Beneficial Effects on Maintaining Mechanical Ventilation During Cardiopulmonary Bypass for Cardiac Surgery on Postoperative Infections
Phase: NA
Conditions: Cardiopulmonary Bypass
Sponsor: Rennes University Hospital

 
 
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VECAR 
 
Beneficial effects on maintaining mechanical ventilation during 
cardiopulmonary bypass for cardiac surgery on postoperative infections 
 
Sponsor : CHU de Rennes, 2 rue Henri le Guilloux, 35033 Rennes cedex 9 
 
Coordinating investigator: Professeur Jean-Marc TADIE, Service des maladies infectieuses et réanimation 
médicale, CHU de Rennes – Hôpital de Pontchaillou, 35033 Rennes cedex 9. Tél : 02.99.28.42.48 – Email : 
jeanmarc.tadie@chu-rennes.fr   
 
Pharmacovigilance : Dr Catherine Mouchel, Service de Pharmacologie – Centre d’Investigation Clinique, 
Inserm 1414, CHU de Rennes – Hôpital de Pontchaillou, 2 rue Henri le Guilloux, 35033 Rennes cedex 9. 
Tél : 02.99.28.91.96 – Email : catherine.mouchel@chu-rennes.fr    
 
Methodologist : Pr Bruno Laviolle, Centre d’Investigation Clinique, Inserm 1414, Unité de 
Méthodologie/biométrie, Hôpital de Pontchaillou, 2 rue Henri le Guilloux, 35033 Rennes cedex 9. Tél.: 
02.99.28.96.68 – Email: bruno.laviolle@chu-rennes.fr 
 
Biostatistician 
: 
Alain 
Renault, 
Centre 
d’Investigation 
Clinique, 
Inserm 
1414, 
Unité 
de 
Méthodologie/biométrie, Hôpital de Pontchaillou, 2 rue Henri le Guilloux, 35033 Rennes cedex 9. Tél.: 
02.99.28.91.93 – Email: alain.renault@chu-rennes.fr 
 
Coordination and monitoring : Direction de la Recherche et de l’Innovation, CHU de Rennes – Hôpital de 
Pontchaillou, 2 rue Henri le Guilloux, 35033 Rennes cedex 9. Tél. : 02.99.28.25.55 – Email : drc@chu-
rennes.fr  
 
Version history log 
Version submitted to the authorities: Version 1.0 du 10/07/2017 
Version accepted to the authorities: Version 2.0 du 18/10/2017 
 

 
 
 
 
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SPONSOR : 
CHU Rennes (Rennes University Hospital) 
CLINICAL TRIAL PROTOCOL 
VECAR 
TRIAL CODE : 
35RC16_9908_VECAR 
N°ID-RCB: 
2017-A01246-47 
STRATEGY 
Cardiopulmonary bypass for cardiac surgery on 
postoperative infections : patients ventilated versus 
patients without mechanical ventilation during 
cardiopulmonary bypass 
COMPLETE TITLE 
 
Beneficial 
effects 
on 
maintaining 
mechanical 
ventilation during cardiopulmonary bypass for 
cardiac surgery on postoperative infections  
INDICATION(S) (TARGET) 
Cardiopulmonary bypass for cardiac surgery on 
postoperative infections 
COORDINATING INVESTIGATOR 
Professeur Jean-Marc Tadié 
Service des maladies infectieuses et réanimation 
médicale 
CHU de Rennes – Hôpital de Pontchaillou 
2 rue Henri le Guilloux 
35033 Rennes Cedex 9 
PROTOCOL VERSION NO. 
2.0 
DATE OF PROTOCOL 
18/10/2017 
CPP 
Approved on 30/08/2017 
By the Committee for the Protection of Persons 
SOOM III 
ANSM 
Date of authorisation: 18/10/2017 
Authorisation no.: 2017101700296 
This study is supported by the INSERM 1414 Clinical Investigation Center of Rennes, 
certified ISO 9001 for the methodology, conduct and analysis of clinical studies (certificate N° 
2016/71476.1). 
                
 
THIS CONFIDENTIAL DOCUMENT IS THE PROPERTY OF CHU RENNES. NO 
UNPUBLISHED INFORMATION CONTAINED IN THIS DOCUMENT CAN BE 
DISCLOSED WITHOUT THE PRIOR WRITTEN AUTHORISATION OF CHU RENNES. 

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TABLE OF CONTENTS 
 
 
1 
GENERAL INFORMATION ............................................................................................................. 11 
1.1 Title ........................................................................................................................................................ 11 
1.2 Sponsor .................................................................................................................................................. 11 
12.1Identification ..................................................................................................................................... 11 
1.2.2Signature of protocol on behalf of the sponsor ................................................................................ 11 
1.2.3Person responsible for study on the side of the sponsor .................................................................. 11 
1.3 Coordination and monitoring of study ................................................................................................... 11 
1.4 Investigators ........................................................................................................................................... 11 
1.4.1Coordinating investigator ................................................................................................................ 11 
1.4.2Associated investigators................................................................................................................... 11 
1.5 Associated scientific partners ................................................................................................................ 11 
1.6 Vigilance ................................................................................................................................................ 11 
1.7 Methodologist – biostatistician .............................................................................................................. 11 
1.8 Scientific Committee ............................................................................................................................. 12 
1.9 Independent Data and Safety Monitoring Board ................................................................................... 12 
1.10 Independent validation committee ....................................................................................................... 12 
2 
SCIENTIFIC RATIONALE AND GENERAL DESCRIPTION OF STUDY ............................... 12 
2.1 Name and description of the disease ...................................................................................................... 12 
2.2 Summary of results of non-clinical trials and clinical trials available and relevant regarding the 
research involving the human person study concerned ............................................................................... 16 
2.3 Summary of benefits, if applicable, and of foreseeable and known risks for the person who is a Patient 
in the research study ..................................................................................................................................... 16 
2.3.1Benefits ............................................................................................................................................. 16 
2.3.1.1 Individual benefits .................................................................................................................... 16 
2.3.1.2 Collective benefits .................................................................................................................... 16 
2.3.2Risks ................................................................................................................................................. 17 
2.3.2.1 Individual risks......................................................................................................................... 17 
Physical risks and constraints .......................................................................................................... 17 
Psychological risks and constraints ................................................................................................. 17 
Socio-economic risks and constraints .............................................................................................. 17 
2.3.2.2 Collective risks ......................................................................................................................... 17 
2.3.3Benefit / risk ratio ............................................................................................................................ 17 
2.4 Statement indicating that the study will be conducted in compliance with the protocol as well as with 
good clinical practices and legislative and regulatory conditions in force .................................................. 17 
2.5 References to the scientific literature and to relevant data used as a reference for the study ................ 17 
3 
STUDY OBJECTIVES ........................................................................................................................ 17 
3.1 Primary objective ................................................................................................................................... 17 
3.2 Secondary objectives ............................................................................................................................. 17 
4 
STUDY DESIGN .................................................................................................................................. 18 
4.1.1Primary evaluation criteria ............................................................................................................. 18 
4.1.2Secondary evaluation criteria .......................................................................................................... 18 
4.2Description of study methodology .......................................................................................................... 18 
4.2.1Experimental design......................................................................................................................... 18 
4.2.2Conduct of study .............................................................................................................................. 18 
4.2.2.1. Screening phase ...................................................................................................................... 18 
4.2.2.2. Inclusion phase ....................................................................................................................... 18 
4.2.2.3. Follow-up ................................................................................................................................ 19 

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4.3 Description of the measures taken to reduce and prevent bias .............................................................. 20 
4.3.1Randomization ................................................................................................................................. 20 
4.3.2Methods of blinding ......................................................................................................................... 20 
4.4 Expected duration of participation of persons and description of chronology and of duration of all 
study periods including monitoring, if applicable ....................................................................................... 20 
4.5 Description of rules for permanent or temporary discontinuation ......................................................... 20 
4.5.1Discontinuation of participation of a person in study ..................................................................... 20 
4.5.2Discontinuation of part or of the entire study .................................................................................. 20 
5 
SCREENING AND INCLUSION OF PERSONS FROM THE STUDY ....................................... 21 
5.1 Inclusion criteria .................................................................................................................................... 21 
5.2 Non-inclusion criteria ............................................................................................................................ 21 
5.3 Methods of recruitment .......................................................................................................................... 21 
6 
TREATMENTS ADMINISTERED IN THE STUDY...................................................................... 21 
7 
EVALUATION OF SAFETY ............................................................................................................. 21 
7.1 Definitions .............................................................................................................................................. 21 
7.2 Investigator’s role .................................................................................................................................. 22 
7.2.1Notification of serious adverse events ............................................................................................. 22 
7.2.2Notification of non-serious adverse events ...................................................................................... 22 
7.2.3Protocol specific features ................................................................................................................ 22 
7.3 Sponsor’s role ........................................................................................................................................ 22 
7.3.1Analysis of serious adverse events ................................................................................................... 22 
7.3.2Scoring of causal relationship ......................................................................................................... 22 
7.3.3Declaration of unexpected serious adverse events .......................................................................... 22 
7.3.4Transmission of annual safety reports ............................................................................................. 22 
7.3.5Declaration of other safety data ...................................................................................................... 23 
7.4 Expected adverse effects ........................................................................................................................ 23 
8 
STATISTICS ........................................................................................................................................ 23 
8.1 Description of planned statistical methods, including schedule of planned interim analysis ................ 23 
8.1.1Descriptive analysis ......................................................................................................................... 23 
8.1.2Comparison of groups at inclusion .................................................................................................. 23 
8.1.3Analysis of the primary criteria ....................................................................................................... 23 
8.1.4Analysis of other criteria ................................................................................................................. 23 
8.1.5Analysis of adverse events ............................................................................................................... 23 
8.2 Planned number of persons to be enrolled in the study, and planned number of persons in each centre 
with its statistical justification ..................................................................................................................... 23 
8.3 Planned degree of statistical significance .............................................................................................. 24 
8.4 Method of management of missing, unused or invalid data .................................................................. 24 
8.5 Choice of persons to include in the analysis .......................................................................................... 24 
9 
RIGHT OF ACCESS TO DATA AND SOURCE DOCUMENTS ................................................. 24 
9.1 Access to data ........................................................................................................................................ 24 
9.2 Source documents .................................................................................................................................. 24 
9.3 Confidentiality of data ........................................................................................................................... 24 
10 
QUALITY CONTROL AND ASSURANCE..................................................................................... 24 
11 
ETHICAL CONSIDERATIONS ........................................................................................................ 25 
11.1 Regulatory and institutional review ..................................................................................................... 25 
11.2 Substantial changes .............................................................................................................................. 25 
11.3 Information for patients and written informed consent form ............................................................... 25 
11.4 Compensation of patients ..................................................................................................................... 25 

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11.5 Registration in the national file of persons who are patients in research involving the human person 25 
12 
DATA PROCESSING AND RETENTION OF DOCUMENTS AND DATA ............................... 25 
12.1 Case report forms and data entry ......................................................................................................... 25 
12.2 CNIL .................................................................................................................................................... 25 
12.3 Archiving ............................................................................................................................................. 25 
13 
INSURANCE ........................................................................................................................................ 26 
14 
STUDY FEASIBILITY ....................................................................................................................... 26 
15 
RULES PERTAINING TO PUBLICATION .................................................................................... 26 
16 
LIST OF APPENDIX .......................................................................................................................... 26 

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SIGNATURES 
 
INVESTIGATOR’S SIGNATURE 
I have read all pages of this clinical trial protocol for which the CHU of Rennes is the sponsor. I 
confirm that it contains all information necessary for the correct conduct of the study. I agree to 
conduct the study in compliance with the protocol and terms of conditions which are defined in it. 
I agree to conduct the study while complying with the conditions of: 
 
- 
Principles of the “Declaration of Helsinki”,  
- 
The rules and recommendations of international good clinical practice ((ICH-E6) and 
French good clinical practice (rules of good clinical practice for biomedical research 
studies of medicinal products for human use - decisions of 24 November 2006), 
- 
National legislation and regulations pertaining to clinical trials, 
- 
Compliance with the Clinical Trials Directive of the EU [2001/20/EC].  
 
I also agree that investigators and other qualified members of my team may have access to copies 
of this protocol and documents pertaining to the correct conduct of the study enabling them to 
work in compliance with conditions contained in these documents.  
 
NAME : Professeur Jean-Marc TADIE 
 
Signature :  
 
 
 
Date : 18/10/2017 
 
 
SPONSOR’S SIGNATURE 
Sponsor : CHU de Rennes 
 
NAME : GAUDRON Pascal 
 
Signature :  
 
 
 
Date : 18/10/2017 
 

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SYNOPSIS 
 
TITLE 
Beneficial effects on maintaining mechanical ventilation during cardiopulmonary 
bypass for cardiac surgery on postoperative infections  
SPONSOR 
CHU of Rennes 
COORDINATING 
INVESTIGATOR  
Professeur Jean-Marc Tadié 
Service des maladies infectieuses et réanimation médicale 
CHU de Rennes – Hôpital de Pontchaillou 
2 rue Henri le Guilloux 
35033 Rennes Cedex 9 
PROTOCOL VERSION 
2.0 
RATIONALE / CONTEXT  
Cardiopulmonary bypass (CBP) during cardiac surgery induces a systemic 
inflammatory response associated with an immune dysregulation and a significant 
pulmonary dysfunction. First, the inflammatory response, usually attributed to 
surgical trauma, contact of blood with artificial surfaces, and ischemia reperfusion 
injury, is responsible for a postoperative immunodepression. For instance, an early 
impairment of lung cellular immune response after CPB, which could promote the 
development of postoperative pneumonia, has been found. Along these lines, a 
downregulation of human leukocyte antigen-DR antigen (HLA-DR) expression on 
monocytes and an increase in plasma interleukin 10 (IL-10) associated with the 
occurrence of nosocomial infections have been reported. Second, CPB induces a 
pulmonary dysfunction, which ranges from a temporary and clinically insignificant 
reduction in arterial oxygenation to a life-threatening injury manifested as acute 
respiratory distress syndrome (ARDS). This phenomenon is of multifactorial 
sources, but one of the main mechanisms is the occurrence of atelectasis during 
surgery. Atelectasis has been associated with lung injury and release of cytokines 
by shear forces on alveoli and small airways. However, it is not clear whether this 
injury is due to a recruitment/derecruitment phenomenon (i.e., atelectrauma) or 
whether it might by itself lead to the release of cytokine. Since CPB mechanically 
circulates and oxygenates blood bypassing the heart and lungs, usual procedure 
during CPB is to stop mechanical ventilation (MV) (apnea). Nevertheless, 
maintaining MV with positive expiratory pressure (PEEP) during CPB diminished 
the occurrence of atelectasis and the postoperative inflammatory response. Thus, 
we investigated the effects of maintaining MV during CPB for cardiac surgery on 
postoperative immunodepression and found that maintaining MV during CPB 
decreased postoperative immune dysfunction and could be an interesting strategy 
to diminish the occurrence of postoperative infection (nosocomial infection) 
without hampering the surgical procedure. However, these findings have to be 
confirmed in a clinical trial using the incidence of nosocomial infection as an 
endpoint. 
ORIGINALITY AND 
INNOVATIVE ASPECTS 
While several researches projects studied the effects of maintaining MV on 
postoperative pulmonary function and/or inflammation, the innovative nature of 
this work is based on objective morbidity endpoint. Indeed, this study, based on 
our previous works, will explore the beneficial immunological changes induced by 
maintaining MV during CPB using a clinical endpoint: the reduction of 
postoperative infections. Indeed, we have demonstrated that maintaining MV 
decreased IL-10 levels and postoperative lymphopenia which is associated with 
postoperative infections. Moreover, because there is a lack of randomized 
controlled trials to guide optimal intra-operative ventilation, and because 
maintaining MV during CPB is not hampering the surgical procedure, without any 
additional cost, such a strategy reducing postoperative infection have to be studied. 
Lastly, since the menace of complete absence of effective antibiotics to treat 
hospital acquired infections exists, our study will participate to the development of 
innovative treatment and prophylactic approaches. Thus, expected public health 
benefits (or collective benefits) are:   
- Clear benefits for public health since healthcare associated infections in 
hospitals impose significant economic consequences on the nation’s healthcare 
system. 

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- A decrease in the emergence of resistant strains in surgery, hospital and 
general population, since postoperative infections are responsible for antibiotic 
prescription which is the single most important cause of the emergence of drug 
resistance, both in the community and hospital settings. 
PRIMARY OBJECTIVE 
To measure the incidence of postoperative infections in 2 groups of patients: one 
group of patients ventilated and one group of patients without mechanical 
ventilation during cardiopulmonary bypass for cardiac surgery, and demonstrate 
that the incidence of postoperative infections is significantly lower in patients 
ventilated during CPB. 
SECONDARY 
OBJECTIVES  
To demonstrate that, compared to patients without MV during CPB, maintaining 
MV will: 
- Decrease postoperative immunodepression (human leukocyte antigen-DR 
antigen (HLA-DR) expression on monocytes, Indoleamine 2,3-Dioxygenase 
(IDO) activity, plasmatic levels of IL-10 and proportion of myeloid-derived 
suppressor cells (MDSCs)); 
- Decrease postoperative inflammation (plasmatic levels of IL-6 and quantity of 
extracellular vesicles (EV)); 
- Decrease the occurrence of lymphopenia after surgery (defined as an absolute 
lymphocyte count less than 1.2 cells/μL × 10.3); 
- Decrease postoperative exposure to antimicrobials treatment; 
- Decrease postoperative mortality; 
- Decrease postoperative length of stay; 
- Increase the PaO2/FiO2 ratio after surgery; 
- Decrease postoperative duration of MV. 
PRIMARY EVALUATION 
CRITERION  
Primary end point will be the incidence of postoperative infections (ie nosocomial 
infections) within 28 days following cardiac surgery. The diagnosis of a 
postoperative infection will be based on clinical, biochemical, or morphological 
features and confirmed (if possible) by bacteriological data according to CDC 
definitions for nosocomial infections. 
SECONDARY 
EVALUATION CRITERIA  
- Postoperative expression of human leukocyte antigen-DR antigen (HLA-DR) 
on peripheral monocytes at day 0, day 1 and day 7,  
Postoperative plasmatic levels of IL-10 at day 0, day 1  and day 7,  
Postoperative indoleamine 2,3-Dioxygenase (IDO) activity at day 0, day 1 and 
day 7,  
Postoperative proportion of myeloid-derived suppressor cells (MDSCs) at day 
0, day 1  and day 7; 
- Postoperative plasmatic levels of IL-6 at day 0, day 1 and day 7, Postoperative 
quantity of extracellular vesicles (EV) at day 0 and day 1;  
- Postoperative lymphocytes count at day 0, day 1 and day 7;  
- Number of days of exposure to each antibiotic per 1000 inpatient days, defined 
as the number of days (>24 h) of continuous antibiotic treatment (from days 1 
to 28) and duration of antibiotic treatment; 
- Mortality within 28 days following surgery ;  
- Hospital length of stay (max 28 days) defined as the number of days before first 
hospital discharge; 
- PaO2/FiO2 ratio at day 0 and day 1; 
- Duration of MV (max 28 days). 
METHODOLOGY / 
STUDY SCHEDULE 
A prospective, multicenter, single-blind, randomized, parallel-group trial. 
CRITERIA FOR 
INCLUSION OF 
PATIENTS  
- Age ≥ 18 years old;  
- Scheduled for any cardiac surgery (elective surgery) with cardio-pulmonary 
bypass, aortic clamp and cardioplegia, with median sternotomy and bi-
pulmonary ventilation (cardiac valvular surgery (valve replacement or repair), 
coronary artery surgery, ascending aortic surgery and/or combined); 
- Written informed consent. 
NON-INCLUSION 
CRITERIA OF PATIENTS 
- Emergency surgery ; 
- Planned thoracotomy with one lung ventilation ; 
- Patients with known respiratory diseases (current respiratory infections, asthma, 

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chronic obstructive or restrictive pulmonary disease, obstructive apnea 
syndrome) ; 
- Patients already intubated in the peri-operative period ; 
- Immunodepression defined by proven humoral or cellular deficiency, by 
continuous administration of steroids at any dose for more than one month prior 
to hospitalization, high-dose steroids (> 15 mg / kg / day of methylprednisolone 
or Equivalent), radiotherapy or chemotherapy in the previous year;;  
- Need for vasopressor or inotropic agents before surgery ;  
- Any acute infection in the last month before surgery ;  
- Hematological 
disorder, 
autoimmune 
disease, 
immunodeficiency, 
immunosuppressive therapy ; 
- Heart failure with an left ventricular ejection fraction<35% ; 
- Protected person (adults legally protected (under judicial protection, 
guardianship, or supervision), person deprived of their liberty. 
STRATEGIES/PROCEDUR
ES 
During CPB, two settings will be used depending on the randomization:  
- 
absence of MV (and no PEEP) by disconnecting the tracheal tube from the 
ventilator (MV- group) ; 
- 
dead space ventilation using tidal volume of 2.5 mL/kg (predicted body 
weight) with 5-7 cmH2O PEEP (MV+ group). 
 
Immunomonitoring 
parameters 
(HLA-DR 
expression, 
IL-10 
and 
IL-6, 
lymphocytes count, IDO activity, MDSCs, EV) will be obtained after general 
anesthesia and before surgery (D0), at 24 hours (D1) and 7 days (D7) after surgery 
(except EV). HLA-DR expression, MDSCs, EV associated lung injury, IL-10, IL-6 
and IDO activity will be measured in Rennes. 
Ratio of arterial oxygen tension (PaO2) to FIO2 will be obtained before surgery 
(D0, after induction of anesthesia) and 3 h after the end of CPB in the surgical 
intensive care unit (ICU; under baseline MV settings), and the day after surgery 
(D1). 
Occurrence of postoperative infections (an independent committee blinded to 
treatment group will ensure the classification of hospital-acquired infections), 
antibiotics treatment, length of stay, duration of MV, mortality will be recorded 
within the first 28 days following surgery. 
NUMBER OF PATIENTS  
1400 
DURATION OF STUDY  
Recruitment period : 24 months 
Duration of patient monitoring : 28 days 
Duration of analysis of data  : 6 months 
Estimated total duration of study : 31 months 
EXPECTED FINDINGS 
AND IMPACT  
Expected patient benefits are: 
- A significant decrease in the occurrence of postoperative infection. 
- A significant decrease in hospital length of stay. 
- A significant decrease in both mortality and morbidity. 
- A significant decrease in exposure to antibacterial agent which could be harmful 
(as clostridium difficile colitis). 
Expected public health benefits are: 
- Clear benefits for public health since healthcare associated infections in 
hospitals impose significant economic consequences on the nation’s healthcare 
system. 
- A decrease in the emergence of resistant strains in surgery, hospital and general 
population since postoperative infections are responsible for antimicrobials 
prescription which is the single most important cause of the emergence of drug 
resistance, both in the community and hospital settings. 
- Lastly, the threat of complete absence of effective antibiotics to treat 
problematic hospital-acquired infections is fueling the development of 
prophylactic approaches. 
 
 

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LIST OF ABBREVIATIONS 
 
AAR 
 
Act Added by the Research 
ADR 
 
Adverse Reaction 
AE 
 
Adverse event 
ANSM  
Agence Nationale de Sécurité du Médicament et des produits de santé 
AP-HP  
Assistante Publique-Hôpitaux de Paris 
ARC 
 
Act of Routine Care 
ARDS  
Acute respiratory distress syndrome 
CPB 
 
Cardiopulmonary bypass 
CDC 
 
Center for Disease Control and Prevention 
CHU 
 
Centre Hospitalier Universitaire 
CPP 
 
Comité de Protection des Personnes 
CRA 
 
Clinical Research Associate 
CRF 
 
Case Report Form 
EV 
 
Extracellular Vesicles 
FiO2 
 
Fraction of inspired oxygen 
GCP 
 
Good Clinical Practices 
HEGP  
Hôpital Européen Georges-Pompidou 
HLA-DR 
Human leukocyte antigen-DR 
ICH 
 
International Conference on Harmonisation 
ICU 
 
Intensive Care Unit 
IDO 
 
Indoleamine 2,3-Dioxygenase 
IEC 
 
Independent ethics committee 
IL 
 
Interleukin 
INSERM 
Institut national de la santé et de la recherche médicale 
LVEF  
Left ventricular ejection fraction 
MDSCs 
Myeloid-derived suppressor cells 
MR 
 
Methodology of Reference 
MV 
 
Mechanical ventilation 
NO 
 
Nitric Oxide 
PaO2  
Partial pressure of oxygen 
PEEP  
Positive end-expiratory pressure 
PMN  
Polymorphonuclear neutrophils 
REVA  
Réseau Européen de Recherche en Ventilation Artificielle 
SAE 
 
Serious Adverse Event 
SAR 
 
Serious Adverse Reaction 
SAS 
 
Statistical Analysis System 
SUSAR 
Suspected unexpected serious adverse reaction 
TNF 
 
Tumor necrosis factor 

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1 
GENERAL INFORMATION 
1.1 Title 
Beneficial effects on maintaining mechanical ventilation during cardiopulmonary bypass for cardiac surgery on 
postoperative infections 
 
1.2 Sponsor 
 
12.1Identification 
CHU de Rennes 
2, rue Henri le Guilloux 
35033 Rennes cedex 9 
 
 
1.2.2Signature of protocol on behalf of the sponsor 
Pascal GAUDRON, Director of Research 
CHU de Rennes 
2, rue Henri le Guilloux 
35033 Rennes cedex 9 
 
 
1.2.3Person responsible for study on the side of the sponsor 
Pascal GAUDRON, Director of Research 
CHU de Rennes 
2, rue Henri le Guilloux 
35033 Rennes cedex 9 
 
1.3 Coordination and monitoring of study 
Direction of Research 
CHU de Rennes 
2, rue Henri le Guilloux 
35033 Rennes cedex 9 
 
1.4 Investigators 
 
1.4.1Coordinating investigator 
Professeur Jean-Marc Tadié 
Service des maladies infectieuses et réanimation médicale 
CHU de Rennes – Hôpital de Pontchaillou 
2 rue Henri le Guilloux 
35033 Rennes Cedex 9 
Tel.: 02.99.28.42.48 
Email: jeanmarc.tadie@chu-rennes.fr 
 
 
1.4.2Associated investigators 
See Appendix 1 
 
1.5 Associated scientific partners 
Professeur Karin Tarte 
Laboratoire d’Immunologie – Thérapie Cellulaire et Hématopoïèse 
CHU de Rennes – Hôpital de Pontchaillou 
2 rue Henri le Guilloux 
35033 Rennes Cedex 9 
 
1.6 Vigilance 
Dr Catherine Mouchel, Centre d’Investigation Clinique, Inserm 1414, Unité de Pharmacologie Clinique, Hôpital de 
Pontchaillou, 2 rue Henri le Guilloux, 35033 Rennes Cedex 9, France. Tel.: 02.99.28.91.96 – Email: 
catherine.mouchel@chu-rennes.fr 
 
1.7 Methodologist – biostatistician 
Methodologist : Pr Bruno Laviolle, Centre d’Investigation Clinique, Inserm 1414, Unité de Méthodologie/biométrie, 
Hôpital de Pontchaillou, 2 rue Henri le Guilloux, 35033 Rennes cedex 9, France. Tel.: 02.99.28.96.68 – Email: 
bruno.laviolle@chu-rennes.fr 
 

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Biostatistician : Alain Renault, Centre d’Investigation Clinique, Inserm 1414, Unité de Méthodologie/biométrie, 
Hôpital de Pontchaillou, 2 rue Henri le Guilloux, 35033 Rennes cedex 9, France. Tel.: 02.99.28.91.93 – Email: 
alain.renault@chu-rennes.fr 
 
1.8 Scientific Committee 
The mission of the Scientific Committee is to settle scientific, methodological and ethical problems raised by the trial 
and to monitor its proper conduct. It will be constituted at the beginning of the study with 5 members, including the 
coordinating investigator, the methodologist, a representative from the sponsor, and two members among the 
associated teams. It will meet after each interim analysis to study the recommendations of the data and safety 
monitoring board and will take the final decision to stop the trial if needed. 
The Scientific Committee will solve practical problems arising during the course of study and may decide to amend 
the protocol. If such amendments are done, the relevant Independent Ethics Committee and the Competent Authority 
will be notified. The Scientific Committee will send to investigators all the information necessary for the proper 
conduct of the study. 
 
1.9 Independent Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board will be constituted at the beginning of the study with 5 members 
who are not involved in the study, including an intensivist, an anesthesiologist, a cardiac surgeon, an infectiologist, a 
methodologist/statistician.  
In order to prematurely stop the study in case of efficacy, two interim analyses are planned. These analyses will be 
performed on the primary endpoint but will also evaluate safety data in order to rapidly detect any unexpected serious 
adverse events. 
The Data and Safety Monitoring Board will meet after each interim analysis and at the end of the study. It can also 
meet on request of the coordinating investigator or the methodologist if serious adverse events or results which can 
jeopardize the existence of the protocol occur. 
The Data and Safety Monitoring Board will propose to stop the study if the interim statistical analyses reach 
significance or if it appears that study continuation would be contrary to ethics rules (occurrence of serious adverse 
events, publication of trial results providing the answer to the question...). 
 
1.10 Independent validation committee 
The validation committee will include 3 members, an infectiologist, a bacteriologist, and an intensivist. They will be 
in charge to validate the occurrence of nosocomial infections and the date of occurrence and will be blinded to the 
study arm (blinded evaluation of the primary endpoint). They will be provided with a standardized patient record 
containing all required document necessary harmonize patients’ evaluations. 
 
 
2 
SCIENTIFIC RATIONALE AND GENERAL DESCRIPTION OF STUDY 
2.1 Name and description of the disease 
Cardiopulmonary bypass (CPB) is a technique that temporarily takes over the function of the heart and lungs during 
cardiac surgery. CBP during cardiac surgery induces a systemic inflammatory response associated with an immune 
dysregulation and a significant pulmonary dysfunction (1-9). These two phenomena have been well characterized. 
First, the inflammatory response, usually attributed to surgical trauma, contact of blood with artificial surfaces, and 
ischemia-reperfusion injury. Although often innocuous, such inflammation might contribute to postoperative 
complications such as lung injury, bleeding disorders and organs failure (1, 2, 4, 6, 10-12). Moreover, while the 
inflammation proceeds, some key players of the immune system become immunosuppressed exposing patients to 
postoperative infections (3, 13, 14). Secondly, CPB induced pulmonary dysfunction ranges from a temporary and 
clinically insignificant reduction in arterial oxygenation to life-threatening injury manifested as acute respiratory 
distress syndrome (7, 8, 15-17). This phenomenon is of multifactorial sources, but one of the main mechanisms is the 
occurrence of atelectasis during surgery, may be due to airway closure related to the absence of lung ventilation during 
CPB (9). Indeed, since CPB mechanically circulates and oxygenates blood bypassing the heart and lungs, the 
usual procedure during CPB is to stop MV (apnea). 
Because maintaining MV during CPB diminishes postoperative inflammation, a relationship between pulmonary 
dysfunction and postoperative immunosuppression has been investigated with convincing results. However, these 
findings have to be confirmed in a clinical trial using the incidence of nosocomial infection as an endpoint. 
 
A. Cardiopulmonary bypass induced immunosuppression 
CPB is associated with a generalized inflammatory response with immune paresis which predisposes to the 
development of postoperative infections and sepsis. This systemic inflammatory response includes activation of 
platelets, polymorphonuclear neutrophils (PMNs), monocytes, macrophages (2, 3, 5, 18, 19). However, it is currently 

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accepted that CPB-induced inflammatory response is accompanied by immunosuppression, which can last several 
days or weeks after surgery, increasing the risk to develop postoperative infections. Several studies have demonstrated 
that circulating levels of interleukin 6 (IL-6), interleukin 10 (IL-10) and tumor necrosis factor alpha (TNF-α) increased 
dramatically (1). Furthermore, among changes of monocyte function observed after CPB, a down-modulation of 
monocyte molecules expressions, especially for HLA-DR (mHLA-DR), has been demonstrated (4, 11). In terms of 
functionality, monocytes with decreased HLA-DR have been shown to be unable to mount a pro-inflammatory 
response to any bacterial challenge or to properly present antigens to T cells. In terms of clinical information, 
decreased mHLA-DR has been shown to be predictive of both fatal outcome and septic complications after trauma, 
surgery, pancreatitis, burn and septic shock (6, 13, 20, 21). Of note, there are several lines of evidence suggesting that 
IL-6 and TNF-α play a pivotal role during acute inflammation, whereas IL-10 is an immunosuppressive cytokine that 
could be involved in HLA-DR downregulation (22).  
Mekontso et al. have shown that bactericidal activity of PMNs against Staphylococcus aureus was decreased after 
cardiac surgery (3). In a prospective study, Chalk et al. have also reported a dysfunction of pulmonary macrophages 
after CPB. In particular, they have described an early impairment of lung cellular immune response, which could 
promote the development of postoperative pneumonia (13). Along these lines, observational studies have 
demonstrated that patients undergoing cardiac surgery with CPB have a high risk for nosocomial infections (23, 24). 
Moreover, a downregulation of HLA-DR expression on monocytes and an increase in plasma IL-10 levels were 
associated with the occurrence of nosocomial infections (5, 13, 21). In previous studies, the delayed-type 
hypersensitivity response, IL-6 concentrations and number of HLA-DR epitopes have been shown to correlate with 
clinical outcome for cardiac surgery, major abdominal surgery, and patients with trauma (5). 
Infections are the most common non-cardiac complication after cardiac surgery. Infection in the setting of 
cardiac surgery increases morbidity, mortality, and cost. These infections can require prolonged treatment with 
antibiotics, additional surgery, or both. Several studies have found that 15-20% of patients will experience 
postoperative infections. In a recent prospective study, 15% of patients developed postoperative infections which 
dramatically affected survival and readmissions (23-26). The authors found that prolonged ventilation and transfusion 
were associated with adverse outcomes and emphasized the considerable opportunities for improving outcomes and 
preventing postoperative infection. However, no pharmacological strategies have reduced this immunosuppression 
(glucocorticoids, protease inhibitors, heparin, phosphodiesterase inhibitors, antioxidants…) (5, 18, 19, 25, 27-31). In a 
prospective, randomized, double-blind, placebo-controlled study, Tepaske et al. aimed to ascertain whether oral 
immune-enhancing nutritional supplement taken for at least 5 days before an operation in high-risk patients 
undergoing cardiac surgery improves preoperative host defense and subsequently reduces postoperative infections and 
organ dysfunction. They demonstrated that CPB decreased dramatically HLA-DR expression on monocytes in both 
group. However they found that concentration of IL-6 was significantly lower in the treatment group than in the 
control group (5). Although these results are interesting, no study has demonstrated that its finding could be 
generalized to other patients. 
 
Cardiopulmonary bypass during cardiac surgery promotes inflammatory response and immune dysfunction that 
increase the occurrence of postoperative infection. Reducing postoperative inflammation will decrease 
postoperative immunosuppression and therefore will decrease patient morbidity. 
 
B. Cardiopulmonary bypass induced pulmonary dysfunction 
After cardiac surgery, pulmonary dysfunction is a frequently encountered complication which could increase 
postoperative ICU stay and result in a significantly increased mortality (7, 15, 32). Inflammatory response to CPB and 
ischemic damage of the lungs have been considered as major causes of respiratory failure after cardiac surgery, and 
there have been numerous reports of successful reduction of post- CPB lung injury by controlling inflammatory 
response or pulmonary ischemia (7, 16). However, recent studies have demonstrated that this phenomenon was of 
multifactorial sources, but one of the main mechanisms is the occurrence of atelectasis during surgery (8, 9, 33-37). 
Since CPB mechanically circulates and oxygenates blood bypassing the heart and lungs, usual procedure during CPB 
is to stop MV (apnea), which could induce atelectasis.  Atelectasis has been associated with lung injury and release of 
cytokines (tumor necrosis factor α [TNF-α]) by shear forces on alveoli and small airways (9, 36, 38). However, it is 
not clear whether this injury is due to a recruitment/derecruitment phenomenon (i.e., atelectrauma) or whether it might 
by itself lead to the release of cytokines (38-40). This injury could be aggravated by MV. Although MV is an essential 
support during surgery or in patients admitted to the intensive care unit, clinical and experimental studies have shown 
that it could be harmful and could induce lung injury. Pulmonary and immune cells can convert mechanical stimuli 
into biological signals that will lead to inflammation (38). This sterile inflammation both locally and systemically will 
cause immunosuppression. Nevertheless, maintaining MV and addition of a positive end-expiratory pressure (PEEP) 
during CPB for cardiac surgery diminished the occurrence of atelectasis and the postoperative inflammatory response 
without hampering the surgical progress (1, 9, 35). 

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Continued ventilation during cardiopulmonary bypass results in lesser inflammatory responses and improves 
postoperative pulmonary function. Continuation of ventilation during CPB leads to an attenuated inflammatory 
and anti-inflammatory responses. This strategy might therefore improve patient outcome. 
 
C. Previous studies supporting our hypothesis 
We have already conducted three different studies that strongly support our hypothesis. Main results are 
summarized as follow: 
 
1. Partitioning of exhaled nitric oxide (NO) in ventilated patients undergoing cardiac surgery 
(Appendix 4): In this observational study, our objectives were to assess the changes in exhaled nitric 
oxide (NO) after CPB, taking into account the anatomical origin of its production using a method 
allowing the partitioning of exhaled NO between its bronchial and alveolar origins. We hypothesized that 
exhaled NO change often evidenced after CPB could be due to the absence of ventilation during CPB 
resulting in airway closure (transient atelectasis), and that this change could be prevented by MV with 
positive end-expiratory pressure during CPB. We found that a frank decrease in exhaled NO originating 
from the bronchial tree after CPB without MV. This significant decrease seemed related to airway closure 
since dead space MV with PEEP prevented it.  At least two hypotheses could have been raised, firstly 
persistent airway closure (∼atelectasis) may explained the decrease in exhaled NO by reducing epithelial 
surface and consequently maximum flux from bronchi (41-43); secondly, inflammatory processes related 
to CPB may led to a generalized decrease in NO production due to the post-insult immune paralysis (44). 
 
Thus, we conducted a prospective study to investigate the effects of maintaining lung ventilation during CPB 
in patients undergoing cardiac surgery on postoperative immune dysfunction using IL-10 and HLA-DR as 
major endpoints. 
 
2. Immune dysfunction after cardiac surgery with cardiopulmonary bypass: beneficial effects of 
maintaining mechanical ventilation (Appendix 5) 
Because maintaining MV (MV) with PEEP during CPB diminishes postoperative inflammation, we 
decided to investigate the relationship between pulmonary dysfunction and postoperative 
immunosuppression. We thus conducted a prospective study to investigate the effects of maintaining lung 
ventilation during CPB in patients undergoing cardiac surgery on postoperative immune dysfunction using 
IL-10 and HLA-DR as major endpoints (Appendix 5). We also investigated the CD14+HLA-DRlo/- 
monocytes, which have been described as immunosuppressive monocytic myeloid-derived suppressor 
cells (Mo-MDSCs) in humans (45), before and after CPB.  
Main results were as follow:  
1. We found that patients ventilated during CPB had lower postoperative levels of immunosuppressive 
IL-10 and proinflammatory TNF-α, and a higher postoperative lymphocytes count. These beneficial 
effects on postoperative immunosuppression could be related to an enhancement in pulmonary 
function because maintaining MV during CPB abolished the postoperative decrease in PaO2/FIO2 
ratio. 
2. We also found that total lymphocyte count was significantly decreased after cardiac surgery in non-
ventilated patients compared with patients ventilated during CPB. This finding was of major interest 
since lymphopenia has been associated with immune dysfunction during septic shock, and it has been 
shown that low absolute lymphocyte counts were predictive of postoperative sepsis (46, 47). In a 
recent retrospective study, Drewry et al. have demonstrated that persistent lymphopenia after sepsis 
predicted mortality and could be a valuable biomarker of immunosuppression because lymphopenia 
predicted an increased risk of secondary infection (48). However, no study has been conducted in 
patients undergoing cardiac surgery.  
 
Since we found that total lymphocyte count was significantly decreased after cardiac surgery in non-ventilated 
patients compared with patients ventilated during CPB. 
Mechanisms involved in postoperative lymphopenia had to be studied. 
 
 
 
 

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3. Cardiopulmonary bypass induced lymphopenia and decreased lymphocyte proliferation ability: IL-
10 as a potential therapeutic target to reduce postoperative infection (Appendix 6) 
Perioperative lymphopenia has been linked with an increased risk of postoperative infectious 
complications in orthopedic surgery or abdominal surgery (47, 49). There is no data in cardiac surgery. 
We performed an observational study in patients undergoing cardiac surgery with CPB and found: 
1. In a cohort of patients (n=986), persistent lymphopenia within 5 days following cardiac surgery with 
CPB was associated with the occurrence of postoperative infection (ie nosocomial infections). 
2. Cardiac surgery induced lymphocytes apoptosis after CPB. 
3. Lymphocytes from patients were less likely to proliferate after CPB. 
4. Indoleamine 2,3-dioxygenase (IDO) and Interleukin 10 (IL-10) were involved in CPB-induced 
decrease lymphocyte proliferation ability. 
 
D. Selected biomarkers for immunomonitoring and pulmonary function 
Interleukin 6 (IL-6): IL-6 is an inflammatory cytokine with wide-ranging biological effects. Cytokines are released in 
response to tissue injury or an inflammatory stimulus. They act locally and systemically to generate a variety of 
physiologic responses, principal among them is the acute phase response (50). Since maintaining MV should decrease 
postoperative inflammation, plasmatic IL-6 levels should be lower in the ventilated group than in patients without MV 
during CPB. 
Interleukin 10 (IL-10): IL-10 is an immunosuppressive cytokine that could be involved in HLA-DR downregulation 
(22), and an increase in TNF-α has been shown to be counterbalanced by early expression of anti-inflammatory IL-10 
(51). Thus, strategies that could decrease postoperative IL-10 levels could be of interest to decrease postoperative 
infectious complications. Since maintaining MV should decrease postoperative immunosuppression, plasmatic IL-10 
levels should be lower in the ventilated group than in patients without MV during CPB. 
Lymphocytes: Lymphopenia has been associated with immune dysfunction during septic shock, and it has been 
shown that low absolute lymphocyte counts were predictive of postoperative sepsis (46, 47). In a recent retrospective 
study, Drewry et al. have demonstrated that persistent lymphopenia after sepsis predicted mortality and could be a 
valuable biomarker of immunosuppression because lymphopenia predicted an increased risk of secondary infection 
(48). 
Indoleamine 2,3-dioxygenase (IDO): IDO plays a pivotal role in immune tolerance (52). IDO catalyzes the first and 
limiting step of tryptophan catabolism, resulting in suppression of T cell proliferation in vitro and in vivo. In addition, 
the tryptophan-depleting activity of IDO affects the growth of several pathogens, so that IDO activation could have 
beneficial, as well as detrimental, consequences on host defenses against infections (53). 
mHLA-DR: The loss of HLA-DR expression on monocytes indicates their functional deactivation and is supposed to 
be a determining factor of the immunodeficiency. Several studies have found that decreased mHLA-DR has been 
shown to be predictive of both fatal outcome and septic complications after trauma, surgery, pancreatitis, burn and 
septic shock (20, 21). 
Myeloid-derived suppressor cells (MDSCs): MDSCs described in cancer and inflammatory processes are involved 
in sepsis-induced immune suppression and have been found to contribute to T-cell dysfunction in septic patients (54). 
We have demonstrated that postoperative proportion of MDSCs was subsequently significantly increased after cardiac 
surgery with CPB (1) 
Extracellular vesicles: EV are emerging as important “surrogate markers” of many diseases states as well as of 
physiologically less accessible tissues such as endothelial cells, liver, lungs or bone marrow. In the post cardiac 
surgery context a recent and promising literature described the vast implication of EVs in the inflammation, 
endothelial failure and immunosuppression development (55). These recent progresses in understanding the post 
cardiac surgery pathophysiology remain to be validated in clean clinical settings. 
PaO2/FiO2 ratio: The PaO2/FIO2 ratio is a commonly used indicator of lung function in critically ill patients, to 
define and characterize the severity of the acute respiratory distress syndrome (ARDS) and this ratio is still a central 
element of the new ARDS definition (Berlin definition). In addition, clinicians utilize this ratio to track change in lung 
conditions, to set positive end expiratory pressure (PEEP), to assess the response to different ventilatory strategies 
(56). 
 
E. Postoperative infections diagnosis 
Patients were examined daily by the clinical team for the presence of infection. Definitions of The diagnosis of a 
postoperative infection will be based on clinical, biochemical, or morphological features and confirmed (if possible) 
by bacteriological data according to CDC definitions for nosocomial infections (Appendix 7). Of note, an independent 
committee blinded to treatment group will ensure the classification of hospital-acquired infections. 
 

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Our different works suggest that maintaining MV during CPB for cardiac surgery decreases postoperative 
immune dysfunction and could be an interesting strategy to diminish the occurrence of postoperative 
nosocomial infection without hampering the surgical procedure. However, these findings have to be confirmed 
in a clinical trial using the incidence of nosocomial infection as an endpoint. This is the aim of this present study 
 
2.2 Summary of results of non-clinical trials and clinical trials available and relevant regarding the research 
involving the human person study concerned  
A. Summary of results of non-clinical trials and clinical trials available regarding CBP induced 
immunosuppression 
Several studies have found that CPB induced immunosuppression (1-6, 9-13, 19, 25, 28, 29, 32, 57).  
However, to our best knowledge, only one study have demonstrated that pharmacological approach could decreased 
CPB induced immunosuppression and decreased postoperative infection. In a prospective, randomized, double-blind, 
placebo-controlled study, Tepaske et al. aimed to ascertain whether this oral immune-enhancing nutritional 
supplement taken for at least 5 days before an operation in high-risk patients undergoing cardiac surgery improves 
preoperative host defense and subsequently reduces postoperative infections and organ dysfunction. They 
demonstrated that CPB decreased dramatically HLA-DR expression on monocytes in both group. However they found 
that concentration of interleukin 6 was significantly lower in the treatment group than in the control group. Authors 
concluded that intake of an oral immune enhancing nutritional supplement for 5 days preoperatively improves 
preoperative host defense, as expressed by improved delayed-type hypersensitivity response, increased number of 
HLA-DR epitopes, decreased concentrations of interleukin 6, reduced number of postoperative infections, and better 
preserved renal function. However, in the control group, patients received significantly higher levels of blood cell 
transfusions and presented a higher postoperative fluid balance, two major factors of postoperative immune 
dysfunction (5). 
 
B. Summary of results of non-clinical trials and clinical trials available regarding CBP induced pulmonary 
dysfunction 
Several ventilatory strategies have been suggested as beneficial when applied during CPB (15, 16, 34, 35). However, 
there is still a questionable impact on the long term clinical outcome in treated patients.  
The main results could be summarized as follow: 
1. Continued MV with PEEP during CPB improved postoperative PaO2/FiO2 ratio (1, 9). 
2. Continued MV with PEEP during CPB may decrease duration of MV after surgery (17). 
3. Continued MV with PEEP during CPB attenuated the postoperative systemic immune response (7, 17). 
4. Continued MV with PEEP during CPB attenuated the postoperative immunodepression (1). 
 
Of note, there is no recruiting or ongoing clinical trial studying CPB induced immunosuppression and 
mechanical ventilation registered to clinicaltrials.gov. 
 
2.3 Summary of benefits, if applicable, and of foreseeable and known risks for the person who is a Patient in 
the research study 
 
2.3.1Benefits 
2.3.1.1 Individual benefits 
Expected patient benefits are: 
- 
A significant decrease in the occurrence of postoperative infection. 
- 
A significant decrease in hospital length of stay. 
- 
A significant decrease in both postoperative mortality and morbidity. 
- 
A significant decrease in exposure to antibacterial agent which could be harmful (as clostridium difficile colitis). 
 
2.3.1.2 Collective benefits 
Since the menace of complete absence of effective antibiotics to treat problematic hospital acquired infections 
exists, our study will participate to the development of innovative treatment and prophylactic approaches. Thus, 
expected public health benefits (or collective benefits) are:   
- Clear benefits for public health since healthcare associated infections in hospitals impose significant economic 
consequences on the nation’s healthcare system. 
- A decrease in the emergence of resistant strains in surgery, hospital and general population since postoperative 
infections are responsible for antimicrobials prescription which is the single most important cause of the emergence of 
drug resistance, both in the community and hospital settings. 
 

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2.3.2Risks 
No specific risks (individual or collective) are likely to occur: 
- 
Maintaining MV during CPB did not hamper surgical procedure ; 
- 
Several studies have found benefits to maintain MV, mainly in biological parameters; however no study has 
demonstrated its impact on postoperative infections.  
 
2.3.2.1 Individual risks 
Physical risks and constraints 
Main constraints are blood withdrawn from patients. However, volume withdrawn will not induce any physical side 
effect. 
 
 Psychological risks and constraints 
The patients will not present any specific psychological risks or constraints associated with this study. The 
psychological risks to the patients included in this trial are the same as for any patient requiring cardiac surgery. 
 
Socio-economic risks and constraints 
The patients will not present any specific socio-economic risks or constraints associated with this study. The 
psychological risks to the patients included in this trial are the same as for any patient requiring cardiac surgery. 
 
2.3.2.2 Collective risks 
None. 
 
 
2.3.3Benefit / risk ratio 
Given the expected benefits and low specific risks, the benefit/risk ratio is highly favourable. 
 
2.4 Statement indicating that the study will be conducted in compliance with the protocol as well as with good 
clinical practices and legislative and regulatory conditions in force 
The sponsor and the investigator also agree that this study will be conducted: 
- 
in compliance with the protocol, 
- 
in compliance with local and international good clinical practice currently in force, 
- 
in compliance with legislative and regulatory conditions currently in force in participating countries. 
 
2.5 References to the scientific literature and to relevant data used as a reference for the study 
See appendix 2 
 
 
3 
STUDY OBJECTIVES 
3.1 Primary objective 
To measure the incidence of postoperative infections in 2 groups of patients: one group of patients ventilated and one 
group of patients without mechanical ventilation during cardiopulmonary bypass for cardiac surgery, and demonstrate 
that the incidence of postoperative infections is significantly lower in patients ventilated during CPB. 
 
3.2 Secondary objectives 
To demonstrate that, compared to patients without MV during CPB, maintaining MV will: 
- 
Decrease postoperative immunodepression (human leukocyte antigen-DR antigen (HLA-DR) expression on 
monocytes, Indoleamine 2,3-Dioxygenase (IDO) activity, plasmatic levels of IL-10 and proportion of myeloid-
derived suppressor cells (MDSCs)); 
- 
Decrease postoperative inflammation (plasmatic levels of IL-6 and quantity of extracellular vesicles (EV); 
- 
Decrease the occurrence of lymphopenia after surgery (defined as an absolute lymphocyte count less than 1.2 
cells/μL × 10.3); 
- 
Decrease postoperative exposure to antimicrobials treatment; 
- 
Decrease postoperative mortality; 
- 
Decrease postoperative length of stay; 
- 
Increase the PaO2/FiO2 ratio after surgery; 
- 
Decrease postoperative duration of MV. 
 
 
 
 

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4 
STUDY DESIGN 
4.1 Study evaluation criteria 
 
4.1.1Primary evaluation criteria 
Primary end point will be the incidence of postoperative infections (ie nosocomial infections) within 28 days 
following cardiac surgery. The diagnosis of a postoperative infection will be based on clinical, biochemical, or 
morphological features and confirmed (if possible) by bacteriological data according to CDC definitions for 
nosocomial infections (appendix 7). 
 
 
4.1.2Secondary evaluation criteria 
Immunomonitoring:  
- 
Postoperative expression of HLA-DR on peripheral monocytes at day 0, day 1 and day 7,  
Postoperative levels of IL-10 at day 0, day 1  and day 7,  
Postoperative indoleamine 2,3-Dioxygenase (IDO) activity at day 0, 1 and 7 
Postoperative proportion of MDSCs at day 0, day 1  and day 7; 
- 
Postoperative levels of IL-6 at day 0, day 1  and day 7, 
Postoperative quantity of EV at day 0 and day 1;  
- 
Postoperative lymphocytes count at day 0, 1 and 7;  
- Number of days of exposure to each antibiotic per 1000 inpatient days, defined as the number of days (>24 h) of 
continuous antibiotic treatment (from days 1 to 28); duration of antibiotic treatment; 
- Mortality within 28 days following surgery ;  
- Hospital length of stay (max 28 days) defined as the number of days before first hospital discharge; 
- PaO2/FiO2 ratio at day 0 and day 1; 
- Duration of MV (max 28 days). 
 
4.2Description of study methodology  
 
4.2.1Experimental design 
A prospective, multicenter, single-blind, randomized, parallel-group trial. 
 
 
4.2.2Conduct of study 
4.2.2.1. Screening phase 
During the day of the consultation with a cardiac surgeon, the patients fulfilling the inclusion criteria and after 
verification of the exclusion criteria, will be proposed to participate to the study. Informed consent will be obtained 
during the consultation. If necessary, after this information session the patient can reconsider his/her decision within a 
period of time.  
 
4.2.2.2. Inclusion phase  
The patients will be randomized the day of surgery before induction of anesthesia. 
Data collected at inclusion: The following data were collected: age, sex male, body mass index (BMI), EuroScore, 
type of surgery (isolated coronary artery bypass graft (CABG), single valve, surgery on multiple valve, CABG plus 
valve), coexisting medical conditions (Hypertension, diabetes mellitus, previous cerebrovascular event 
(stroke/transient ischemic attack), peripheral vascular disease, preoperative creatinine, chronic renal dysfunction), 
antibiotic prophylaxis. 
Description of surgery:  
- 
General anesthesia will be induced with propofol and sufentanil (or remifentanil) and will be followed by 
cisatracurium for muscular relaxation. Anesthesia, muscle relaxation, and analgesia will be respectively 
maintained with inhaled sevoflurane during off-pump surgery or propofol infusion during CPB and boluses of 
atracurium and sufentanil (or remifentanil). 
- 
For baseline ventilation, the patients will receive volume-controlled ventilation with a tidal volume of 6-8 mL/kg 
of predicted body weight and a ventilatory frequency of 10 to 15 per minute (end-tidal carbon dioxide between 34 
and 38 mmHg). Inspired oxygen fraction (FIO2) will be adjusted to ensure a peripheral oxygen saturation of > 
92%, inhalation-to-exhalation ratio will be 1:2, and the level of PEEP will be 5-7 cmH2O. 
- 
During CPB, two settings will be used depending on the study arm:  
o In the control group (MV- group):  absence of MV (and no PEEP) by disconnecting the tracheal tube 
from the ventilator; 
o In the MV + group: dead space ventilation using tidal volume of 2.5 mL/kg/pbw (predicted body 
weight) with 5-7 cmH2O PEEP. 
- 
After CPB, a recruitment maneuver will be performed. Recruitment maneuver consisted of applying a continuous 
positive airway pressure of 30 cm of water for 30 seconds, and then ventilatory parameters will be turned back to 

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baseline settings. All postoperative patients will be admitted to the intensive care unit (ICU) and will be ventilated 
with volume-controlled ventilation, VT=6-8 ml/Kg/pbw, FiO2 of 60% and PEEP of 5cmH2O. 
 
4.2.2.3. Follow-up 
Data collected after surgery: duration of procedure, duration of CPB, duration of aortic cross-clamping, antibiotics 
treatments, duration of MV, length of stay in ICU, hospital length of stay, mortality. 
Immunomonitoring parameters (HLA-DR expression, IL-10 and IL-6, lymphocytes count, Indoleamine 2,3-
Dioxygenase activity, MDSCs and EV) will be obtained after general anesthesia and before surgery (D0, at 24 hours 
(D1) and 7 days (D7) (except EV) after surgery.  
HLA-DR expression, IL-10, IL-6 and IDO activity will be measured in Rennes. 
Ratio of arterial oxygen tension (PaO2) to FIO2 will be obtained before surgery (D0) after induction of anesthesia and 
3 h after the end of CPB in the surgical intensive care unit (ICU; under baseline MV settings), and the day after 
surgery (D1). 
 
Occurrence of postoperative infections within 28 days following cardiac surgery will be monitored. An independent 
committee blinded to treatment group will ensure the classification of hospital-acquired infections. Antibiotics 
treatment, length of stay, duration of MV, mortality will be recorded within the first 28 days following surgery. 
 
 
 
Screening 
Phase 
Inclusion Phase (D0)  
Surgery 
D1 
D7 
D28 
Information document 
X 
 
 
 
 
Clinical Examination 
(check the selection criteria) 
X 
 
 
 
 
Written informed consent 
X 
Or X (later) 
 
 
 
Randomization  
 
X 
 
 
 
Patient characteristics and clinical data 
 
X 
 
 
 
Data surgery 
 
X 
 
 
 
HLA-DR* and MDSCs* 
 
X 
X 
X 
 
IL-10* 
 
X 
X 
X 
 
IL-6* 
 
X 
X 
X 
 
IDO activity* 
 
X 
X 
X 
 

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EV* 
 
X 
X 
 
 
Lymphocytes count 
 
X 
X 
X 
 
Pa02/Fi02 
 
X 
After induction of 
anesthesia and 3 h after 
the surgery 
X 
 
 
Nosocomial infections recording 
 
X 
Antibiotics treatment 
 
X 
Lenght of stay 
 
X 
Duration of MV 
 
X 
Mortality 
 
X 
Adverse events recording 
 
X 
* HLA-DR expression, MDSCs, EV, IL-10, IL-6 and IDO activity will be measured in Rennes. 
 
4.3 Description of the measures taken to reduce and prevent bias 
 
4.3.1Randomization 
Randomization will be stratified per centre. 
Randomization will be performed in the centres via a webinterface (Ennov Clinical, Ennov Group, Paris, France). A 
document to help use this tool will be provided to the investigators. 
 
 
4.3.2Methods of blinding  
This project is a randomized single-blinded (patient) trial. 
 
4.4 Expected duration of participation of persons and description of chronology and of duration of all study 
periods including monitoring, if applicable 
Recruitment period: 24 months 
Duration of patient monitoring: 28 days 
Duration of analysis of data: 6 months 
Estimated total duration of study: 31 months  
Starting with inclusion of the first patient, the sponsor has to inform without delay the local health agency and the 
ethics committee of the actual date of start-up of the study. The actual date of start-up = date of signature of consent 
form by the first person who is a Patient in the study. 
The date of end of the study will be transmitted by the sponsor to the ethics committee and to the local health agency 
within 90 days or earlier according to local regulations. The date of end of the study corresponds to the last visit of the 
last person who is a Patient in the study. 
 
4.5 Description of rules for permanent or temporary discontinuation  
 
4.5.1Discontinuation of participation of a person in study 
Patients can withdraw their consent and ask to withdraw from the study at any time and for whatever reason. If a 
Patient discontinues the study before its completion, the investigator must document the reasons as completely as 
possible.  
In fact, the investigator can temporarily or permanently discontinue the study treatment for any reason which is in the 
best interest of the Patient. 
If a Patient is lost to follow-up, the investigator will make every effort to resume contact with that person. 
 
 
4.5.2Discontinuation of part or of the entire study 
Unexpected events or new information pertaining to the study strategy, in light of which the study objectives or 
clinical programme probably would not be achieved, can lead the sponsor to terminate the study. 
In case of early permanent discontinuation of the study, the information will be sent by the sponsor within 15 days to 
the relevant country health agency and to the ethics committee or earlier according to local regulations. 
 
 
 
 
 

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5 
SCREENING AND INCLUSION OF PERSONS FROM THE STUDY 
5.1 Inclusion criteria 
- 
Age ≥ 18 years old;  
- 
Scheduled for any cardiac surgery (elective surgery) with cardio-pulmonary bypass, aortic clamp and 
cardioplegia, with median sternotomy and bi-pulmonary ventilation (cardiac valvular surgery (valve replacement 
or repair), coronary artery surgery, ascending aortic surgery and/or combined); 
- 
Written informed consent. 
 
5.2 Non-inclusion criteria  
- 
Emergency surgery ; 
- 
Planned thoracotomy with one lung ventilation ; 
- 
Patients with known respiratory diseases (current respiratory infections, asthma, chronic obstructive or restrictive 
pulmonary disease, obstructive apnea syndrome) ; 
- 
Patients already intubated in the peri-operative period ; 
- 
Immunodepression defined by proven humoral or cellular deficiency, by continuous administration of steroids at 
any dose for more than one month prior to hospitalization, high-dose steroids (> 15 mg / kg / day of 
methylprednisolone or Equivalent), radiotherapy or chemotherapy in the previous year ;  
- 
Need for vasopressor or inotropic agents before surgery ;  
- 
Any acute infection in the last month before surgery ;  
- 
Hematological disorder, autoimmune disease, immunodeficiency, immunosuppressive therapy ;  
- 
Heart failure with an left ventricular ejection fraction<35% ; 
- 
Protected person (adults legally protected (under judicial protection, guardianship, or supervision), person 
deprived of their liberty. 
 
5.3 Methods of recruitment 
Informed consent will be obtained the day of consultation for cardiac surgery or before randomization the day of 
surgery. 
 
 
6 
TREATMENTS ADMINISTERED IN THE STUDY 
6.1 Authorised treatments 
Besides immunosuppressive drugs listed below, every treatment are authorized during the study period.  
 
6.2 Unauthorised treatments 
Only immunosuppressive drugs within 7 days following cardiac surgery.  
 
6.3 Emergency treatment 
All emergency treatment required during anesthesia are allowed in the study. 
 
 
7 
EVALUATION OF SAFETY  
7.1 Definitions 
- 
Adverse event (AE): any untoward medical occurrence in a person who is a Patient in a research involving the 
human person study, whether or not this occurrence is related to the study. 
- 
Serious Adverse Event (SAE): Severity is defined as one of the following occurrences : 
. 
Death 
. 
A life-threatening condition 
. 
persistent or significant disability or incapacity 
. 
Hospitalisation 
. 
Prolongation of hospitalisation 
. 
Malformation/congenital anomaly 
. 
Potentially serious event (an adverse clinical event or a laboratory test result with a serious feature or 
considered as such by the investigator) 
- 
Adverse Reaction (ADR): any untoward and unintended reaction linked to the study.  
- 
Serious adverse reaction (SAR): a serious adverse event with a causal relationship to the study. 
- 
Unexpected adverse reaction: an adverse reaction whose type, severity, intensity or outcome does not agree with 
informations contained in the protocol. 

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- 
Causal relationship: relation between the AE and the study. An Adverse Event related to the the study will become 
an AR. 
7.2 Investigator’s role  
 
7.2.1Notification of serious adverse events 
Every serious adverse event related to the study strategy or not, expected or unexpected, expect those mentioned on 
the paragraph 7.2.3, must be reported within 24 hours by the investigator to the sponsor on a “Serious adverse event” 
form on which will be indicated the date of occurrence, criterion of severity, intensity, relationship with the strategy 
evaluated (or the study), and the outcome. 
It must be sent by fax to the number indicated on the form. The person in charge of Pharmacovigilance is Catherine 
Mouchel (phone: 02-99-28-91-96, e-mail: catherine.mouchel@chu-rennes.fr). 
The period in which serious adverse events should be reported begins from the day of the written informed consent to 
the last visit of the patient. 
The narrative must be completed and sent to the sponsor as soon as new relevant information is obtained. Copies of 
the patient’s medical record must be attached as well as results of laboratory tests. 
Whenever a serious adverse event persists at the end of the study, the investigator must follow the patient until the 
event is considered resolved. 
 
 
7.2.2Notification of non-serious adverse events 
All other Adverse Events, except those mentionned on the paragraph 7.1.3, will be reported on the “adverse event” 
page of the case report form specifying the date of occurrence, the description, severity, duration, method of 
resolution, causal relationship and the decisions made. 
 
 
7.2.3Protocol specific features 
The following events: postoperative infections will be recorded as primary evaluation criterion in the case report form 
and not as adverse events. Indeed, for this trial where efficacy endpoint can also be SUSARs, the integrity of the 
clinical trial may be compromised if the blind is systematically broken. Under these circumstances, the sponsor will 
treat postoperative infections as disease related and not subject to systematic unblinding and expedited reporting 
(Detailed guidance on the collection, verification and presentation of adverse event/reaction reports arising from 
clinical trials on medicinal products for human use (‘CT-3’) (2011/C 172/01) paragraph 7.11.1). As planned in the 
study, they will be analysed at the time of interim analyses (two interim analyses after inclusion of 1/3 and 2/3 of the 
patients) which will permit to show potential difference between the two groups during the study. 
 
7.3 Sponsor’s role 
 
7.3.1Analysis of serious adverse events 
The sponsor must evaluate the following: 
- 
the causal relationship of serious adverse events (all adverse events for which the investigator or the sponsor 
considers that a causal relationship with the strategy can be reasonably considered, are considered as suspected 
adverse reactions. If the sponsor’s evaluation of the event differs from the investigator’s, both opinions are 
mentioned in the statement sent to the competent authority if this statement is necessary), 
- 
and their expected or unexpected feature, using the reference document in force. 
 
 
7.3.2Scoring of causal relationship 
Conforming to the recommendations of ICH on the management of adverse events in clinical trials – ICH E2B (R3), 
version of May 12th, 2005 – an evaluation of the imputability is required for all declared SAE’s.  
 
 
7.3.3Declaration of unexpected serious adverse events 
The sponsor reports all suspected unexpected serious adverse reactions (SUSAR) to ANSM (Agence Nationale de 
Sécurité du Médicament et des produits de santé), and to investigators within the regulatory time periods for reporting: 
if seriousness is death or life-threatening, SUSARs must be notified immediately; for other type of seriousness, 
SUSARs must be notified within 15 days (follow-up will be sent within 8 days). 
 
 
7.3.4Transmission of annual safety reports 
On the anniversary date of the first consent, the sponsor writes a safety report containing: 
- 
the list of serious adverse events which may be related to the strategy studied, including expected and unexpected 
serious effects, 
- 
a succinct and critical analysis of safety of patients who are Patients in the study. 
It is sent to local regulatory agency and to the ethics committee within 60 days following the anniversary of the first 
consent. 
 

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7.3.5Declaration of other safety data 
Every safety finding that can alter the benefit/risk ratio of the strategy or changes in conduct of the trial must 
immediately be notified to the sponsor. The report form will be the subject of an immediate report to the competent 
authorities (ANSM) and the ethic committee. 
 
7.4 Expected adverse effects 
No adverse effects are expected since several clinical studies, using the same ventilator strategies did not describe AE.  
No specific risks (individual or collective) are likely to occur: 
- 
Maintaining MV during CPB did not hamper surgical procedure ; 
- 
Several studies have found benefits to maintain MV, mainly in biological parameters; however no study has 
demonstrated its impact on postoperative infections.  
Main constraints are blood withdrawn from patients. However, volume withdrawn will not induce any physical side 
effect. 
 
 
8 
STATISTICS 
Statistical analysis will be performed on all randomized and evaluated patients (intention to treat analysis). It will be 
performed with SAS software (SAS Institute, Cary, NC, USA) in the Methodology/Biometrics department of the 
Inserm 1414 Clinical Investigation Centre of Rennes (certified ISO 9001 for the methodology, management and 
analysis of clinical studies). 
 
8.1 Description of planned statistical methods, including schedule of planned interim analysis 
 
8.1.1Descriptive analysis 
A first overall descriptive analysis and analysis by group will be performed. This consists of separate estimates, 
numbers and percentages for qualitative variables, means, standard error, medians and interquartile intervals for 
quantitative variables. The normal feature of the distribution of quantitative variables will be checked (Shapiro test). 
 
 
8.1.2Comparison of groups at inclusion 
Student’s t test or a Mann-Whitney test if necessary will be used to compare quantitative variables, and a Chi² or 
Fisher’s exact test if necessary will be used to compare qualitative variables between two groups at inclusion. 
 
 
8.1.3Analysis of the primary criteria 
The primary endpoint (rate of nosocomial infection at day-28 after CPB) will be compared between the two groups 
with the Chi²test. 
Two interim analyses after inclusion of 1/3 and 2/3 of the patients, and one final analysis are planned. Stopping rules 
will use the alpha spending function with the O’Brien-Fleming boundary. The cumulative values of alpha for each 
analysis are: 0.00021 at the first analysis, 0.01202 at the second analysis and 0.04626 at the final analysis (nTerim, 
V1.1, Statistical solutions Ltd, Cork, Ireland). The trial will be stopped early if the significance of the Chi² test is 
below these alpha values. 
 
 
8.1.4Analysis of other criteria 
For the analysis of the other endpoints, the same strategy as for baseline comparisons will be used. 
In addition, censored endpoints (survival) will be compared using the log-rank test. 
Continuous endpoints repeatedly measured during the study will be compared using a repeated measure two-way 
(time, group) analysis of variance. 
For all these analyses, adjustments can be made in case of heterogeneity at inclusion. 
 
 
8.1.5Analysis of adverse events 
Possible adverse events are coded according to the MedDRA classification and are the patient of a descriptive 
analysis. 
 
8.2 Planned number of persons to be enrolled in the study, and planned number of persons in each centre with 
its statistical justification 
Our hypothesis is that 15% of the patients without MV during CPB (MV- group) will have post-operative infection at 
day 28. A total sample size of 1392 patients (696 per group) is required to achieve 80% power to detect a decrease in 
the rate of postoperative infection in patients with MV during CPB (MV+ group) to 10%, using a two-sided test with a 
type I error of 5% (nTerim, V4.0, Statistical solutions Ltd, Cork, Ireland), 1400 will be included to take into account 
potential non evaluable patients (death during surgery, lost to follow-up…). 
 

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8.3 Planned degree of statistical significance 
Except for the interim analyses described in chapter 8.1.3, a p value <0.05 will be considered as significant for all 
analyses. 
 
8.4 Method of management of missing, unused or invalid data 
Missing data will not be replaced. Mixed models can be used in analysis of repeated data. 
 
8.5 Choice of persons to include in the analysis 
This trial is an intention to treat study, that is all randomized and evaluated patients will be analysed. 
 
 
9 
RIGHT OF ACCESS TO DATA AND SOURCE DOCUMENTS 
9.1 Access to data 
In compliance with GCP: 
- 
the sponsor is in charge of obtaining the agreement of all parties involved in the study to ensure direct access to all 
sites of study conduct, source data, source documents and reports with the aim of quality control and of an audit 
by the sponsor, 
- 
investigators will make available to persons in charge of monitoring, of quality control or audit of the study 
documents and individual data which are strictly necessary for such checking, in compliance with legislative and 
regulatory conditions in force (articles L.1121-3 and R.5121-13 of the French public health code). 
 
9.2 Source documents  
Source data defined as all documents or original items which make it possible to demonstrate the existence or 
accuracy of data or of a finding recorded in the clinical study will be kept for 15 years by the investigator or by the 
hospital if it involves a hospital medical dossier. 
Source documents consist of a medical dossier, originals of laboratory test results, imaging examination reports, etc. 
 
9.3 Confidentiality of data 
In compliance with conditions concerning confidentiality of data to which persons in charge of quality control of the 
biomedical study have access (article L.1121-3 of the French public health code), in compliance with conditions 
pertaining to confidentiality of information in particular concerning the type of investigational medicinal products, the 
tests, persons who are Patients in the study and results obtained (article R. 5121-13 of the French public health code), 
persons having direct access will take all necessary precautions with the aim of ensuring confidentiality of information 
pertaining to the investigational medicinal products, tests, the persons who are patients in the study and in particular 
concerning their identity as well as that of results obtained. 
These persons, in the same capacity as the investigators themselves, are patient to professional secrecy (according to 
conditions defined by articles 226-13 and 226-14 of the French penal code). 
During the study or at its end, data collected on persons who are patients in the study and forwarded to the sponsor by 
the investigators (or all other specialised participants) will be made anonymous (deletion of Patients’ names). 
They must not in any event clearly reveal the names of the persons concerned or their address.  
Only the first letter of the surname and of the first name of the patient are recorded, together with the code number 
specific for the study indicating the order of inclusion of patients.  
The sponsor will make certain that each person who is a patient in the study has provided his or her written agreement 
for access to his/her personal individual data and strictly necessary for quality control of the study. 
 
 
10 
QUALITY CONTROL AND ASSURANCE 
A Clinical Research Associate (CRA) designated by the sponsor will ensure proper conduct of the study and the 
quality of data collected, in agreement with the Standard Operating Procedures applied in the CHU of Rennes and in 
compliance with Good Clinical Practice as well as legislative and regulatory conditions in force. 
The investigator and members of his team agree to make themselves available at Quality Control visits carried out at 
regular intervals by the Clinical Research Associate. At these visits the following items will be reviewed: 
- 
informed consent, 
- 
compliance with study protocol and procedures defined in it, 
- 
quality of data collected in the case report forms: accuracy, missing data, consistency of data with "source" 
documents (medical dossiers, appointment diaries, originals of laboratory test results, etc.). 
In addition, the investigators agree to be auditedby the sponsor as well as inspected by the competent authorities. All 
data, all documents and reports can be subject to audits and regulatory inspections without being opposed by medical 
secrecy. 

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11 
ETHICAL CONSIDERATIONS 
11.1 Regulatory and institutional review 
The protocol, information form and certificate of consent of the study will be submitted to the relevant independent 
ethics committee (IEC) for review. 
Notification of a favourable opinion from the IEC will be transmitted to the sponsor of the study and to the competent 
authority. An application for authorisation will be sent by the sponsor to local regulatory authority prior to start of 
study. 
 
11.2 Substantial changes 
In case of a substantial change made to the study protocol by the investigator, it will be approved by the sponsor. The 
latter must obtain prior to start of study a favourable opinion from the ethics committee and authorisation from the 
relevant health authority in the setting of their respective competence. Additional consent from persons participating 
in the study will be collected if necessary. 
 
11.3 Information for patients and written informed consent form 
Patients will be completely and truly informed in terms which are understandable to them of the objectives and 
constraints of the study, the possible risks incurred, measures of supervision and safety necessary, of their right to 
refuse to participate in the study or of the possibility of retracting their agreement at any time. 
All this information is contained in an information and consent form given to the patient. Free, informed and written 
consent from the patient will be collected by the investigator, or a doctor representing him prior to final inclusion in 
the study. A copy of the information and consent form signed by both parties will be given to the patient; the 
investigator will keep the original of it.  
 
11.4 Compensation of patients 
None. 
 
11.5 Registration in the national file of persons who are patients in research involving the human person 
None. 
 
 
12 
DATA PROCESSING AND RETENTION OF DOCUMENTS AND DATA 
12.1 Case report forms and data entry 
All information required by the study protocol must be recorded in the case report forms and an explanation must be 
provided for any missing data. Data must be collected progressively as obtained and recorded explicitly in the case 
report forms.  
An electronic case report form (e-CRF) will be made available and data entry will be completed in centres through a 
WEB interface (Clinsight software, Ennov, Paris (75), France). It solely requires an internet connection and a browser. 
An aid document for use of this tool will be provided to investigators. The interface between the CRA and the 
investigator thus will be promoted, making possible the collection and control of data at a distance. Tests of control of 
consistency of data will be incorporated in electronic format. An audit function is incorporated in the e-CRF thus 
making it possible to follow any change in study data. This function also makes it possible to clearly identify the 
person who made a change as well as the date. A justification possibly can be incorporated in comment. 
If requested, a paper copy will be printed at the end of the study, authenticated (dated and signed) by the investigator 
and a copy will be sent to the sponsor and archived. 
Data analysis will be carried out by statisticians of the Biostatistics Unit Department of Pharmacology of Rennes. 
 
12.2 CNIL 
This study falls within the scope of the “Methodology of Reference” (MR-001) established by the Commission 
Nationale Informatique et Liberté (CNIL). The CHU of Rennes, sponsor of the study, has signed an agreement of 
compliance with this “Methodology of Reference”. 
 
12.3 Archiving 
The following documents will be kept in the respective departments until the end of the period of practical utility. 
These documents are:  
- 
The study protocol and its Appendixes, and possible amendments, 
- 
The original signed informed information and consent forms, 
- 
Individual data (authenticated copies of raw data), 
- 
Monitoring documents, 
- 
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- 
The study final report. 
At the end of the period of practical utility, the documents will be archived by the sponsor for at least 15 years after 
the end of the study or its early discontinuation, in compliance with institutional practices. 
Archived documents cannot be moved or destroyed without agreement of the sponsor. All data, all documents and 
reports can be subject to an audit or inspection. 
 
 
13 
 INSURANCE 
The sponsor will take out, for the duration of the study, insurance covering the sponsors civil responsibility as well as 
that of all doctors involved in conduct of the study. They will also insure the total compensation of all harmful 
consequences of the study for persons who are Patients in it and their heirs, except when evidence is provided that the 
harm is not causally related to a fault of the sponsor or that of any participant, without it being possible to oppose the 
intervention of a third party or the voluntary withdrawal of a person who had initially consented to be participated in 
the study. 
 
 
14 
STUDY FEASIBILITY 
Two smaller scale studies (pilot studies) have been already conducted to test the plan and method of this research 
study with convincing results (Appendixes 4-5-6). 
Eligibility criteria and study design will not hinder enrollment expectations. With 7 centers (almost 10 000 CPB/years) 
enrollment goals will be achieved. 
There are no known open competing studies registered to clinicaltrials.gov (September 2016). 
Study plan does not conflict with currently accepted practice. 
Study has been found to be of great scientific interest among potential co-investigators in surgery, anesthesiology and 
intensivist. 
This study has been endorsed by the REVA network (Appendix 8). 
 
 
15 
RULES PERTAINING TO PUBLICATION 
Scientific presentations and reports corresponding to the study will be written under the responsibility of the 
coordinating investigator of the study with the agreement of the responsible investigators.  
First author: Jean-Marc Tadié 
Last author: Erwan Flecher 
The co-authors of the report and of publications will be the investigators and clinicians involved (cardiac surgeon and 
anaesthesiologist), on a pro rata basis of their contribution in the study, as well as the biostatistician and associated 
researchers.  
Rules on publication will follow international recommendations (N Engl J Med, 1997; 336:309-315). 
The study will be recorded on a freely accessible website (Clinical Trials) prior to inclusion of the first patient in the 
study. 
 
 
16 
LIST OF APPENDIX 
Appendix 1: List of investigators 
Appendix 2: References to the scientific literature 
Appendix 3: Lettre d’information et formulaire de consentement 
Appendix 4: Nitric Oxide cardiac surgery 
Appendix 5: Mechanical ventilation immunological effects 
Appendix 6: CPB induced lymphopenia 
Appendix 7: CDC Infections criteria 
Appendix 8: Endorsement REVA