Low Tidal MEChanical Ventilation Against NO Ventilation During Cardiopulmonary Bypass Heart Surgery

Study Overview
=================
Brief Summary
-----------------
BACKGROUND. Postoperative pulmonary complications are a leading cause of morbidity and mortality after cardiac surgery. To this date, there are no recommendations regarding mechanical ventilation associated with cardiopulmonary bypass (CPB) during the surgery and anesthesiologists perform either no ventilation (noV) at all during CPB or maintain a low-tidal volume ventilation (LTV). Indirect evidence points towards better pulmonary outcomes when LTV is performed but no proper prospective trial with large inclusion of all types of cardiac surgery has been published. DESIGN. The MECANO trial is a single-center, double-blind, randomized controlled trial comparing two mechanical ventilation strategies, noV and LTV, during cardiac surgery with CPB. 1500 patients will be included for whom planned cardiac surgery with CPB is performed. They will be randomized between noV and LTV, on a 1:1 ratio. The noV group will receive no ventilation during CPB. The LTV group will receive 5 acts/minute with a tidal volume of 3 mL/kg and positive end-expiratory pressure of 5 cmH2O. Primary endpoint will be composite of overall death, early respiratory failure defined as PaO2/FiO2 ratio <200 mmHg at one-hour after arrival in the ICU, heavy oxygenation support (defined as a patient requiring either non-invasive ventilation, mechanical ventilation or high flow oxygen) at 2 days after arrival in the ICU or ventilator acquired pneumoniae defined by Center of Disease Control. Lung recruitment manoeuvers will be performed for noV and LTV groups, at the end of surgery and at the arrival in ICU with an insufflation at +30 cmH20 during 5 seconds. Secondary endpoints are those composing the primary endpoint with the addition of pneumothorax, CPB duration, quantity of postoperative bleeding, red blood cells transfusions, revision surgery requirements, length of stay in the ICU and in the hospital and total hospitalization costs. Patients will be followed until hospital discharge. SUMMARY. The MECANO trial compares a no-ventilation to a low-tidal volume strategy for mechanical ventilation during cardiac surgery with CPB, regarding a primary composite outcome including death, respiratory failure and pneumoniae.

Detailed Description
-----------------
BACKGROUND. Ventilator-acquired pneumonia (VAP) are a common postoperative complication and account for a large part of post-cardiac surgery morbidity and mortality. Incidence of VAP depends on numerous factors, some of which are pulmonary collapsus and atelectasis during cardiopulmonary bypass, a lowering of bronchial arterial blood flow and a systemic inflammation response syndrome during and after cardiopulmonary bypass (CPB). On the one hand, CPB allows blood oxygenation during cardiac surgery, regardless of heartbeat and oscillations, allowing surgeon to operate without disturbance. On the other hand, postoperative pulmonary complications appear to be more frequent when no mechanical ventilation is maintained while under CPB. Recent meta-analysis found oxygenation improvement after the weaning from CPB when low-tidal-volume (LTV) ventilation was maintained or after lung recruitment maneuvers (LRM), as compared to when there was no ventilation (noV). Furthermore, maintaining mechanical ventilation would reduce the inflammation response and tissue damage. The design of these studies did not provide with clinical hard endpoints such as respiratory complications, death or length of stay, hence, an unquestionable standardized strategy of lung protection during CPB has not been evidenced at this time and there are no scientific recommendations on whether mechanical ventilation has to be maintained during cardiac surgery or not, notably between low-tidal volume ventilation (LTV) and no-ventilation (noV). The investigators aim to prove superiority of LTV over noV strategy during CPB in cardiac surgery, in order to decrease postoperative respiratory complications. DESIGN. The MECANO trial is a single-center, double-blind, non-pharmacological, randomized controlled trial comparing two mechanical ventilation strategies, LTV and noV, during cardiac surgery with CPB. Population. All patients aged more than 18 years will be eligible planned for cardiac surgery with CPB will be eligible. All patients will provide written informed consent before their inclusion in the trial. Endpoints. Primary endpoint will be composite of overall death, early respiratory failure defined as PaO2/FiO2 ratio <200 at one-hour after arrival in the ICU, heavy oxygenation support (defined as a patient requiring either non-invasive ventilation, mechanical ventilation or high flow oxygen) at 2 days after arrival in the ICU or ventilator acquired pneumoniae defined by Center of Disease Control. Secondary endpoints are those composing the primary endpoint with the addition of pneumothorax, CPB duration, volume of postoperative bleeding, red blood cells transfusions, requirements for revision surgery, length of stay in the ICU and in the hospital and total hospitalization costs. Patients will be followed until hospital discharge. Randomization. Patients will be randomized by the anesthesiologist when arriving in the operating room, between LTV and noV arm, on a 1:1 ratio, using a web software. Only the anesthesiologist will be aware of the allocation arm in order for him to perform the necessary ventilation strategy, however, physicians outside the operating room (hence, study investigators) will not be aware of the treatment arm. Any deviation from the protocol will be recorded, as will be the reason of deviation. Intervention. The noV group will receive no ventilation during CPB. The LTV group will receive 5 acts/minute with a tidal volume of 3 mL/kg and positive end-expiratory pressure of 5 cmH2O. Lung recruitment maneuvers will be performed in both groups, at the end of surgery, and at the arrival in ICU with insufflation at +30 cmH20 during 5 seconds. In ICU, ventilation strategy will be lung-protective with: tidal volume=6 ml/kg of ideal body weight, PEEP=5 cmH2O, FiO2 set to obtain PaO2 between 200 and 250 mmHg, inspiration/expiration time ratio = 1:2. Other therapeutics will be left to the appreciation of the critical care medicine specialist. Data collection. All data will be recorded on a dedicated CRF. Preoperative data will be collected prior to the surgery (age, height, weight, Euroscore 2, smoking status, diabetes, peripheral arterial disease, pulmonary comorbidity, forced expiratory volume in one second, pulmonary infection in the past 30 days, creatininemia). Variables linked to the surgery will be: type of surgery, duration of CPB, number of red blood cells transfusions, number and reasons of manual insufflations. Daily visit will record temperature, PaO2, FiO2, ventilation mode, hemoglobinemia, leucocytemia, quantity of bleeding and any of the endpoints listed above. Time to events will be recorded as well. Follow up will be maintained until hospital discharge. Statistical considerations Sample-size calculation was based on a two-sided alpha error of 0.05 and a 80% power. On the basis of respiratory insufficiency incidence after cardiac surgery, the investigators anticipate at least 25% of patients presenting postoperative respiratory complications. A relative improvement in the incidence of primary outcome of 20% between the 2 arms (odd-ratio 0.8 in favor of LTV arm as compared to noV arm) is expected. The required sample size is then 720 patients per group, 1440 patients in total. Accounting for attrition ratio, 1500 patients will be included. Intermediary analysis will be performed. Data analysis. Patients will be analyzed following intention to treat principle. Logistic regression will be performed for statistical analysis. Relative risks with 95% confidence intervals and differences between medians with 95% confidence intervals will be calculated when appropriate. Two-sided significance tests will be used throughout. The investigators will infer a subgroup effect if the interaction term of treatment and subgroup is statistically significant at P <0.05.

Official Title
-----------------
Low Tidal MEChanical Ventilation Against NO Ventilation During Cardiopulmonary Bypass Heart Surgery : a Randomized Controlled Trial

Conditions
-----------------
Respiratory Failure, Atelectasis, Pneumonia, Pneumothorax, Bleeding, Surgery--Complications, Cardiac Disease

Intervention / Treatment
-----------------
* Procedure: Low tidal volume ventilation (LTV arm)
* Procedure: No ventilation (noV arm)
* Procedure: Lung recruitment manoeuver


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion: more than 18 years old ability to provide an informed consent planned surgery surgical intervention with cardio-pulmonary bypass, aortic clamp and cardioplegia. Exclusion: impossibility to wean CPB at the end of cardiac surgery

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Low tidal volume ventilation (LTV arm)<br>During cardiopulmonary bypass, mechanical ventilation is maintained with 5 acts/minute, tidal volume = 3 ml/kg (ideal body weight) with positive end-expiratory pressure = 5 cmH2O | Procedure: Low tidal volume ventilation (LTV arm)<br>* During cardiopulmonary bypass, mechanical ventilation is maintained with settings described above.<br>Procedure: Lung recruitment manoeuver<br>* An insufflation with positive end-expiratory pressure +30 cmH20 during 5 seconds. At the end of cardiopulmonary bypass, in the operative room. And after transfer to the ICU (intensive care unit).<br>|
| Placebo Comparator: No ventilation (noV arm)<br>No mechanical ventilation during cardiopulmonary bypass. | Procedure: No ventilation (noV arm)<br>* During cardiopulmonary bypass, no mechanical ventilation is performed.<br>Procedure: Lung recruitment manoeuver<br>* An insufflation with positive end-expiratory pressure +30 cmH20 during 5 seconds. At the end of cardiopulmonary bypass, in the operative room. And after transfer to the ICU (intensive care unit).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause mortality or early respiratory failure or Late respiratory failure or Ventilator acquired pneumonia and early pneumonia | Composite outcome with all-cause in-hospital mortality, early respiratory failure defined as PaO2/FiO2 ratio <200 at the first hour after transfer in ICU after surgery, late respiratory failure defined as heavy oxygenation support (non-invasive ventilation, high flow oxygen or mechanical ventilation) two days after surgery and pneumonia (early or ventilator acquired) defined by Center of Disease Control (CDC) criteria (2016 guidelines). | From date of randomization until the date of first documented event or date of death from any cause, whichever came first, assessed up to 24 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| All-cause in-hospital mortality | All-cause in-hospital mortality | From date of randomization until date of death from any cause, assessed up to 24 months. | 
| Early respiratory failure | PaO2/FiO2 ratio <200 at the first hour after transfer in ICU after surgery | Assessed at one hour after transfer in postoperative ICU | 
| heavy oxygenation support | requirement of non-invasive ventilation, high flow oxygen or mechanical ventilation | Assessed 2 days after surgery | 
| Pneumonia (early or ventilator-acquired) | pneumonia (early or ventilator acquired) defined by Center of Disease Control (CDC) criteria (2016 guidelines), diagnosed while in-hospital after the cardiac surgery. | From date of randomization until the date of first documented event, assessed up to 24 months. | 
| Length of stay in the ICU | Length of stay in the intensive care unit (ICU) (days) after the initial cardiac surgery | Assessed at the end of hospitalization, through study completion, assessed up to 24 months. | 
| Length of stay in the hospital | Length of stay in the hospital (days) after the initial cardiac surgery | Assessed at the end of hospitalization, through study completion, assessed up to 24 months. | 
| Cost of hospitalization | Cost of hospitalization (euros) | Assessed at the end of hospitalization, through study completion, assessed up to 24 months. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Cardiac surgery, Mechanical ventilation, Cardiopulmonary bypass, Atelectasis, Pneumonia