and nosocomial 
pneumonia (45-52). The dreaded sequence of incomplete gastric emptying, gastroesophageal 
reflux, aspiration, and nosocomial pneumonia is a constant concern for healthcare workers. 
Ventilator-associated pneumonia (VAP) remains a major complication of mechanical 
ventilation seen in 8% to 27% of patients and responsible for longer ICU stays and an 
increased risk of death in some patients (53). The measure most commonly used to prevent or 
decrease the risk of intolerance consists in discontinuing or markedly decreasing the flow rate 
of enteral feed. This measure diminishes the energy and nutrient intakes, which no longer 
meet the needs of the patient.  In a prospective observational study, a negative energy balance 
in surgical ICU patients was associated with undernutrition, which in turn correlated with a 
higher rate of infections and with increased mortality in the most severely ill patients (54). In 
contrast, parenteral nutrition appears to be the safest means of delivering the required amounts 
of energy and protein. 
The lower intestinal tract can also be the site of complications characterized by ischemia 
despite patency of the blood vessels, a condition known as nonocclusive mesenteric ischemia 
(NOMI) (55). NOMI may affect 20% to 30% of ICU patients with severe circulatory failure. 
Intense splanchnic vasoconstriction designed to preserve blood flow to essential organs (the 
brain, heart, and kidneys) can result in necrotizing enterocolitis, a condition that is fatal in 
70% to 100% of cases (56, 57). The main causative factors are medications (catecholamines, 
vasoconstrictors, cardiovascular drugs), patient characteristics (chronic hemodialysis, heart 
surgery, multiple trauma), and critical complications (acute respiratory distress syndrome, 
septic shock, cardiogenic shock, fluid and sodium overload) (58-60). The potential role for 
enteral nutrition in the development of NOMI remains controversial. A study involving 
superior mesenteric artery blood-flow measurement 3 h after the introduction of nutritional 
support in volunteer ICU patients failed to conclusively resolve this issue (61). Enteral 
nutrition was associated with a greater than 50% blood-flow increase and parenteral nutrition 
with a greater than 60% decrease, indicating a theoretical risk of a mismatch between oxygen 
supply and demand in the splanchnic territory in patients with acute circulatory failure 
receiving enteral nutrition. 
Another contributor to the current underuse of early enteral nutrition in many patients is 
the conflicting nature of findings from available studies. In addition, no study to date has 
demonstrated that a specific nutritional modality is associated with decreased mortality. 

 
 
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International recommendations rest chiefly on metaanalyses whose interpretation is rendered 
difficult by the heterogeneity of the included studies (2, 13, 14). These studies included a 
predominance of surgical patients, many of whom were not receiving ventilatory assistance 
and had low critical-illness severity. The most recent metaanalysis, published in 2009, 
underlines the heterogeneity and sample-size inadequacies of the study populations, which 
preclude definitive conclusions about treatment benefits in some cases (14). In a metaanalysis 
confined to trials that used the intention-to-treat approach, i.e., nine of 465 trials, mortality 
was higher with enteral nutrition (62). In this metaanalysis, mortality in patients given early 
parenteral nutrition (within 24 h after ICU admission) was 56% lower than in patients given 
late enteral nutrition (more than 48 h after ICU admission). The uncertainty surrounding 
current recommendations has been acknowledged by their authors, who have emphasized the 
need for adequately powered and randomized trials in homogeneous patient populations.  
Several recent studies evaluated supplemental parenteral nutrition in patients with failure 
to reach their target nutrient intakes due to poor tolerance of early enteral nutrition. The 
optimal time for initiating combined parenteral and enteral nutrition is controversial, with 
North-American societies recommending delayed introduction of parenteral nutrition after the 
first week and European societies arguing for early combined nutrition designed to rapidly 
reach the theoretical energy target (4, 6). A very recent, large, randomized, multicenter trial 
(EPaNIC trial) compared these two strategies (63). All patients having a Nutritional Risk 
Screening score >3 were included, i.e., over 4500 patients. The primary outcome measure was 
ICU stay length, which was shorter by 1 day in the group given late parenteral nutrition. The 
nosocomial infection rate and mechanical ventilation duration were higher in the early-
parenteral-nutrition group. In contrast, no significant differences were found for ICU or 
hospital mortality rates. The authors concluded that early addition of parenteral nutrition to 
enteral nutrition, within the first ICU week, provided no benefits and increased the length of 
stay. These results should be interpreted in the light of the low overall ICU mortality rate 
(6.2%) and limited duration of mechanical ventilation (2 days) related to the predominance of 
heart-surgery patients, which preclude definitive conclusions regarding mortality. In contrast, 
in a randomized trial from Switzerland that has so far been reported only during meetings, the 
early adjunction of parenteral nutrition in patients whose nutritional targets were not achieved 
by enteral nutrition was associated with a significant decrease in the nosocomial infection rate 
(64). Although these two studies reflect the current high level of interest in early nutritional 
support in ICU patients, neither was designed to compare the parenteral to the enteral route. 
Instead, both studies sought to determine whether supplemental parenteral nutrition in patients 

 
 
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with intolerance to enteral nutrition should be started early or only after the first week. Thus, 
neither study provides any information on the possible superiority of one route over the other. 
To date, no large prospective randomized trial has demonstrated that early enteral nutrition 
improves survival in ICU patients, a fact that leaves room for active controversy (65-67). 
The current situation can be summarized as follows. 
1. International recommendations indicate that early enteral nutrition should be preferred 
over parenteral nutrition.  
2. Adherence to this guideline is poor in many patients, for a number of reasons: 
a. Concern about potential complications of the recommended strategy and/or the 
need to manage these complications when they occur result in an increased work 
load and in delayed or absent use of early enteral nutrition. 
b. The available data (metaanalyses) are conflicting. 
c. The authors of the recommendations acknowledge that their guidelines rest on 
converging arguments and indirect studies but not on sound evidence, most 
notably from randomized trials having adequate statistical power and using 
relevant clinical outcome measures. 
d. The highly conflicting results of recent studies on supplemental early parenteral 
nutrition constitute indirect evidence that the issue remains unresolved. 
3. There is therefore a pressing need to conduct a study capable of determining whether the 
enteral route is superior over the parenteral route for early nutritional support in ICU 
patients. This study must be conducted in a population of selected patients at high risk for 
death and/or secondary complications, most notably infections, in whom the 
implementation of optimal nutritional support is likely to have the greatest consequences 
and to raise the greatest difficulties. 
Patients with shock requiring both invasive mechanical ventilation and vasoactive amines 
have a particularly high level of illness severity associated with high risks of death, secondary 
complications, intolerance to early enteral nutrition, and mesenteric vascular complications. 
For these patients, most recommendations indicate that early enteral nutrition should not be 
started until the hemodynamic situation is controlled (2, 4, 6). Therefore, either enteral 
nutrition is delayed or parenteral nutrition is given initially (19). However, the greatest 
benefits from enteral nutrition were reported in this type of population. In a retrospective 
analysis of data from 1174 patients treated with mechanical ventilation and vasoactive agents 

 
 
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(68), early enteral nutrition (within 48 h after starting mechanical ventilation) was associated 
with a lower mortality rate compared to the group given late enteral nutrition. In the subgroup 
analysis, the benefits from early enteral nutrition were greatest in the sickest patients (usually 
those having the greatest dependency on vasoactive agents) and in the patients who failed to 
improve promptly (i.e., who had marked vasoactive agent dependency throughout the first 48 
h of treatment). Another retrospective study of 2528 patients requiring mechanical ventilation 
for longer than 48 h produced similar findings (12). In the patients with the worst severity-of-
illness scores (APACHE II>25, SAPS II>56, and MPM-0<0.54) at baseline, ICU and hospital 
mortality rates were significantly lower with early vs. late enteral nutrition. Thus, severe 
illness and established circulatory failure do not contraindicate early enteral nutrition, 
provided the initial life-sustaining interventions are appropriate. Nevertheless, regarding the 
nutritional strategy in this type of patient, adherence to recommendations is extremely 
variable and the recommendations themselves are unclear because they do not rest on a body 
of sound evidence allowing definitive conclusions.  
The objective of this research project is therefore to obtain unequivocal confirmation, in 
an appropriate number of patients and using a prospective multicenter randomized controlled 
trial design, of the hypothesis that early first-line enteral nutrition decreases day-28 all-cause 
mortality in patients with shock treated with mechanical ventilation and vasoactive amines, 
compared to early first-line parenteral nutrition. 
The NUTRIREA2 trial provides the opportunity to answer two additional questions, via 
an ancillary study for each. 
1. Is enteral nutrition associated with better preservation of gut mucosa integrity compared to 
parenteral nutrition? 
Published studies suggest that enteral nutrition may help to preserve gut mucosal integrity 
and function. More specifically, enteral nutrition may maintain normal gut permeability and 
preserve the gut lymphoid tissue (11, 23, 69). In addition, experimental data suggest that the 
risk of bacterial translocation may increase with parenteral nutrition and decrease with enteral 
nutrition (16, 70-72). These effects of enteral nutrition may diminish the risk of systemic 
inflammatory response syndrome and organ failure (29, 73). These theoretical benefits may, 
however, be offset by the risk of gut mucosal ischemia possibly associated with enteral 
nutrition (61, 74). Furthermore, they have not been demonstrated in critically ill patients, 
particularly those with mechanical ventilation and shock. The NUTRIREA2 trial provides a 
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and function in this population. Such a comparison can be performed readily in everyday 
practice by assaying two molecules recently identified as reliable markers for gut failure as 
seen in some critically ill patients (75-77). Citrulline is an amino acid produced from 
glutamine by enterocytes. Plasma citrulline levels reflect the mass of functional enterocytes. 
Intestinal fatty acid-binding protein (I-FABP, also known as FABP2) is a small protein found 
in the cytosol of small-bowel enterocytes that is released into the capillaries when the 
enterocytes are damaged. Plasma I-FABP is a marker for enterocyte lysis. Assaying both 
plasma citrulline and plasma I-FABP may provide an evaluation of gut failure in critically ill 
patients and may allow discrimination between enterocyte damage (low plasma citrulline and 
high plasma I-FABP) and enterocyte dysfunction (low plasma citrulline and normal plasma I-
FABP), although both mechanisms may be interlinked (78). The hypothesis underlying this 
ancillary study is that gut mucosal integrity and function are better in patients given first-line 
enteral nutrition compared to those given parenteral nutrition. Higher plasma citrulline levels 
and lower plasma I-FABP levels in the enteral-nutrition group than in the parenteral-nutrition 
group would support this hypothesis. 
2. Is enteral nutrition associated with a higher risk of gastric-content aspiration compared to 
parenteral nutrition?  
Risk factors for gastric-content microaspiration in critically ill patients include 
gastroesophageal reflux, gastric distension, damage to the inferior and superior esophageal 
sphincters, and impairment of the glottic closure reflex that normally prevents aspiration (79, 
80). Several studies involving technetium 99m (99mTc) labeling of gastric contents have 
established that gastric-fluid microaspiration is common in critically ill patients receiving 
both endotracheal ventilation and enteral nutrition (81-84). However, to our knowledge, no 
studies have specifically addressed the role for enteral nutrition in the occurrence of 
microaspiration. The objective of this ancillary study is to compare the frequency of gastric-
content microaspiration in patients given enteral versus parenteral nutrition during the 
NUTRIREA2 trial. The new knowledge of risk factors for microaspiration provided by this 
study may help to improve strategies for preventing microaspiration and VAP.  
 
5.6  Overview of potential benefits and, where applicable, of 
predictable and known risks for the patients participating in the 
research project 

 
 
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By comparing two strategies for nutritional support initiation, this study will strive to 
standardize the initiation of nutritional support in patients treated with mechanical ventilation 
and one or more vasoactive amines. At the acute phase of their ICU management, the study 
patients will receive a single nutritional modality, i.e., either parenteral nutrition (early 
parenteral group, P group) or enteral nutrition (early enteral group, E group) for at least 72 h 
and no longer than 7 days. Each of these two modalities will be used according to a pre-
defined protocol that will include an estimate of energy needs based on body weight. Beyond 
the first study week, the ICU teams will give preference to the enteral route, except in patients 
with acute bowel disease constituting an absolute contraindication to enteral nutrition. Thus, 
parenteral and enteral intakes will be combined according to each patient’s needs. 
The standardization of nutritional support will constitute in itself a source of benefits to 
the study patients (15). This study generates no additional risks to the patients. Nutritional 
support, whether delivered enterally or parenterally, is among the first-line treatments used 
routinely in the ICU. Raising healthcare worker awareness about good clinical practice in the 
area of nutritional support receives careful attention as a matter of course in ICUs. Finally, to 
date, no study has produced definitive information on the risks and benefits of enteral versus 
parenteral nutrition.  
Similarly, the ancillary studies will pose no additional risks to the patients. More 
specifically, they will require no additional biological-sample collections. The citrulline and I-
FABP assays in Ancillary Study 1 will be performed on a fraction of the blood samples drawn 
for the routine management of critically ill patients. These blood samples will simply need to 
be increased slightly (by about 2 mL). The pepsin and salivary amylase assays needed for 
Ancillary Study 2 will be performed on tracheal aspirates obtained as part of the standard care 
of patients receiving mechanical ventilation. Thus, no additional procedures are required. 
 
5.7  Statement that the research project will be conducted in compliance 
with the study protocol and with good clinical practice guidelines 
The investigator undertakes to ensure that this research is conducted  
- in compliance with the study protocol and 
- in compliance with current French and international good clinical practice guidelines. 
 
5.8  Description of the study population 

 
 
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This study will include adults admitted to the ICU and eligible for enteral or parenteral 
nutrition within 24 h after endotracheal intubation (or within 24 h after ICU admission if 
intubation occurred before ICU admission), for a predicted duration of at least 2 days. 
Furthermore, eligibility for study inclusion will require a serious critical illness defined as a 
need for vasoactive amine therapy to treat shock combined with invasive mechanical 
ventilation started within the past 24 h. The controlled nutritional-support strategy will be 
used only during the acute phase of intensive care, defined as the first 7 days in the ICU. 
Section 5 describes the inclusion and exclusion criteria used to select the study patients. 
 
 

 
 
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3) STUDY OBJECTIVES  
 
5.9  Primary objective  
The primary objective of this research project is to assess the hypothesis that a strategy 
involving first-line early enteral nutrition decreases day-28 all-cause mortality in 
mechanically ventilated patients receiving vasoactive amine therapy for shock, compared to a 
strategy involving first-line early parenteral nutrition. 
 
5.10 
 Secondary objectives  
The secondary objectives consist in comparing the following variables in the two groups: 
▪ Nosocomial infections: 
o VAP: proportion of patients with at least one VAP episode, VAP incidence 
density, number of VAP episodes 
o Bacteremia: proportion of patients with at least one episode of bacteremia, 
incidence density of bacteremia 
o Central venous catheter (CVC)-related infections: proportion of patients with at 
least one CVC-related infection, incidence density of CVC-related infections 
o Urinary tract infections: proportion of patients with at least one urinary tract 
infection, incidence density of urinary tract infections 
o Soft tissue infections: proportion of patients with at least one soft tissue infection, 
incidence density of soft tissue infections 
▪ Descriptive bacteriological data (organisms recovered and antibiotic resistance profile for 
each nosocomial infection)  
▪ Proportion of patients with at least one episode of vomiting or regurgitation 
▪ Proportion of patients with at least one episode of diarrhea 
▪ Proportion of patients with at least one episode of constipation 
▪ Proportion of patients with at least one episode of documented bowel ischemia 
▪ Number of calories delivered enterally and parenterally each day 
▪ Volume of enteral and parenteral feed delivered each day 
▪ Ratio of prescribed over delivered calories 
▪ ICU mortality, day-90 mortality, and hospital mortality 

 
 
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▪ Changes in nutritional markers during follow-up (measured at the end of mechanical 
ventilation, on day 7 in patients on mechanical ventilation for more than 7 days, and at 
ICU discharge) 
▪ Proportion of patients with at least one episode of liver dysfunction (liver function will be 
evaluated at the end of mechanical ventilation, on day 7 in patients on mechanical 
ventilation for more than 7 days, and at ICU discharge) 
▪ ICU stay length 
▪ Hospital stay length 
▪ Total time on mechanical ventilation 
▪ Body weight changes from ICU admission to day 7 and from ICU admission to ICU 
discharge 
 
5.11 
Objectives of the ancillary studies 
− 
Ancillary study 1  
o Primary objective: To demonstrate that a strategy involving early first-line 
enteral nutrition is associated with improved preservation of gut mucosal 
integrity, as assessed based on the plasma citrulline level at H72, compared to 
a strategy involving early first-line parenteral nutrition 
o Secondary objectives: To compare the effects of enteral and parenteral 
nutrition on the course of organ failures, bacteremia, gastrointestinal 
intolerance, bowel transit time, and plasma citrulline and I-FABP levels 
 
− 
Ancillary study 2 
o Primary objective: To evaluate the impact of enteral nutrition on 
microaspiration of gastric content 
o Secondary objective: To evaluate the impact of enteral nutrition on 
microaspiration of pharyngeal secretions 
 
 
 
 
5.12 
Impact 
If the study hypothesis is confirmed, then early enteral nutrition will become the 
reference standard method of nutritional support in mechanically ventilated patients with 

 
 
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shock, based on improvements in morbidity and mortality rates and in the overall outcome of 
patients at the acute phase of ICU management. 
The ancillary studies will clarify the impact on gut function of the route of administration 
of nutritional support, as well as the pathophysiology of gastric-content aspiration, in patients 
receiving mechanical ventilation. 
 
 
 

 
 
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4) STUDY CONCEPTS 
 
5.13 
 Detailed descriptions of the primary endpoint and, where 
applicable, of the secondary endpoints 
 
4.1.1 Primary endpoint 
The primary endpoint is all-cause mortality by day 28 (D28). Information on this endpoint 
will be collected on the 28th day after inclusion of the patient in the study. For patients 
who have been discharged, information on the primary endpoint will be collected by a 
telephone call to the patient at home.  
 
4.1.2 Secondary endpoint 
▪ Proportion of patients with at least one VAP episode (numerator in each group: total 
number of patients with at least one VAP episode during mechanical ventilation or 
within 2 days after extubation; denominator: total number of patients included in the 
relevant group). 
The diagnosis of VAP will be suspected based on the development or persistence of 
lung infiltrates on the chest radiograph with at least two of the following criteria: body 
temperature ≥38.5 or ≤35.5ºC, leukocytosis (>10 000/mm3) or leukopenia 
(<4000/mm3), and purulent tracheobronchial aspirate. The diagnosis will have to be 
confirmed by a positive semi-quantitative bacteriological test: bronchoalveolar lavage 
(>10-4 cfu/mL), brush (>10-3 cfu/mL), tracheal aspirate (>10-6 cfu/mL), or protected 
distal specimen (>10-3 cfu/mL) (53, 69). 
▪ VAP incidence density per 1000 days of mechanical ventilation, i.e., ratio of the 
number of patients with at least one VAP episode during mechanical ventilation or 
within 2 days after extubation over the period at risk defined as follows:  
o total number of mechanical ventilation days in patients without VAP 
o mechanical ventilation days before the first VAP episode in patients with VAP 
▪ Number of VAP episodes per patient 
▪ Other nosocomial infections:  
o Bacteremia: proportion of patients with at least one episode of bacteremia and 
incidence density per 1000 ICU days 

 
 
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o CVC-related infections: proportion of patients with at least one CVC-related 
infection and incidence density per 1000 CVC days 
o Urinary tract infections: proportion of patients with at least one episode of 
urinary tract infection and incidence density per 1000 urinary-catheter days 
o Soft tissue infections: proportion of patients with at least one soft tissue 
infection and incidence density per 1000 ICU days 
o Other nosocomial infections: proportion of patients with other nosocomial 
infections and incidence density per 1000 ICU days 
▪ Proportion of patients with at least one nosocomial infection 
▪ Descriptive bacteriological data: organisms recovered in the overall population of 
nosocomial infections and antimicrobial resistance profiles 
▪ Proportion of patients with at least one episode of vomiting or regurgitation while on 
mechanical ventilation 
▪ Proportion of patients with at least one episode of diarrhea defined as liquid stools in a 
volume greater than 300 mL/24 hours in patients with a fecal collector or as more than 
four loose stools/24 hours (15). 
▪ Proportion of patients with at least one documented episode of bowel ischemia defined 
as absent blood flow in one of the main arteries supplying the bowel (superior 
mesenteric artery, inferior mesenteric artery, or celiac artery) with evidence of bowel 
wall compromise on an imaging study (computed tomography angiography [CTA], 
angiography, or magnetic resonance angiography [MRA]) or presence of criteria for 
colonic ischemia according to the Favier classification system (stage I, petechiae; 
stage II, petechiae and superficial ulcers; and stage III, necrotic ulcers and polypoid 
lesions) by endoscopy (rectosigmoidoscopy or colonoscopy) (70) 
▪ Number of calories (in Kcal) delivered enterally and parenterally:  
o daily mean during the first week 
o daily mean throughout the time on mechanical ventilation 
▪ Ratio (as a %) of prescribed over delivered calories delivered enterally and parenterally:  
o daily mean during the first week 
o daily mean throughout the time on mechanical ventilation 
o proportion of patients who achieved their calorie target on each follow-up day 
▪ Volume of liquid feed (in mL) delivered 
o daily mean during the first week 
o daily mean throughout the time on mechanical ventilation 

 
 
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▪ ICU mortality, 90-day mortality, and hospital mortality; to confirm deaths by day 90, 
we will search the epidemiological causes-of-death database (CépiDc, Centre 
d’épidémiologie sur les causes médicales de décès). 
▪ Mean changes in serum albumin, prealbumin, transthyretin, and C-reactive protein 
(CRP) measured at baseline, at the end of mechanical ventilation, on day 7 (in patients 
on mechanical ventilation for more than 7 days), and at ICU discharge 
▪ Proportion of patients with at least one episode of liver dysfunction during follow-up; 
liver function will be evaluated at the end of mechanical ventilation, on day 7 (in 
patients on mechanical ventilation for more than 7 days), and at ICU discharge; liver 
dysfunction will be defined as serum bilirubin >50 µmoL/L and/or elevation >3N in 
one or more liver enzymes (-glutamyltransferase, alkaline phosphatase, and ASAT-
ALAT). 
▪ ICU stay length 
▪ Hospital stay length 
▪ Time on mechanical ventilation 
▪ Changes in mean body weight determined at baseline, on day 7, and at ICU discharge 
 
4.1.3 Endpoints for the ancillary studies 
− 
Ancillary study 1  
o Primary outcome measure: plasma citrulline level at H72 
o Secondary outcome measures: SOFA score; plasma levels of citrulline and I-
FABP on D0, D3, and D8; proportion of patients whose plasma I-FABP is 
≥100 pg/mL on D0, D3, and D8; proportion of patients whose plasma citrulline 
is ≤10 μL/L on D0, D3, and D8; mean plasma I-FABP; mean plasma citrulline; 
proportion of patients with at least one episode of bacteremia; proportion of 
patients with at least one episode of gastrointestinal intolerance; proportion of 
patients with at least one episode of diarrhea; in the enteral-nutrition group, 
cumulative calorie intake over the first 3 days and on D7; impossibility of 
administering enteral nutrition. 
 
 
− 
Ancillary study 2 

 
 
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o Primary 
outcome 
measure: 
proportion 
of 
patients 
with 
abundant 
microaspiration  
o Secondary outcome measures: salivary amylase levels in tracheal aspirates 
 
5.14 
Description of the research project methodology with a study 
diagram including scheduled visits and investigations 
 
4.2.1 Study design 
 
This multicenter randomized controlled open trial will compare two parallel groups of 
patients receiving mechanical ventilation and vasoactive amine therapy and given early 
nutritional support according to one of two strategies (first-line enteral nutrition versus first-
line parenteral nutrition) at the acute phase of ICU management (D1 to D7). 
 
4.2.2 Conduct of the study 
 
 
4.2.2.1 Inclusion 
 
Patients will be included in the study within 24 h after intubation, or within 24 h after 
ICU admission if they were intubated before ICU admission. Study inclusion will occur after 
the usual initial life-sustaining interventions required in patients with shock managed using 
ventilatory support. The study will include patients requiring vasoactive amine therapy after 
volume expansion if indicated and any evaluation procedures dictated by the clinical 
condition. These initial treatment and evaluation decisions will be at the discretion of the 
physician in charge of each patient, who will follow standard procedures in the relevant study 
ICU.  
Information about the study and collection of consent to study participation will involve 
the patient if he or she is conscious and the next of kin otherwise. If informed consent is 
obtained from the next of kin, informed consent will be sought from the patient as soon as he 
or she recovers a sufficient level of consciousness.  
A log of patients considered for study participation will be kept and will include any 
reasons for non-inclusion and refusals of consent. 

 
 
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After checking the inclusion and non-inclusion criteria, as well as consent to participation 
given by the patient or next of kin, the investigator will be able to include the patient. At 
inclusion, demographic data, patient characteristics, and vital signs will be collected: date of 
birth, sex, date of ICU admission, reason for ICU admission, McCabe and Knaus scores, 
chronic co-morbidities, body weight, height, BMI, SOFA score, and SAPS II. 
 
4.2.3 Nutritional support protocol  
The nutritional support protocol, including measures designed to evaluate tolerance, will 
be standardized as indicated below. 
a. General principles 
Nutritional support will be started as soon as possible after the initiation of invasive 
mechanical ventilation and no later than 24 hours after intubation or after ICU admission in 
patients intubated before ICU admission.  
The calorie target for each patient will be estimated based on body weight as 20-25 
Kcal/Kg/day during the acute phase (7 days at the most) then 25-30 Kcal/Kg/day from day 7 
to extubation. In obese patients (BMI> 30 Kg/m²), the body weight yielding a BMI of 30 will 
be used to estimate the calorie target.  
Nutritional support will be prescribed as a flow rate (mL/hour) and started at the 
prescribed flow rate (as opposed to increased gradually). The feed will be delivered 
continuously, over the 24-hour cycle, with no interruptions. Actual feed delivery will be 
monitored regularly based on the volumes delivered relative to the predefined daily calorie 
targets. In addition, special attention will be directed to avoiding delays. Any interruption in 
feed delivery will be reported to the ICU physician in charge. Except in special situations, 
nutritional support will not be interrupted while transporting the patient. However, when 
enteral or parenteral nutrition must be interrupted (e.g., for a specific gastrointestinal or 
radiological investigation), the flow rate will not be increased to compensate for the 
interruption. Finally, the patient will be in the semi-recumbent supine position with the torso 
at 30° to 45° from the horizontal plane. 
b. Enteral nutrition  
Isoosmotic isocaloric normal-protein polymeric preparations will be used during the first 
week, after which the choice of feed will be at the discretion of the physician. The enteral 
nutrition preparation will be delivered continuously, over the 24-hour cycle, with no 

 
 
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interruptions, via a 14-French silicone gastric tube. Tube position in the middle of the 
stomach will be checked on a radiograph obtained at ICU admission or immediately after tube 
placement, as well as when the tube is changed or repositioned. Special attention will be 
directed to the risk of tube obstruction, particularly when administering medications: the tube 
will be flushed regularly with 20-30 mL of water.  
A predefined protocol will be used to manage upper gastrointestinal intolerance to enteral 
nutrition (Appendix 1) (71). The tolerance of enteral nutrition will be monitored based only 
on episodes of significant vomiting or regurgitation (passage of enteral nutrition formula into 
the mouth, outside the mouth, or into the endotracheal tube in the absence of care procedures 
or mobilization). The residual gastric volume will not be monitored. Intolerance to enteral 
nutrition will be defined as the presence of significant vomiting or regurgitation. Minimal 
regurgitation or vomiting triggered by tracheal aspiration or oral cavity care will not be taken 
to indicate intolerance. Intolerance to enteral nutrition will lead to the following two 
measures: 
▪ First, initiation of treatment with a prokinetic agent after confirmation that there are 
no contraindications and after obtaining a prescription by a physician. The study 
ICUs will use the prokinetic agent of their choice, according to their standard practice. 
The prokinetic agent will be continued until enteral nutrition at the highest prescribed 
flow rate has been well tolerated for 48 hours. The prokinetic agent will then be 
discontinued. 
▪ Second, if the intolerance persists despite prokinetic therapy, the flow rate will be 
decreased by 25 mL/h, every 6 hours, until the signs of intolerance resolve. Therefore, 
enteral nutrition will be stopped (and the gastric tube placed under suction) only in 
patients with intolerance despite a flow rate ≤25 mL/h. All interruptions in enteral 
nutrition delivery must be reported to the intensivist in charge. This precaution is 
particularly important in patients receiving insulin. Enteral nutrition will be resumed at 
the prescribed flow rate (appropriate to the patient’s needs) after 6 hours have elapsed 
with no further signs of intolerance. (71). 
c. Parenteral nutrition  
Ternary admixtures packaged in bags and containing the three groups of macronutrients 
will be used according to standard practice in each participating center. Supplemental 
electrolytes will be supplied in a solution separate from the parenteral feed, according to the 
needs of each patient. Parenteral nutrition will be delivered continuously, over the 24-hour 

 
 
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cycle, with no interruptions, via a central venous catheter (CVC). Special attention will be 
directed to preventing infections by complying with the standard protocols for CVC insertion 
and maintenance used in each of the participating centers. Proper positioning of the CVC will 
be checked using a radiograph. 
d. Additional intakes (water, electrolytes, trace elements, and vitamins) 
Additional water and electrolytes will be given intravenously according to the needs of 
each individual patient as assessed by the physician in charge and in compliance with 
standard practice in each study ICU.  
Intravenous vitamins, trace elements and, when appropriate, will be given according to the 
needs of each individual patient, using the standard preparations and protocols available in 
each study ICU.  
These components will not be added to the parenteral nutrition bags. Instead, they will be 
given using a separate intravenous bag and line, continuously over the 24-hour cycle; if 
needed, this separate preparation will be shielded from light using aluminum foil.  
 
4.2.4 Study intervention: first-line enteral or parenteral nutrition  
After study inclusion, patients will be allocated at random to one of two nutritional-
support strategies (Figure 1). 
In the parenteral-nutrition group (P group), the patients will receive first-line 
parenteral nutrition for at least 72 hours. After these 72 hours, the course of action will 
depend on the results of the daily hemodynamic status evaluation. If the hemodynamic 
condition is stable (no vasoactive amines for 24 consecutive hours and arterial lactic acid 
level below 2 mmol/L) and the enteral route can be used, parenteral nutrition will be stopped 
and immediately replaced by enteral nutrition at the flow rate needed to achieve the 
previously defined calorie target. If on the contrary the patient still requires vasoactive amine 
therapy and/or the arterial lactic acid level is equal to or greater than 2 mmol/L, parenteral 
nutrition will be continued for a total of 7 days (168 hours). On day 8, in the absence of 
contraindications to enteral nutrition, parenteral nutrition will be stopped and enteral nutrition 
started. Supplemental parenteral nutrition may be added subsequently in the event of 
intolerance to enteral nutrition precluding the achievement of the predefined calorie targets.  
In the enteral-nutrition group (E group), the patients will receive first-line enteral 
nutrition. In the event of persistent gastrointestinal intolerance precluding achievement of the 

 
 
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predefined calorie targets, supplemental parenteral nutrition may be added starting on day 8 in 
compliance with North-American recommendations and with the recently published study by 
Casaer (6, 72). Isoosmotic isocaloric normal-protein polymeric preparations will be used 
during the first week, after which the choice of the preparation will be at the discretion of the 
physician. To minimize the risk of gastric intolerance and consequently of vomiting, the 
volume of supplemental water given enterally will be as small as possible during the first 
study week.  

 
 
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Figure 1: Protocol 
 
 
 
P group (ternary admixture used routinely in the 
study center) 
Start at 20-25 Kcal/Kg/d  
+ trace elements and vitamins 
E group (isocaloric preparation used routinely in the 
study center) 
Start at 20-25 Kcal/Kg/d  
+ trace elements and vitamins 
Continue P 
(20 Kcal/Kg/d) 
- E: 25-30 Kcal/Kg/d 
- Supplemental P possible if persistent intolerance to E 
No vasoactive amines for 24 consecutive hours 
AND lactic acid <2 mmol/L 
AND patient eligible for enteral nutrition 
D3 
 
 
 
 
 
 
 
 
 
 
 
 
 
D7 
Stop P and start E 
20 Kcal/Kg/d 
NO 
YES 
Daily reevaluation 
D1 
 
 
 
 
D2 
EVALUATION AFTER 72 H OF P 
Stop P 
D8 
Monitor E 
No supplemental P  
(see protocol for managing 
intolerance, Appendix 1) 
Monitor E 
(see protocol for managing intolerance, Appendix 1) 
D Extubation = End of study 
RANDOMIZATION = D0 
Patient started on invasive mechanical ventilation in the ICU within the past  
24 h or, if mechanically ventilated before ICU admission, admitted to the ICU 
within the past 24 h, given vasoactive amine therapy, and having none of the 
exclusion criteria 
D
8 

 
 
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4.2.5 Monitoring of intestinal transit 
The volume and appearance of the stools will be monitored daily.  
The occurrence of constipation (no stool for more than 6 days) or diarrhea (more than 300 
mL of liquid stool or 4 loose stools per day) will be reported and will lead to the appropriate 
diagnostic and therapeutic management (Appendix 2)  (15, 73, 74). 
 
4.2.6 Special situations  
▪ Patients in the prone position: intolerance to enteral nutrition is particularly common 
in this position and will be prevented via prophylactic prokinetic treatment started at 
the first turn in the prone position (75, 76). 
▪ Patients receiving insulin therapy: very close monitoring and strict application of the 
insulin-therapy protocol used in each study-center institution are crucial. Blood 
glucose targets will be at the discretion of each study center according to their usual 
practice and protocols. In addition, 
o in the event of a decrease in the enteral feed flow rate due to poor tolerance of 
enteral nutrition (regurgitations), blood glucose levels will be determined at 
least hourly during the first 2 hours following the flow rate reduction; if blood 
glucose levels remain stable, the patient will be returned to the frequency of 
monitoring specified in the insulin-therapy protocol; 
o In the event nutritional support is discontinued, blood glucose levels will be 
determined hourly for as long as the patient remains off enteral nutrition. 
▪ Patients who are re-intubated or re-admitted to the ICU: if this event occurs at the 
acute management phase (<7 days after first use of mechanical ventilation), the patient 
will be managed in the same way as during the first period of intubation, until the end 
of the acute phase. Thus, a patient allocated at random to the enteral-nutrition group (E 
group) will remain in this group for at least the first 7 days of management. If the 
event occurs after the end of the acute phase, the method of nutritional support will be 
at the discretion of the physician in charge. 
 
4.2.7 Patient follow-up  
The following will be recorded until the patient is extubated: vital signs, nutrition 
monitoring data, laboratory tests, and data relevant to nosocomial infections. The patient will 

 
 
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be followed-up to hospital discharge, D28, and D90. At these time points, vital status will be 
recorded. Below is a flowchart of patient follow-up. 
 
 
Inclu-
sion 
Rando-
mization 
D0* 
D1 to Dn 
End of 
study 
D28 
D90 
Eligibility: check inclusion and 
exclusion criteria 
X 
 
 
 
 
 
 
Patient information and consent 
X 
 
 
 
 
 
 
 Randomization 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Characteristics 
 
 
X 
 
 
 
 
Ventilation 
 
 
X 
 
 
 
 
Laboratory tests 
 
 
X 
X* 
 
 
 
SOFA 
 
 
X 
X 
 
 
 
Nutritional evaluation 
 
 
X 
X 
 
 
 
Treatments used 
 
 
X 
X 
 
 
 
Daily calorie intake 
 
 
 
X 
 
 
 
Nosocomial infections 
 
 
 
X 
 
 
 
Final extubation  
 
 
 
 
X 
 
 
Final discontinuation of nutritional 
support 
 
 
 
 
X 
 
 
Survived / died 
 
 
 
 
X 
X 
X 
 
*from time at inclusion to 11:59 pm 
 

 
 
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Design of the ancillary studies 

 
 
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Ancillary study 1  
The plasma citrulline and I-FABP assays on D0, D3, and D8 will be performed using 
blood drawn as part of the standard care of critically ill patients; the volume of each blood 
sample will be increased slightly (by about 2 mL) to allow these assays. For amino acid 
chromatography, blood will be drawn in a lithium heparin tube, which will be transported on 
ice as promptly as possible to the medical biochemistry laboratory. At arrival at the laboratory 
and within 2 hours after blood collection, the sample will be centrifuged (4°C, 1900 rpm, 10 
minutes) and the plasma stored at -70 °C until the analysis.  
The samples will be centralized at the Biology Center of the Besançon Teaching Hospital. 
After thawing and deproteinization, ion-exchange chromatography will be performed on a 
Hitachi L-8800 analyzer (Hitachi, Tokyo, Japan).  
I-FABP will be assayed using a blood sample drawn into an EDTA tube, which will be taken 
as rapidly as possible to the medical biochemistry laboratory. At arrival at the laboratory, the 
sample will be centrifuged (4°C, 1500 rpm, 15 minutes) and the plasma stored at -70°C until 
analysis by ELISA (Hycult Biotech, Uden, The Netherlands) at the Biology Center of the 
Besançon Teaching Hospital. 
 
Ancillary study 2 
Tracheal aspiration will be performed according to standard practice in the study centers. 
All tracheal aspirates obtained within 48 hours after randomization for the NUTRIREA2 trial 
will be stored frozen at each study center. The frozen aspirates will be sent to the 
Biochemistry Department of the Lille Teaching Hospital (Dr. M. Balduyck, Dr. F. Zerimech, 
and Dr. P. Maboudou), where the pepsin and salivary amylase assays will be performed.  
The measures taken to prevent microaspiration will comply with current 
recommendations and with standard practice in each study center. They will consist of the 
following:  
• Endotracheal tube cuff pressure kept at about 25 cm H2O; 
• Semi-recumbent patient position; 
• Application of at least 5 cmH2O of positive end-expiratory pressure (PEP) in patients 
without contraindications;  
• Daily evaluation of criteria for weaning off mechanical ventilation, to minimize the 
duration of mechanical ventilation; 
• No routine prophylactic treatment of stress-induced ulcers; and 
•  Limited use of sedation and application of a sedation management protocol. 

 
 
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5.15 
4.3 Description of measures taken to minimize and avoid 
biases 
4.3.1 Random allocation 
The randomization scheme will be stratified on the study site. Patient category 
(postoperative or medical) will not be used for stratification, as the distribution between 
postoperative and medical patients is expected to be heavily skewed (based on earlier studies, 
surgical patients are expected to contribute only 10% of the study population). Random 
allocation will be performed using the electronic case-report form available at each study 
center. 
 
4.3.2 Blinding methods 
The trial will be open, since nutritional support requires the intervention of a nurse and 
involves two different routes of administration (enteral or parenteral), one for each group of 
study patients.  
 
Given the absence of blinding, the secondary endpoints relevant to nosocomial infections 
will be validated by an adjudication committee. Nosocomial infections are of the utmost 
clinical importance, and the results of our study may have a major impact on future patient 
management. Consequently, a very high level of uniformity in data collection is crucial to 
ensure that highly reliable results are obtained. 
 
 
4.4 Expected duration of study patient participation and description of the time 
sequence and duration of all trial periods, including follow-up, where 
applicable 
The duration of participation of each patient in the study will depend on the time to 
extubation. The vital status of each patient will be recorded at ICU discharge, at hospital 
discharge, on D28, and on D90. For patients discharged before D28 and/or D90, a telephone 
interview will be arranged. 
Study recruitment is expected to last 30 months, yielding a total patient follow-up time of 
36 months. 
 
 
4.5 Reasons for permanent or temporary study discontinuation 

 
 
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4.5.1 Patient withdrawal from the study 
The patients or next of kin may ask to withdraw from the study at any time and for any 
reason. In the event of secondary withdrawal of consent to participation in the research 
project, none of the data collected since study inclusion of the patient will be used, in 
compliance with the wishes of the patient or next of kin. Withdrawal of a patient from the 
study will have no impact on the standard care delivered to the patient for the condition that 
prompted the hospital admission. The laboratory tests specific to the study nutritional-support 
protocol will not be performed. All investigations and treatment decisions will be at the 
discretion of the physician in charge of the patient.  
 
Should a patient be lost to follow-up, all data for that patient collected since study 
inclusion will be used, and the investigator will make every effort to contact the patient. 
 
4.5.2 Discontinuation of all or part of the study 
Given that this study investigates standard practice, no study discontinuation criteria have 
been defined in advance, except the following: 
1. scientific publication resulting in a consensus that challenges the primary study 
hypothesis or the method used to treat mechanically ventilated patients;  
2. interim analysis conducted by the independent data monitoring committee and 
showing an early significant difference in the primary endpoint . 
 
4.6 Data collection 
All the study data are collected routinely in ICUs for the management of mechanically 
ventilated patients with shock.  
 
Demographics and clinical data 
▪ At inclusion: date of birth, sex, date of ICU admission, reason for ICU admission, 
McCabe and Knaus scores, chronic co-morbidities, body weight, height, BMI, and 
SOFA score 
▪ at H24: SAPS II and SOFA score 

 
 
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▪ follow-up: date of final extubation, date of ICU discharge, date of hospital discharge 
(Acute care hospital), vital status at ICU discharge, and vital status at hospital 
discharge 
 
Nutritional data, every day, until extubation of the patient: name of the enteral or 
parenteral preparation; target number of calories; volume and calories delivered each day; 
vomiting (yes/no every 4 hours, with the time of any vomiting episodes); decrease or 
discontinuation of nutritional support (yes/no); reason for decreasing or discontinuing 
nutritional support (vomiting, diarrhea, acute pseudoobstruction of the colon, other acute 
abdominal symptoms, abdominal complication, imaging study/other); presence, volume, and 
appearance of the stools (yes/no every 4 hours, exact volume in mL and, where applicable, 
qualitative description as normal/liquid/mucopurulent/mucous/bloody); and diarrhea with its 
presumed cause (intolerance to nutritional support, medication, Clostridium difficile, other). 
 
Treatments given: Every day, until extubation of the patient: prokinetic agent (dose/24 h), 
polyethylene-glycol (dose/24 h), neostigmine (dose/24 h), sedation (dose/24 h and nature of 
the hypnotic and/or opioid agents), neuromuscular blockers (dose /24 h), catecholamines 
(dobutamine, noradrenaline, or adrenaline; yes/no regardless of duration and dose), renal 
replacement therapy (yes/no), antibiotics (yes/no), insulin (total dose/24 h), volume of IV 
fluids (total/24 h), and gastric anti-secretory agents (sucralfate, proton-pump inhibitors, 
histamine receptor antagonists, other). 
 
Laboratory data 
▪ D1: hemoglobin, leukocytes, platelets, Na, K, Ca2+, Ph, PaO2, PaCO2, pH, arterial 
lactic acid, bicarbonate, urea, creatinine, bilirubin, ASAT-ALAT, gamma-glutamyl 
transpeptidase, alkaline phosphatase, and total protein 
▪ Daily from D1 to D7 (if extubation before D7: on the day of extubation then stop): 
PaO2, arterial lactic acid, bilirubin, ASAT-ALAT, gamma-glutamyl transpeptidase, 
alkaline phosphatase, glucose, protein, Na, K, Ca²+, Ph,, creatinine, and SOFA 
▪ Albumin, pre-albumin, transthyretin, and CRP on D1 and D7 or on the day of 
extubation 

 
 
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Nosocomial infections (one data-collection form per infection): VAP (date, organism, 
resistance profile), bacteremia (date, organism, resistance profile), intravascular catheter-
related infection (date of the diagnosis, organism, resistance profile), urinary tract infection 
(date of the diagnosis, organism, resistance profile), soft tissue infection (date of the 
diagnosis, organism, resistance profile); and other (type, date of the diagnosis, organism, 
resistance profile). 
 
Invasive devices: endotracheal tube (dates of insertion and removal), intravascular 
catheters (dates of insertion and removal), and urinary catheters (dates of insertion and 
removal) 
Additional data collected during the ancillary studies 
− Ancillary study 1  
Plasma citrulline and I-FABP assays on D0, D3, and D8. Blood will be drawn by the nurse in 
charge of the patient as part of standard care. Each blood sample will be labeled with the 
number assigned to the patient, the first initial of the patient’s last and first names, the 
patient’s date of birth, the date and time of sample collection, and the number assigned to the 
sample. 
For amino acid chromatography, the blood samples will be centrifuged within 2 hours after 
collection (4°C, 1900 rpm, 10 minutes) and the plasma stored at -70 °C at the study center.  
For the I-FABP assay, the blood samples will be centrifuged (4°C, 1500 rpm, 15 minutes) and 
the plasma stored at -70°C until the analysis. 
An accredited transporter will take the samples to the Biology Center of the Besançon 
Teaching Hospital, where they will be processed. The samples will be destroyed after the 
assays are performed. 
− 
Ancillary study 2 
D0, D3, and D8: pepsin and salivary amylase assays in all tracheal aspirates  
The tracheal aspirate samples will be collected by the nurse in charge of the patient, according 
to standard practice. Each sample will be labeled with the number assigned to the patient, the 
first initial of the patient’s last and first names, the patient’s date of birth, the date and time of 
sample collection, and the number assigned to the sample. Each tracheal aspirate sample 
(about 1-2 mL per aspirate) will be stored at -20 °C at the biochemistry department of each 

 
 
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study center. An accredited transporter will take the samples to the Biology and Pathology 
Center of the Lille Teaching Hospital, under the responsibility of Dr Balduyck, Dr Zerimech, 
and Dr Maboudou, for blinded assays of pepsin and salivary amylase. Pepsin levels will be 
measured using an ELISA, under the responsibility of Dr. Zerimech and Dr Balduyck, at the 
Molecular Biochemistry-Biology Laboratory headed by Pr. N. Porchet, Biochemistry 
Department, Lille Teaching Hospital. The amylase assays will be performed under the 
responsibility of Dr Maboudou at the Biochemistry, Proteins, and Predictive Biology 
Laboratory headed by Pr N. Porchet, Biochemistry Department, Lille Teaching Hospital. A 
colorimetric enzyme assay will be used. The level of salivary amylase will be computed as the 
difference between total and pancreatic amylase levels. The samples will be destroyed after 
the assays are performed. 
 
 
 
5 SELECTION AND EXCLUSION OF PATIENTS FOR THE STUDY 
 
5.16 
 Inclusion criteria to be met by study participants 
▪ Invasive mechanical ventilation for an expected duration of at least 48 hours 
▪ Nutritional support started within 24 h after intubation  
▪ Treatment with a vasoactive amine (adrenaline, dobutamine, or noradrenaline) via a 
central venous catheter 
▪ Age older than 18 years 
▪ Informed about the study and having consented to participation in the study 
▪ Covered by the French public health insurance system 
 
5.17 
 Noninclusion criteria to be absent in study participants 
▪ Invasive mechanical ventilation started more than 24 h earlier 
▪ Patient admitted for an acute gastrointestinal condition that contraindicates enteral 
nutrition 
▪ Surgery on the gastrointestinal tract within the past month 
▪ History of gastrectomy, esophagectomy, duodenopancreatectomy, bypass surgery, 
gastric banding, or short bowel syndrome 

 
 
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▪ Gastrostomy or jejunostomy 
▪ Specific nutritional needs, such as pre-existing long-term home enteral or parenteral 
nutrition 
▪ Active gastrointestinal bleeding 
▪ Dying patient – not-to-be-resuscitated order or other treatment-limitation decision at 
ICU admission 
▪ Adult under guardianship 
▪ Pregnancy, recent delivery, or lactation 
▪ Department of corrections inmate 
▪ Institutionalized patient 
▪ Prior inclusion in a randomized trial designed to compare enteral and parenteral 
nutrition  
▪ Contraindication to parenteral nutrition: known hypersensitivity to egg or soybean 
proteins or to another component, inborn error in amino-acid metabolism, or severe 
familial dyslipidemia affecting triglyceride levels 
 
5.3 Recruitment modalities 
Participation in the study will be suggested to all patients admitted to the study ICUs, 
given vasoactive amine therapy, placed under invasive mechanical ventilation for an expected 
duration of at least 48 h, and requiring early enteral or parenteral nutritional support. 
 
5.4 Contraindication to participation in another research project 
Patients included in this study will not be eligible for participation in other studies that 
compare enteral and parenteral nutrition and/or that have the same objectives. 
 
 
5.5Critères d’inclusion des personnes qui se prêtent aux études 
ancillaires 
Patients meeting the criteria for inclusion in the NUTRIREA2 trial will be eligible for 
inclusion in the ancillary studies, after the patient, a relative, or a surrogate receives 
information and states that he/she has no objection to inclusion in the ancillary studies (see 
the specific patient information document in the appendix). 

 
 
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6 PRODUCTS ADMINISTERED TO THE STUDY PARTICIPANTS   
 
6.1  Study intervention 
We will evaluate two strategies for initiating nutritional support: first-line parenteral 
nutrition and first-line enteral nutrition. Patients allocated at random to the enteral-nutrition 
group (E) will receive enteral nutrition only; and those allocated at random to the parenteral-
nutrition group (P group) parenteral nutrition only for at least 72 hours and until day 7 of 
invasive mechanical ventilation, except if the physician in charge decides that the clinical 
situation mandates continued parenteral nutrition. In both groups, nutritional support will be 
started within 24 h after intubation. The selection of nutritional preparations will be at the 
discretion of the investigators according to availability and standard protocols used in each 
ICU. 
The daily calorie target in both groups is 20-25 Kcal/Kg/day at the acute phase of ICU 
management, in compliance with current recommendations (4-6, 77). This calorie intake is 
adequate in over 90% of ICU patients with systemic insults and equals 1.3- to 1.5-fold the 
mean resting energy expenditure (REE) estimated using simplified equations. In addition, this 
calorie intake avoids overnutrition, which may induce deleterious effects (metabolic and 
hepatobiliary complications) (77-79). 
In the enteral-nutrition group (E group), the patients will receive first-line enteral nutrition. 
In the event of persistent intolerance precluding achievement of the calorie targets, 
supplemental parenteral nutrition may be added starting on day 8 (6, 72). 
In the parenteral-nutrition group (P group), the course of action will be guided by the 
hemodynamic evaluations conducted daily starting 72 hours after parenteral nutrition 
initiation and until day 7. A stable hemodynamic status is defined for this study as 
discontinuation of the vasoactive amines and a normal level of arterial lactic acid (<2 
mmol/L). As soon as these two criteria are met, the patient will be switched from parenteral to 
enteral nutrition, in the absence of absolute contraindications to the enteral route. The calorie 
targets and mode of nutritional-support initiation are identical to those in the early enteral-
nutrition group (E group). Starting on D8, in patients without contraindications to enteral 
feeding, the enteral route will be substituted for the parenteral route. 

 
 
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After extubation, regardless of the time since randomization, decisions about the 
continued need for, and optimal route of, nutritional support will be at the discretion of the 
physician in charge of the patient. 
 
6.2 Treatments that may be used 
 
All the medications whose use is standard practice for ICU patients will be used 
according to the specific needs of each patient. 
 
6.3 Treatments that may not be used 
 
Given that this study evaluates standard care, no medication used according to its 
marketing authorization is contraindicated. 
 
 

 
 
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7 STATISTICS 
 
The statistical analysis will be carried out at the CIC INSERM 202 under the 
responsibility of Bruno Giraudeau. The analyses will be performed using SAS 9.2 and R 
software. 
 
7.1 Description of planned statistical methods, with the schedule of 
planned interim analyses 
The statistical analysis will be conducted according to a predefined plan. The analysis 
will follow the intention-to-treat (ITT) approach, as recommended for superiority studies. 
Two interim analyses will be performed, given the need for a large number of included 
patients. A statistical analysis report will be written to describe all the findings to be 
communicated, according to CONSORT Statement recommendations, while taking into 
account the specific features of the trial, i.e., the nonpharmacological nature of the 
intervention (http://www.consort-statement.org/). 
 
7.1.1 Description of the groups at baseline 
The groups established by randomization will be compared using descriptive statistics. 
No statistical tests will be performed. 
 
7.1.2 Analysis populations 
The ITT approach will be used: each patient will remain in the group assigned by 
randomization, regardless of subsequent events. 
 
7.1.3 Analysis of the primary endpoint 
Day-28 mortality will be reported as the point estimate with the 95% confidence interval 
in each group. Day-28 mortality will be compared between the two groups using the chi-
square test. 
 
 

 
 
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7.1.4 Analysis of secondary endpoints  
▪ For the analysis of patients with at least one nosocomial infection,  
o  we will use a competitive-risk model, with death as the competing risk, since 
patients who have died cannot experience nosocomial infections; 
o in addition, the proportion of patients having at least one nosocomial infection will 
be analyzed in the same way as the primary endpoint, in order to obtain a 
sensitivity analysis of observed results. 
 
▪ VAP  
o proportion of patients with at least one VAP episode: the method used will be the 
same as for nosocomial infections, with not only death as a competing risk, but 
also time to extubation +2 days, since after this point any episode of pneumonia 
would not be classified as a VAP episode; 
o VAP incidence density as the point estimate with the 95% confidence interval; 
o number of VAP episodes per patient analyzed using a negative binomial 
regression model with no offset variable 
▪ Bacteremia, central venous catheter (CVC)-related infections, urinary tract infections, soft 
tissue infections: each of these categories of infection will be analyzed using the same 
method as for the pooled nosocomial infections 
▪ Descriptive bacteriological data (organisms recovered with their resistance profiles for 
each nosocomial infection): only descriptive analyses will be performed 
▪ Proportion of patients with at least one episode of vomiting or regurgitation: the method 
will be the same as for the primary analysis 
▪ Proportion of patients with at least one episode of diarrhea: the method will be the same as 
for the primary analysis 
▪ Proportion of patients with at least one episode of constipation: the method will be the 
same as for the primary analysis 
▪ Proportion of patients with at least one documented episode of acute pseudoobstruction of 
the colon (Ogilvie syndrome): the method will be the same as for the primary analysis 
▪ Proportion of patients with at least one documented episode of bowel ischemia: the 
method will be the same as for the primary analysis 
▪ Proportion of patients with at least one mechanical complication of CVC insertion: the 
method will be the same as for the primary analysis 

 
 
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▪ Proportion of patients with at least one episode of CVC obstruction or other dysfunction 
requiring a change of CVC: the method will be the same as for the primary analysis 
▪ The number of calories delivered each day by the enteral and parenteral routes: changes 
over time in delivered calories will be represented graphically by boxplots created each 
day on the same graph; changes over time will be compared between the two groups using 
a mixed linear model, after data transformation if necessary 
▪ Volume of enteral and parenteral feeds delivered each day: the analysis  method will be 
the same as for the number of calories 
▪ Ratio of prescribed over delivered calories: the proportions of patients who achieved their 
daily calorie target will be determined at each follow-up time point (in days) and will be 
compared between the two groups using a logistic random effects model 
▪ ICU mortality, 90-day mortality, and hospital mortality: day-90 mortality will be analyzed 
in the same way as day-28 mortality; for ICU and hospital mortality rates, competing-risk 
models will be used, as ICU discharge and hospital discharge compete with death during 
the stay 
▪ Nutritional markers and body weight: changes over time in nutritional markers and body 
weight will be analyzed using the method described above for the number of calories 
delivered 
▪ Proportion of patients with at least one episode of liver dysfunction: the method will be 
the same as for the primary objective 
▪ Times in the ICU, in the hospital, and on mechanical ventilation will be compared 
between the two groups using nonparametric Wilcoxon tests 
 
 
 
7.1.5 Analysis of the outcome measures for the ancillary studies 
− ANCILLARY STUDY 1 
o Analysis of the primary outcome measure 
Plasma citrulline levels at H72 will be analyzed using the approach described for the 
calorie intake. 
 
 
 
 
 
 

 
 
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o Analysis of the secondary outcome measures 
▪ SOFA score: SOFA score changes over time will be evaluated graphically by placing 
daily boxplots on the same graph. For between-group comparisons of SOFA score 
changes over time, a mixed linear model will be built, after transformation of the data if 
needed. 
▪ Plasma citrulline and I-FABP levels at D0, D3, and D8: the changes in these variables 
over time will be evaluated graphically by placing daily boxplots on the same graph. For 
between-group comparisons, a mixed linear model will be built, after transformation of 
the data if needed.  
▪ Proportion of patients whose plasma I-FABP is ≥100 pg/mL on D0, D3, and D8: the 
analysis method will be the same as for the primary NUTRIREA2 outcome measure. 
▪ Proportion of patients whose plasma citrulline is ≤10 L/L on D0, D3, and D8: the 
analysis method will be the same as for the primary NUTRIREA2 outcome measure. 
▪ Proportion of patients with at least one episode of bacteremia: the analysis method will be 
the same as for the primary NUTRIREA2 outcome measure.  
▪ Proportion of patients with at least one episode of gastrointestinal intolerance: the 
analysis method will be the same as for the primary NUTRIREA2 outcome measure.  
▪ Proportion of patients with at least one episode of diarrhea: the analysis method will be 
the same as for the primary NUTRIREA2 outcome measure. 
 
 
− ANCILLARY STUDY 2  
o Analysis of the primary outcome measure 
The chi-square test will be applied to compare the proportion of patients with abundant 
microaspiration in the two groups. The odds ratio with its 95% confidence interval will be 
computed. 
o Analysis of the secondary outcome measures 
Patient characteristics in the two groups will be compared. Qualitative variables will be 
compared using either the chi-square test or Fisher’s exact test. Shapiro-Wilk’s test will be 
applied to determine whether the quantitative variables are normally distributed. These 
quantitative variables will then be compared using Student’s t test if normally distributed and 
the Mann-Whitney U test otherwise. 
 
 
 

 
 
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7.2 Estimated sample size, and estimated numbers of patients recruited 
at each study center, with supporting statistical information 
This clinical randomized controlled superiority trial will seek to demonstrate that the D28 
mortality rate in patients admitted to the ICU and treated with mechanical ventilation and 
vasoactive amines is lower in patients given early enteral nutrition than in patients given early 
parenteral nutrition. Assuming a 37% D28 mortality rate in the parenteral-nutrition group and 
a 5% decrease in mortality with early enteral nutrition (i.e., a D28 mortality rate of 32%), with 
the alpha risk set at 4.9% and the beta risk at 20%, 1427 patients are needed in each group 
(Newcombe, Statist Med 1998; 17:873-890), i.e., a theoretical total of 2854 patients. 
The mortality rates used for the sample size estimation are those obtained in the 
NUTRIREA-1 randomized controlled trial in nine centers (CRICS network), in which similar 
inclusion criteria were used. 
 
Ancillary studies  
− Ancillary study 1  
The primary outcome measure is the plasma citrulline level at H72. To demonstrate a 
significant difference between plasma citrulline levels of 16 moL/L (enteral-nutrition group) 
and 12 moL/L (parenteral-nutrition group), with a standard deviation of 8 moL/L, a two-
tailed test, the alpha risk set at 0.05, and 90% power, 85 patients will be needed in each group 
(170 patients in all). 
− Ancillary study 2 
The primary outcome measure is the proportion of patients with abundant 
microaspiration. We expect that the proportion of patients with abundant microaspiration will 
be 50% in the enteral-nutrition group and 30% in the parenteral-nutrition group. With the 
alpha risk set at 0.05, to obtain 80% power, 94 patients will be needed in each group (188 
patients in all), with simple random sampling. 
 
7.3 Degree of statistical significance planned for the study 
The statistical tests will be performed using a significance threshold of 1% for the interim 
analyses and 4.9% for the final analysis. 
 

 
 
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7.4 Statistical rules for study discontinuation 
We will perform two interim analyses, after inclusion of the first 1000 and the first 2000 
patients, respectively. We will use Peto’s boundary (Peto R, Pike MC, Armitage P, et al. Design and 
analysis of randomized clinical trials requiring prolonged observation of each patient. I. Introduction and 
design. Br J Cancer 1976;34:585-612. PMID): 
- 
the significance level associated with the first interim analysis is 0.01; 
- 
the significance level associated with the second interim analysis is 0.01; 
- 
the significance level associated with the final analysis is 0.049. 
This method yields an overall Type I error of 5%. 
 
7.5 Handling of missing, unused, or invalid data 
In this study, patients from whom consent to the study was not obtained and those who 
secondarily withdrew their consent will not be included in the analyses. Apart from these two 
situations, the likelihood that patients will be lost to follow-up is small. The study patients 
will be admitted to ICUs, and the primary endpoint is objective (D28 mortality). However, 
should there be any patients for whom information on the primary endpoint is missing, then 
these patients would be considered as having died before D28, in both randomized arms. 
 
7.6 Handling of changes to the initial statistical analysis plan 
The statistical analysis plan will be finalized when the database is locked. 
 
7.7 Selection of patients to be included in the analyses 
The analyses will be conducted using the intention-to-treat (ITT) approach. 
 
 
8 RATIONALE FOR REQUESTING CATEGORIZATION OF THE TRIAL 
AS A STUDY OF STANDARD CARE 
 
Given the characteristics of the research project, the chief investigator considers that this 
project is primarily a study of standard care, based on the following arguments: 

 
 
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▪ all the nutritional-support interventions and protocols will be performed according to 
standard ICU practice; 
▪ the study consists in evaluating combinations of diagnostic and prophylactic 
interventions and medical strategies (nutrition administration and monitoring protocol, 
diagnosis of VAP) that are used in everyday practice, i.e., whose indications are 
defined by professional consensus; 
▪ the study does not involve any techniques or strategies that are innovative or obsolete; 
▪ the combination of interventions (enteral or parenteral nutrition) is not new; 
▪ the study consists in comparing two medical strategies (enteral and parenteral 
nutrition) for which no available data indicate that one is better than the other in terms 
of safety or efficacy. 
Indeed,  
• international guidelines recommend a specific management strategy (prefer early 
enteral nutrition over parenteral nutrition)  
• but this strategy is either not used at all or used improperly in a large number of 
patients, for the following reasons: 
1. it is in itself a source of potential complications, and concern about this 
risk and/or the need to manage the complications should they occur result 
in an increased workload and in delayed or absent use of early enteral 
nutrition; 
2. the available studies (metaanalyses) have produced conflicting results; 
3. and the authors of the recommendations acknowledge that their 
guidelines rest on converging data and indirect studies and not on sound 
evidence, most notably from randomized trials that are adequately 
powered and use relevant clinical objectives; 
• the widely conflicting results of recent studies on early supplemental parenteral 
nutrition constitute indirect evidence that the issue remains unsettled. 
▪ Finally, the specific modalities used in the study are expected to minimize risks (by 
increasing the stringency of the enteral and parenteral nutrition delivery protocols) and 
place only negligible constraints on study participants (Article R 1121-3 of the French 
Public Health Code [CSP], decree n° 2006-477, 26 April 2006). 

 
 
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The Poitiers Ouest III ethics committee (Comité de Protection des Personnes de Poitiers 
Ouest III) has categorized the NUTRIREA-II trial as a study of standard care and has 
approved the conduct of the NUTRIREA-II trial (approval date, 26 January 2012, see letter 
enclosed). 
 
 

 
 
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9 RIGHT OF ACCESS TO THE STUDY DATA AND SOURCE 
DOCUMENTS 
 
9.1 Access to the study data 
The medical data about each patient will be communicated only to the institution with 
which the chief investigator is affiliated or to a person appointed by the chief investigator 
under conditions that ensure the confidentiality of the patient data.  
 
9.2 Source documents  
If needed, the institution to which the chief investigator is affiliated may request direct 
access to the medical record to check the study procedures and/or data, without violating 
confidentiality rules and within the limits set by laws and regulations. 
 
9.3 Data confidentiality  
Individuals having direct access to the study data will take all the necessary precautions 
to ensure the confidentiality of the data pertaining to the study participants, most notably 
regarding their identity and the results obtained during the study. 
These individuals, together with the study investigators, are under an obligation to 
maintain confidentiality (under the conditions defined in articles 226-13 and 226-14 of the 
French penal code). During or at completion of the study, the data collected from the study 
participants and communicated by the individuals involved in the study will be rendered 
anonymous. 
Under no circumstances will the names or addresses of the study participants be included 
in the study data. 
Only the first letter of the last name and the first letter of the first name of each patient 
will be recorded, and these letters will be combined with a number to form a study-specific 
identifier reflecting the order of patient inclusion.  
 
 
 

 
 
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10 QUALITY ASSURANCE  
 
To optimize the conduct of the study, a Clinical Research Assistant (CRA) will be in 
charge of performing the following tasks:  
▪ preparation of the file to be submitted to the ethics committee (Comité de Protection 
des Personnes, CPP) and of the files for the CCTIRS and CNIL; 
▪ finalization of the study documents (e.g., case-report form) and communications 
among individuals involved in conducting the study; 
▪ study initiation in the study centers; 
▪ verification of the data collected for the study; 
▪ and documentation, registering, and reporting of the study data, in compliance with 
Standard Operating Procedures. 
 
 
11 ETHICAL EVALUATION OF THE SPECIFIC MONITORING 
MODALITIES DEFINED IN THE RESEARCH PROTOCOL 
 
11.1 
Ethics committee (Comité de Protection des Personnes, CPP) 
This research protocol and the patient information and consent documents have been 
submitted to the Poitiers CPP, which categorized the trial as a study of standard care and 
approved the conduct of the trial (approval date, 26 January 2012, see letter enclosed). 
 
11.2 
Substantial modifications  
Any substantial modification to the study protocol will be communicated to the ethics 
committee (CPP) to ensure that the suggested modifications have no adverse effect 
whatsoever on the protection afforded to the study participants. 
 
11.3 
Patient information sheet and informed consent form 
The patients will receive full and honest information, delivered in understandable terms, 
about the study objectives and their right to refuse to participate in the study or to withdraw 
from the study at any time. This information will be given in a patient information and 

 
 
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informed consent document, which will be handed to each patient. An information document 
dealing specifically with the ancillary studies will also be given to each patient. 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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12 HANDLING OF THE STUDY DATA AND STORAGE OF THE STUDY 
DOCUMENTS AND DATA 
 
12.1 
Case-report form 
An Internet-based data collection tool will be used for this study. This electronic case-
report form will be available at each of the study centers. Access to the electronic case-report 
form will require only an Internet connection and a browser. A document explaining how to 
use the electronic case-report form will be given to the study investigators. 
Tests designed to check data consistency will be performed as an integral part of the 
electronic format. The electronic case-report form has an audit function that tracks any 
modifications made to the study data. The audit function also clearly identifies the person 
who made the modification, as well as the date. The reason for the modification can be 
supplied as a comment if deemed appropriate. 
 
12.2 
Data entry and analysis 
The data will be entered into an electronic case-report form via an Internet browser. 
The data will be analyzed by a biostatistician at the CIC INSERM202, under the 
responsibility of Bruno Giraudeau. 
 
12.3 
French Data Protection Authority (CNIL) 
Approval of the data handling procedure required for the study will be sought from the 
French Advisory Committee on Data Handling in Healthcare Research (CCTIRS) and, 
subsequently, permission will be requested from the French Data Protection Authority (CNIL) 
regarding the handling of personal data with the goal of conducting research on standard care. 
 
 
13 FUNDING AND INSURANCE 
 
 
 

 
 
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13.1 
Study budget  
Since this study will investigate standard care, the medical interventions will not require 
special funding. The expected total duration of the study is 3 years (30 months for patient 
inclusion and 6 months for follow-up and data verification) for 28 centers. The study will 
therefore require the following financial resources: 
▪ CRA time for 
- 
study monitoring and coordination (10% of a full-time salary, for 3 years): 14 
265 €; 
- 
monitoring visits (study initiation and completion visits, four 2-day visits 
/year/center, i.e., two full-time ARC salaries for 3 years): 285 300 € 
▪ Clinical research technician (CRT) or clinical research nurse (CRN) time in each study 
center to assist in preparing and implementing the electronic case-report form and in 
study coordination and logistics, and to enter data into the electronic case-report form 
(4 to 5 h minimum/patient, i.e., for a mean of 102 patients included in each study 
center, 10% of a full-time salary/year for 3 years): 376 320 € 
▪ Data handling:  
- Data management time to create the electronic case-report form and to monitor 
data quality (20% of a full-time salary the first year and 7% for each of the next 2 
years): 15 096 € 
- Statistical analysis (1 month full-time, during the last year): 5000 € 
▪ Meetings, 
coordinator 
missions 
(three 
1-day-long 
meetings/3 
years 
– 
2 
representatives/center for 28 centers; mean cost of 100 € per trip): 16 800 € 
▪ Travel expenses for on-site study initiation, monitoring, and study completion visits 
(4.5 visits per an and per center on average, i.e.,  378 visits each lasting 2 days, with a 
mean cost of 200 €): 75 600 € 
▪ Stationery for the patient information and consent documents to be given to the 
patients or next of kin, bedside nutrition monitoring charts: 5100 € 
▪ Study report costs (translation and submission: 2000 €) and costs of study result 
presentation at one national meeting (1000 €) and one international meeting (2000 €): 
5000 € 
 
Total budget: 798 481 € (not counting operating expenses estimated at 10%) 
 

 
 
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13.2 
Insurance 
The ethics committee has categorized the trial as a study of standard care, thus indicating 
that study participation involves no additional risks to the patients, and consequently the 
insurance held by the facilities delivering medical care to the study patients will cover the 
activities of the study (article L.1142-2 of the French Public Health Code). 
 
 
 

 
 
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14 STUDY FEASIBILITY 
 
The study will be conducted in the 28 study centers, which include centers belonging to 
the Clinical Research in Intensive Care and Sepsis (CRICS) network. The feasibility of the 
NUTRIREA-2 trial was assessed based on the results of the NUTRIREA-1 trial, in which 
nine CRICS network centers participated during the 8-month study inclusion period. In all, 
1736 patients were evaluated for study eligibility and 452 were included. In this population, 
239 patients received vasoactive amine therapy. After the exclusion of two centers where 
previous organizational difficulties – now resolved – resulted in the inclusion of only very 
few patients, the mean number of patients included per month and per center was 4.3.  These 
data establish the feasibility of NUTRIREA-2 with 28 participating centers and an inclusion 
period of 30 months at the most. 
 
 
 

 
 
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15 PUBLICATION POLICY 
 
Communications and scientific reports relevant to this study will be under the 
responsibility of the chief investigator, who will obtain the approval of the other investigators. 
The co-authors of the study report and publications will be the investigators and clinicians 
involved in the study, in proportion to their contributions to the study, together with the 
biostatistician and associated investigators. 
The publication policy will comply with international recommendations (N Engl J Med, 1997; 
336:309-315). 
 
 
 
 

 
 
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16 APPENDICES 
 

 
 
NUTRIREA-2 
 
 
 
Appendix 1: Protocol for managing upper gastrointestinal intolerance (71) 
 
 
 
 
 
 
 
 
 
▪  
 
 
NO 
NO 
YES 
YES 
YES 
NO 
Ist measure 
 Start a PROKINETIC by medical 
prescription until well tolerated for 48 h 
at prescribed flow rate 
DECREASE flow rate by 25 mL/h 
Dextro /h for 
2 h 
Inform the 
physician 
Re-start at prescribed 
flow-rate 
VOMITING 
REGURGITATION 
VOMITING 
REGURGITATION 
MANDATORY: 
Radiograph to check tube position in middle of stomach before initiating 
enteral nutrition then routinely at each tube change or repositioning  
INITIATE ENTERAL NUTRITION  
as early as possible (<24 hours after intubation) 
Start at maximal flow rate appropriate for prescribed target 
STOP feeding 
for 6 hours 
NGT on suction 
Flow rate ≤25 
mL/h 
PATIENTS IN PRONE 
POSITION 
- 
Routine prokinetic therapy 
starting at first turn prone, by 
medical prescription  
- 
Stop 6 h after last turn prone  
MONITOR GI TOLERANCE  
➔VOMITING/REGURGITATION 
Significant if not during care or mobilization 
IF INSULIN THERAPY 
Check capillary glucose 
hourly until resumption of 
nutrition 
MEDICAL PRESCRIPTION 
of ENTERAL NUTRITION 
2nd measure 
Modify the enteral nutrition 
flow rate 

 
 
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Appendix 2: Protocol for managing diarrhea, from Doig et al. (15) 
 
Clinically significant diarrhea 
Potentially drug-related? 
No change in enteral nutrition 
Continue current feeding 
solution 
Patient on antibiotics? 
Test stool for Clostridium difficile toxin and 
continue nutrition 
Change the feeding solution 
Diarrhea resolved? 
Decrease flow rate until diarrhea 
resolves 
Then increase gradually to desired 
flow rate 
NO 
NO 
YES 
Stop the drug and continue 
enteral feeding 
NO 
YES 
YES 
NO 
YES 

 
 
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17 REFERENCES  
1. 
Erny P. Nutrition de l'agressé. Conférence de consensus de la société francophone de 
nutrition entérale et parentérale. Reanimation Urgences 1998;7:347-356. 
2. 
Heyland DK, Dhaliwal R, Drover JW, Gramlich L, Dodek P. Canadian clinical 
practice guidelines for nutrition support in mechanically ventilated, critically ill adult patients. 
JPEN J Parenter Enteral Nutr 2003;27:355-373. 
3. 
Kondrup J, Allison SP, Elia M, Vellas B, Plauth M. Espen guidelines for nutrition 
screening 2002. Clin Nutr 2003;22:415-421. 
4. 
Kreymann KG, Berger MM, Deutz NE, Hiesmayr M, Jolliet P, Kazandjiev G, 
Nitenberg G, van den Berghe G, Wernerman J, Ebner C, Hartl W, Heymann C, Spies C. 
Espen guidelines on enteral nutrition: Intensive care. Clin Nutr 2006;25:210-223. 
5. 
Martindale RG, McClave SA, Vanek VW, McCarthy M, Roberts P, Taylor B, Ochoa 
JB, Napolitano L, Cresci G. Guidelines for the provision and assessment of nutrition support 
therapy in the adult critically ill patient: Society of critical care medicine and american society 
for parenteral and enteral nutrition: Executive summary. Crit Care Med 2009;37:1757-1761. 
6. 
McClave SA, Martindale RG, Vanek VW, McCarthy M, Roberts P, Taylor B, Ochoa 
JB, Napolitano L, Cresci G. Guidelines for the provision and assessment of nutrition support 
therapy in the adult critically ill patient: Society of critical care medicine (sccm) and american 
society for parenteral and enteral nutrition (a.S.P.E.N.). JPEN J Parenter Enteral Nutr 
2009;33:277-316. 
7. 
Thuong M, Leteurtre S. Recommandations des experts de la société de réanimation de 
langue française. Nutrition entérale en réanimation. Reanimation 2003;12:350-354. 
8. 
Beier-Holgersen R, Brandstrup B. Influence of early postoperative enteral nutrition 
versus placebo on cell-mediated immunity, as measured with the multitest cmi. Scand J 
Gastroenterol 1999;34:98-102. 
9. 
Bortenschlager L, Roberts PR, Black KW, Zaloga GP. Enteral feeding minimizes liver 
injury during hemorrhagic shock. Shock 1994;2:351-354. 
10. 
Gianotti L, Alexander JW, Nelson JL, Fukushima R, Pyles T, Chalk CL. Role of early 
enteral feeding and acute starvation on postburn bacterial translocation and host defense: 
Prospective, randomized trials. Crit Care Med 1994;22:265-272. 
11. 
Hadfield RJ, Sinclair DG, Houldsworth PE, Evans TW. Effects of enteral and 
parenteral nutrition on gut mucosal permeability in the critically ill. Am J Respir Crit Care 
Med 1995;152:1545-1548. 

 
 
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12. 
Artinian V, Krayem H, DiGiovine B. Effects of early enteral feeding on the outcome 
of critically ill mechanically ventilated medical patients. Chest 2006;129:960-967. 
13. 
Marik PE, Zaloga GP. Early enteral nutrition in acutely ill patients: A systematic 
review. Crit Care Med 2001;29:2264-2270. 
14. 
Doig GS, Heighes PT, Simpson F, Sweetman EA, Davies AR. Early enteral nutrition, 
provided within 24 h of injury or intensive care unit admission, significantly reduces mortality 
in critically ill patients: A meta-analysis of randomised controlled trials. Intensive Care Med 
2009;35:2018-2027. 
15. 
Doig GS, Simpson F, Finfer S, Delaney A, Davies AR, Mitchell I, Dobb G. Effect of 
evidence-based feeding guidelines on mortality of critically ill adults: A cluster randomized 
controlled trial. JAMA 2008;300:2731-2741. 
16. 
Braga M, Gianotti L, Costantini E, Di Francesco A, Socci C, Paganelli G, Ossi C, Di 
Carlo V. Impact of enteral nutrition on intestinal bacterial translocation and mortality in 
burned mice. Clin Nutr 1994;13:256-261. 
17. 
Braga M, Gianotti L, Vignali A, Cestari A, Bisagni P, Di Carlo V. Artificial nutrition 
after major abdominal surgery: Impact of route of administration and composition of the diet. 
Crit Care Med 1998;26:24-30. 
18. 
Braunschweig CL, Levy P, Sheean PM, Wang X. Enteral compared with parenteral 
nutrition: A meta-analysis. Am J Clin Nutr 2001;74:534-542. 
19. 
Elke G, Schadler D, Engel C, Bogatsch H, Frerichs I, Ragaller M, Scholz J, 
Brunkhorst FM, Loffler M, Reinhart K, Weiler N. Current practice in nutritional support and 
its association with mortality in septic patients--results from a national, prospective, 
multicenter study. Crit Care Med 2008;36:1762-1767. 
20. 
Gramlich L, Kichian K, Pinilla J, Rodych NJ, Dhaliwal R, Heyland DK. Does enteral 
nutrition compared to parenteral nutrition result in better outcomes in critically ill adult 
patients? A systematic review of the literature. Nutrition 2004;20:843-848. 
21. 
Heyland DK, Dhaliwal R. Early enteral nutrition vs. Early parenteral nutrition: An 
irrelevant question for the critically ill? Crit Care Med 2005;33:260-261. 
22. 
Kudsk KA, Croce MA, Fabian TC, Minard G, Tolley EA, Poret HA, Kuhl MR, Brown 
RO. Enteral versus parenteral feeding. Effects on septic morbidity after blunt and penetrating 
abdominal trauma. Ann Surg 1992;215:503-511; discussion 511-503. 
23. 
Li J, Kudsk KA, Gocinski B, Dent D, Glezer J, Langkamp-Henken B. Effects of 
parenteral and enteral nutrition on gut-associated lymphoid tissue. J Trauma 1995;39:44-51; 
discussion 51-42. 

 
 
NUTRIREA-2 
 
Version n°3 datée du 20 Janvier 2012 
 
Page 69 sur 73 
24. 
Marik PE, Zaloga GP. Meta-analysis of parenteral nutrition versus enteral nutrition in 
patients with acute pancreatitis. BMJ 2004;328:1407. 
25. 
Moore EE, Jones TN. Benefits of immediate jejunostomy feeding after major 
abdominal trauma--a prospective, randomized study. J Trauma 1986;26:874-881. 
26. 
Moore FA, Feliciano DV, Andrassy RJ, McArdle AH, Booth FV, Morgenstein-
Wagner TB, Kellum JM, Welling RE, Moore EE. Early enteral feeding, compared with 
parenteral, reduces postoperative septic complications. The results of a meta-analysis. Ann 
Surg 1992;216:172-1783. 
27. 
Moore FA, Moore EE, Jones TN, McCroskey BL, Peterson VM. Ten versus tpn 
following major abdominal trauma--reduced septic morbidity. J Trauma 1989;29:916-922; 
discussion 922-913. 
28. 
Peter JV, Moran JL, Phillips-Hughes J. A metaanalysis of treatment outcomes of early 
enteral versus early parenteral nutrition in hospitalized patients. Crit Care Med 2005;33:213-
220; discussion 260-211. 
29. 
Windsor AC, Kanwar S, Li AG, Barnes E, Guthrie JA, Spark JI, Welsh F, Guillou PJ, 
Reynolds JV. Compared with parenteral nutrition, enteral feeding attenuates the acute phase 
response and improves disease severity in acute pancreatitis. Gut 1998;42:431-435. 
30. 
Cahill NE, Dhaliwal R, Day AG, Jiang X, Heyland DK. Nutrition therapy in the 
critical care setting: What is "best achievable" practice? An international multicenter 
observational study. Crit Care Med 2010;38:395-401. 
31. 
Drover JW, Cahill NE, Kutsogiannis J, Pagliarello G, Wischmeyer P, Wang M, Day 
AG, Heyland DK. Nutrition therapy for the critically ill surgical patient: We need to do 
better! JPEN J Parenter Enteral Nutr 2010;34:644-652. 
32. 
Adam S, Batson S. 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;23:261-266. 
33. 
Binnekade JM, Tepaske R, Bruynzeel P, Mathus-Vliegen EM, de Hann RJ. Daily 
enteral feeding practice on the icu: Attainment of goals and interfering factors. Crit Care 
2005;9:R218-225. 
34. 
De Jonghe B, Appere-De-Vechi C, Fournier M, Tran B, Merrer J, Melchior JC, Outin 
H. A prospective survey of nutritional support practices in intensive care unit patients: What 
is prescribed? What is delivered? Crit Care Med 2001;29:8-12. 
35. 
Heyland D, Cook DJ, Winder B, Brylowski L, Van deMark H, Guyatt G. Enteral 
nutrition in the critically ill patient: A prospective survey. Crit Care Med 1995;23:1055-1060. 

 
 
NUTRIREA-2 
 
Version n°3 datée du 20 Janvier 2012 
 
Page 70 sur 73 
36. 
Preiser JC, Berre J, Carpentier Y, Jolliet P, Pichard C, Van Gossum A, Vincent JL. 
Management of nutrition in european intensive care units: Results of a questionnaire. 
Working group on metabolism and nutrition of the european society of intensive care 
medicine. Intensive Care Med 1999;25:95-101. 
37. 
Rice TW, Swope T, Bozeman S, Wheeler AP. Variation in enteral nutrition delivery in 
mechanically ventilated patients. Nutrition 2005;21:786-792. 
38. 
Rohm KD, Schollhorn T, Boldt J, Wolf M, Papsdorf M, Piper SN. Nutrition support 
and treatment of motility disorders in critically ill patients - results of a survey on german 
intensive care units. Eur J Anaesthesiol 2008;25:58-66. 
39. 
Heyland DK, Schroter-Noppe D, Drover JW, Jain M, Keefe L, Dhaliwal R, Day A. 
Nutrition support in the critical care setting: Current practice in canadian icus--opportunities 
for improvement? JPEN J Parenter Enteral Nutr 2003;27:74-83. 
40. 
De B, Chapman M, Fraser R, Finnis M, De Keulenaer B, Liberalli D, Satanek M. 
Enteral nutrition in the critically ill: A prospective survey in an australian intensive care unit. 
Anaesth Intensive Care 2001;29:619-622. 
41. 
Heyland DK, Tougas G, King D, Cook DJ. Impaired gastric emptying in mechanically 
ventilated, critically ill patients. Intensive Care Med 1996;22:1339-1344. 
42. 
McClave SA, Sexton LK, Spain DA, Adams JL, Owens NA, Sullins MB, Blandford 
BS, Snider HL. Enteral tube feeding in the intensive care unit: Factors impeding adequate 
delivery. Crit Care Med 1999;27:1252-1256. 
43. 
Mentec H, Dupont H, Bocchetti M, Cani P, Ponche F, Bleichner G. Upper digestive 
intolerance during enteral nutrition in critically ill patients: Frequency, risk factors, and 
complications. Crit Care Med 2001;29:1955-1961. 
44. 
Montejo JC. Enteral nutrition-related gastrointestinal complications in critically ill 
patients: A multicenter study. The nutritional and metabolic working group of the spanish 
society of intensive care medicine and coronary units. Crit Care Med 1999;27:1447-1453. 
45. 
Bosscha K, Nieuwenhuijs VB, Vos A, Samsom M, Roelofs JM, Akkermans LM. 
Gastrointestinal motility and gastric tube feeding in mechanically ventilated patients. Crit 
Care Med 1998;26:1510-1517. 
46. 
Chapman MJ, Fraser RJ, Bryant LK, Vozzo R, Nguyen NQ, Tam W, Zacharakis B, 
Davidson G, Butler R, Horowitz M. Gastric emptying and the organization of antro-duodenal 
pressures in the critically ill. Neurogastroenterol Motil 2008;20:27-35. 

 
 
NUTRIREA-2 
 
Version n°3 datée du 20 Janvier 2012 
 
Page 71 sur 73 
47. 
Dive A, Moulart M, Jonard P, Jamart J, Mahieu P. Gastroduodenal motility in 
mechanically ventilated critically ill patients: A manometric study. Crit Care Med 
1994;22:441-447. 
48. 
Kolbel CB, Rippel K, Klar H, Singer MV, van Ackern K, Fiedler F. Esophageal 
motility disorders in critically ill patients: A 24-hour manometric study. Intensive Care Med 
2000;26:1421-1427. 
49. 
Landzinski J, Kiser TH, Fish DN, Wischmeyer PE, MacLaren R. Gastric motility 
function in critically ill patients tolerant vs intolerant to gastric nutrition. JPEN J Parenter 
Enteral Nutr 2008;32:45-50. 
50. 
McClave SA, DeMeo MT, DeLegge MH, DiSario JA, Heyland DK, Maloney JP, 
Metheny NA, Moore FA, Scolapio JS, Spain DA, Zaloga GP. North american summit on 
aspiration in the critically ill patient: Consensus statement. JPEN J Parenter Enteral Nutr 
2002;26:S80-85. 
51. 
Ritz MA, Fraser R, Tam W, Dent J. Impacts and patterns of disturbed gastrointestinal 
function in critically ill patients. Am J Gastroenterol 2000;95:3044-3052. 
52. 
Schuster-Bruce M. Gastric emptying in the critically ill. Crit Care Med 2001;29:1293-
1294. 
53. 
Chastre J, Fagon JY. Ventilator-associated pneumonia. Am J Respir Crit Care Med 
2002;165:867-903. 
54. 
Villet S, Chiolero RL, Bollmann MD, Revelly J-P, Cayeux R N M-C, Delarue J, 
Berger MM. Negative impact of hypocaloric feeding and energy balance on clinical outcome 
in icu patients. Clin Nutr 2005;24:502-509. 
55. 
Oldenburg WA, Lau LL, Rodenberg TJ, Edmonds HJ, Burger CD. Acute mesenteric 
ischemia: A clinical review. Arch Intern Med 2004;164:1054-1062. 
56. 
Stockmann H, Roblick UJ, Kluge N, Kunze U, Schimmelpenning H, Kujath P, Muller 
G, Bruch HP. Diagnosis and therapy of non-occlusive mesenteric ischemia (nomi). Zentralbl 
Chir 2000;125:144-151. 
57. 
Yasuhara H. Acute mesenteric ischemia: The challenge of gastroenterology. Surg 
Today 2005;35:185-195. 
58. 
Bradbury AW, Brittenden J, McBride K, Ruckley CV. Mesenteric ischaemia: A 
multidisciplinary approach. Br J Surg 1995;82:1446-1459. 
59. 
Schoots IG, Koffeman GI, Legemate DA, Levi M, van Gulik TM. Systematic review 
of survival after acute mesenteric ischaemia according to disease aetiology. Br J Surg 
2004;91:17-27. 

 
 
NUTRIREA-2 
 
Version n°3 datée du 20 Janvier 2012 
 
Page 72 sur 73 
60. 
Thibault R, Pichard C, Wernerman J, Bendjelid K. Cardiogenic shock and nutrition: 
Safe? Intensive Care Med 2010;37:35-45. 
61. 
Gatt M, MacFie J, Anderson AD, Howell G, Reddy BS, Suppiah A, Renwick I, 
Mitchell CJ. Changes in superior mesenteric artery blood flow after oral, enteral, and 
parenteral feeding in humans. Crit Care Med 2009;37:171-176. 
62. 
Simpson F, Doig GS. Parenteral vs. Enteral nutrition in the critically ill patient: A 
meta-analysis of trials using the intention to treat principle. Intensive Care Med 2005;31:12-
23. 
63. 
Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van 
Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, 
Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G. Early versus late 
parenteral nutrition in critically ill adults. N Engl J Med 2011;365:506-517. 
64. 
Heidegger CP, Graf S, Thibault R. Supplemental parenteral nutrition (spn) in intensive 
care unit (icu) patients for optimal energy coverage: Improved clinical outcome. Clin Nutr 
2011;6 (suppl 1):2-3. 
65. 
Bistrian BR, McCowen KC. Nutritional and metabolic support in the adult intensive 
care unit: Key controversies. Crit Care Med 2006;34:1525-1531. 
66. 
Cahill NE, Murch L, Jeejeebhoy K, McClave SA, Day AG, Wang M, Heyland DK. 
When early enteral feeding is not possible in critically ill patients: Results of a multicenter 
observational study. JPEN J Parenter Enteral Nutr 2011;35:160-168. 
67. 
Wernerman J. Guidelines for nutritional support in intensive care unit patients: A 
critical analysis. Curr Opin Clin Nutr Metab Care 2005;8:171-175. 
68. 
Khalid I, Doshi P, DiGiovine B. Early enteral nutrition and outcomes of critically ill 
patients treated with vasopressors and mechanical ventilation. Am J Crit Care 2010;19:261-
268. 
69. 
Hubmayr RD, Burchardi H, Elliot M, Fessler H, Georgopoulos D, Jubran A, Limper 
A, Pesenti A, Rubenfeld G, Stewart T, Villar J. Statement of the 4th international consensus 
conference in critical care on icu-acquired pneumonia--chicago, illinois, may 2002. Intensive 
Care Med 2002;28:1521-1536. 
70. 
Favier C, Bonneau HP, Tran Minh V, Devic J. Endoscopic diagnosis of regressive 
ischemic colitis. Endoscopic, histologic and arteriographic correlations. Nouv Presse Med 
1976;5:77-79. 
71. 
Reignier J, Mercier E, Desachy A, Bellec F, Clavel M, Frat JP, Plantefeve G, Boulain 
T, Quenot JP, Giraudeau B, Group. C. Impact of not monitoring gastric volume in 

 
 
NUTRIREA-2 
 
Version n°3 datée du 20 Janvier 2012 
 
Page 73 sur 73 
mechanically ventlated patients receiving early enteral feeding: A multi-center randomized 
trial. . Intensive Care Med 2011;37:S295. 
72. 
Casaer MP, Mesotten D, Hermans G, Wouters PJ, Schetz M, Meyfroidt G, Van 
Cromphaut S, Ingels C, Meersseman P, Muller J, Vlasselaers D, Debaveye Y, Desmet L, 
Dubois J, Van Assche A, Vanderheyden S, Wilmer A, Van den Berghe G. Early versus late 
parenteral nutrition in critically ill adults. The New England journal of medicine 
2011;365:506-517. 
73. 
Gacouin A, Camus C, Gros A, Isslame S, Marque S, Lavoue S, Chimot L, Donnio PY, 
Le Tulzo Y. Constipation in long-term ventilated patients: Associated factors and impact on 
intensive care unit outcomes. Critical care medicine 2010;38:1933-1938. 
74. 
van der Spoel JI, Oudemans-van Straaten HM, Kuiper MA, van Roon EN, Zandstra 
DF, van der Voort PH. Laxation of critically ill patients with lactulose or polyethylene glycol: 
A two-center randomized, double-blind, placebo-controlled trial. Crit Care Med 
2007;35:2726-2731. 
75. 
Reignier J, Dimet J, Martin-Lefevre L, Bontemps F, Fiancette M, Clementi E, Lebert 
C, Renard B. Before-after study of a standardized ICU protocol for early enteral feeding in 
patients turned in the prone position. Clin Nutr 2010;29:210-216. 
76. 
Reignier J, Thenoz-Jost N, Fiancette M, Legendre E, Lebert C, Bontemps F, Clementi 
E, Martin-Lefevre L. Early enteral nutrition in mechanically ventilated patients in the prone 
position. Crit Care Med 2004;32:94-99. 
77. 
Singer P, Berger MM, Van den Berghe G, Biolo G, Calder P, Forbes A, Griffiths R, 
Kreyman G, Leverve X, Pichard C. Espen guidelines on parenteral nutrition: Intensive care. 
Clin Nutr 2009;28:387-400. 
78. 
Klein CJ, Stanek GS, Wiles CE. Overfeeding macronutrients to critically ill adults: 
Metabolic complications. J Am Diet Assoc 1998;98:795-806. 
79. 
Krishnan JA, Parce PB, Martinez A, Diette GB, Brower RG. Caloric intake in medical 
icu patients: Consistency of care with guidelines and relationship to clinical outcomes. Chest 
2003;124:297-305.