Low tidal volume mechanical ventilation against no ventilation during cardiopulmonary bypass heart surgery (MECANO): study protocol for a randomized controlled trial
Nguyen et al. Trials
Low tidal volume mechanical ventilation against no ventilation during cardiopulmonary bypass heart surgery (MECANO): study protocol for a randomized controlled trial
Lee S. Nguyen 0 3
Messaouda Merzoug 0 3
Philippe Estagnasie 0 3
Alain Brusset 0 3
Jean-Dominique Law Koune 1
Stephane Aubert 2
Thierry Waldmann 2
Jean-Michel Grinda 2
Hadrien Gibert 1
Pierre Squara 0 3
0 Critical Care Medicine Department, CMC Ambroise Paré , 25-27 Boulevard Victor Hugo, 92200 Neuilly-sur-Seine , France
1 Anesthesiology Department, CMC Ambroise Paré , Neuilly-sur-Seine , France
2 Cardiac Surgery Department, CMC Ambroise Paré , Neuilly-sur-Seine , France
3 Critical Care Medicine Department, CMC Ambroise Paré , 25-27 Boulevard Victor Hugo, 92200 Neuilly-sur-Seine , France
Background: Postoperative pulmonary complications are a leading cause of morbidity and mortality after cardiac surgery. There are no recommendations on mechanical ventilation associated with cardiopulmonary bypass (CPB) during surgery and anesthesiologists perform either no ventilation (noV) at all during CPB or maintain low tidal volume (LTV) ventilation. Indirect evidence points towards better pulmonary outcomes when LTV is performed but no large-scale prospective trial has yet been published in cardiac surgery. 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. In total, 1500 patients are expected to be included, without any restrictions. 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 breaths/minute with a tidal volume of 3 mL/kg and positive end-expiratory pressure of 5 cmH2O. The primary endpoint will be a composite of all-cause mortality, early respiratory failure defined as a ratio of partial pressure of oxygen/fraction of inspired oxygen <200 mmHg at 1 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 pneumonia defined by the Center of Disease Control. Lung recruitment maneuvers will be performed in the noV and LTV groups at the end of surgery and at arrival in ICU with an insufflation at +30 cmH20 for 5 seconds. Secondary endpoints are those composing the primary endpoint with the addition of pneumothorax, CPB duration, quantity of postoperative bleeding, red blood cell 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. Discussion: The MECANO trial is the first of its kind to compare in a double-blind design, a no-ventilation to a lowtidal volume strategy for mechanical ventilation during cardiac surgery with CPB, with a primary composite outcome including death, respiratory failure and postoperative pneumonia. Trial registration: ClinicalTrials.gov, NCT03098524. Registered on 27 February 2017.
Cardiopulmonary bypass; Postoperative pulmonary complications; Protective ventilation; Low tidal volume
Ventilator-acquired pneumonia (VAP) is a common
postoperative complication and accounts for a large part
of post-cardiac surgery morbidity and mortality.
Incidence of VAP depends on numerous factors, including
pulmonary collapse and atelectasis during
cardiopulmonary bypass (CPB), lowering of bronchial arterial blood
flow and systemic inflammation response syndrome
during and after CPB [
To date, the impact of mechanical ventilation during
CPB is unknown. On the one hand, CPB allows blood
oxygenation during cardiac surgery, regardless of
heartbeat and oscillations, allowing the 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 [
A recent meta-analysis identified 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) [
maintaining mechanical ventilation may reduce the
inflammation response and tissue damage [
]. As the
design of previous studies did not include hard clinical
endpoints such as respiratory complications, death or
length of stay, there is as yet no evidence for an
unquestionable standardized strategy of lung protection during
CPB and there are no scientific recommendations on
whether mechanical ventilation has to be maintained
during cardiac surgery or not, notably between LTV
ventilation and noV . Last, the nature of the
intervention makes it hard for protocol investigators to blind the
investigators to the intervention, explaining why all trials
assessing mechanical ventilation are open-labeled [
The trial - low tidal mechanical ventilation against no
ventilation during cardiopulmonary bypass heart surgery
(“MECANO”) - aims to prove the superiority of the LTV
compared to the noV strategy during CPB in cardiac
surgery, to decrease postoperative respiratory
complications, assessed by hard clinical endpoints using a
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 (Fig. 1).
All patients aged more than 18 years and planned for
elective cardiac surgery with CPB are eligible.
Thoracoscopic surgery procedures are excluded. The inclusion
and exclusion criteria are shown in Table 1.
The primary endpoint is a composite of overall death, early
respiratory failure defined as partial pressure of oxygen
(PaO2)/fraction of inspired oxygen (FiO2) ratio <200 at
1 hour after arrival in the intensive care unit (ICU), heavy
oxygenation support (defined as a patient requiring either
non-invasive ventilation, mechanical ventilation, or
highflow oxygen) at 2 days after arrival in the ICU or VAP as
defined by the Center of Disease Control [
endpoints are those composing the primary endpoint with
the addition of pneumothorax, CPB duration, volume of
postoperative bleeding, red blood cell transfusions,
requirements for revision surgery, length of stay in the ICU and in
the hospital and total hospitalization costs. Patients are
followed until hospital discharge (Table 2).
Randomization is performed by the anesthesiologist in
charge upon the patient’s arrival in the operating room
using an external interactive web response system
(IWRS). A 1:1 treatment ratio with blocks of various
even size (to prohibit prior guessing of the allocation
group) is used. Thus, physicians outside the operating
room (i.e. study investigators) are not aware of the
treatment arm. Any deviation from the protocol is recorded,
as is the reason for deviation.
The noV group receives no ventilation during CPB. The
LTV group receives 5 breaths/minute with a tidal
volume of 3 mL/kg and positive end-expiratory pressure
(PEEP) of 5 cmH2O. Lung recruitment maneuvers are
performed in both groups at the end of surgery when
thorax is closed and on arrival in the ICU, with
insufflation at +30 cmH20 for 5 seconds. In the ICU, the
ventilation strategy is lung-protective: 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 therapeutic approaches
are left to the decision of the ICU intensivists.
All data are recorded on a dedicated online case report
form (CRF). Preoperative data are collected prior to surgery
(age, height, weight, EuroSCORE 2, smoking status,
diabetes mellitus, peripheral arterial disease, pulmonary
comorbidity, forced expiratory volume in one second,
pulmonary infection in the past 30 days and creatininemia).
Variables linked to the surgery are type of procedure,
duration of CPB (in minutes), number of red blood cell
transfusions and numbers of and reasons for manual
insufflation. Data collected on daily visits are systematically
recorded for 3 days, including temperature, PaO2, FiO2,
ventilation mode, hemoglobinemia, leucocytemia and
quantity of bleeding. Endpoints described earlier and time
to event are tracked throughout hospitalization with follow
up maintained until hospital discharge (Table 3).
Sample-size calculation is based on two-sided alpha
error of 0.05 and 80% power. Based on respiratory
insufficiency incidence after cardiac surgery, we anticipate that
at least 25% of patients will present with postoperative
respiratory complications. We expect a relative
improvement in the incidence of the primary outcome of
20% between the two arms (odds ratio 0.8 in favor of the
LTV arm as compared to the noV arm). The required
sample size is then 720 patients per group, 1440 patients
in total. Accounting for the attrition ratio, 1500 patients
will be included. Interim analyses will be performed. The
sample size will be recalculated after every analysis based
on the conditional probability of the final outcome.
Patients will be analyzed following the intention-to-treat
principle. Binomial regression eventually supplemented
by modified logistic regression (Diaz-Quijano, BMC
Medical Research Methodology 2012, 12:14) and survival
regression will be performed for statistical analysis.
Relative risks and hazard ratio with 95% confidence intervals
and differences between medians with 95% confidence
intervals will be calculated by bootstrapping (3000
iterations) when appropriate. Two-sided significance tests
will be used throughout. We will infer a subgroup effect
if the interaction term of treatment and subgroup is
statistically significant at P <0.05.
Ethical approval and clinical trial authorization
The trial is conducted in adherence to the current version
of the Helsinki Declaration, the French Law on Protection
Preoprative visit Before During Day
(D-1 or D-2 before surgery) anesthesia surgery 1
Follow Close out
of Personal Information and the National Health Law.
The Regional Ethics Committee has approved the study
protocol, which was also approved by the French Data
Protection Agency. The trial protocol is registered at
ClinicalTrials.gov (NCT03098524). Patients are enrolled only
after written informed consent has been obtained.
Postoperative pulmonary complications (PPCs) are
common and serious complications after cardiac surgery
], despite continuing improvements in CPB
techniques and postoperative intensive care. They are
broadly defined as conditions affecting the respiratory
tract that can significantly impact on patient outcomes
and health economics [
During CBP, the lungs are under perfused, non-ventilated
or supplied with low continuous ventilation, depending on
the center protocol [
]. Clinical trials have suggested that
preventive lung-protective ventilation may improve
outcomes in patients undergoing high-surgery [
The goal of the MECANO trial is to compare the effects
of no ventilation during CBP and LTV ventilation of 3
mL/kg with a PEEP of 5 cmH2O during CPB in cardiac
surgery. We believe that the present study has several
strengths. First, the number of patients to be included (n
= 1500) is ambitious. Several previous studies aimed to
prove the beneficial effect of protective ventilation in
cardiac surgery [
]. However, most trials were insufficiently
powered or biased, leading to high heterogeneity and lack
of conclusive results [
]. The CPBVENT trial
(NCT02090205) aims to answer a similar question.
Although multicenter by design, it is a single-blind study
and focuses on indirect outcomes (PaO2/FiO2 ratio only)
instead of harder clinical endpoints such as
hospitalacquired pneumonia or death. This explains why the
number of patients to be included in CPBVENT is smaller
(n = 720 vs. n = 1500 in our study). Moreover, CPBVENT
compares three ventilation strategies (no ventilation,
continuous positive airway pressure (CPAP) and LTV
ventilation), which may decrease the power of the study .
Finally, the inclusion criteria are stricter, decreasing the
possibility to generalize the results.
Second, the MECANO trial addresses observer bias by
using a double-blind design, with investigators only involved
in the post-surgery setting. As such, they are never aware of
the allocation arm of the included patients. Randomization
ensures equity and balance between the two treatment
strategies. In-hospital follow up allows for complete follow up of
all patients and is sufficiently pertinent, as postoperative
pulmonary complications are expected to happen within the
hospital stay after surgery. Third, data on all variables that
may account for the increased risk of postoperative
pulmonary complications are collected at baseline, ensuring
equivalence between the two treatment strategies.
Limitations of the MECANO trial include its single-center
design, although the number of physicians accounts for a
wide scope of practices, all in line with current guidelines.
Second, the surgeon has the final say in the type of
mechanical ventilation, i.e. he can stop any type of ventilation
strategy during CPB as he sees fit. This bias is addressed by
systematically collecting the reason for and number of times
that this may happen. Analyses will be performed on an
intention-to-treat and per-protocol basis. Moreover, this will
generally show how feasible or not, a maintained LTV
ventilation might be and guide clinical practice accordingly.
In conclusion, the MECANO trial should help determine
whether low-tidal ventilation is superior to no-ventilation,
during cardiac surgery with CPB. It is the first
doubleblind trial of this kind, with a large population and focusing
on hard clinical endpoints (Table 2, Additional file 1).
The first patients were randomized on 1 May 2017. The
inclusion of participants is ongoing and is expected to
continue until 15 April 2019.
Additional file 1: SPIRIT 2013 Checklist: Recommended items to address
in a clinical trial protocol and related documents. (DOCX 47 kb)
CPAP: Continuous positive airway pressure; CPB: Cardiopulmonary bypass;
CRF: Case report form; FiO2: Fraction of inspired oxygen; ICU: Intensive care
unit; LRM: Lung recruitment maneuvers; LTV: Low-tidal volume; noV: No
ventilation; PaO2: Partial pressure of oxygen; PEEP: Positive end-expiratory
pressure; PPCs: Post-operative pulmonary complications; VAP:
The authors thank Dr J-F Dreyfus for his statistical expertise and Mr S. Novak
for his contribution and energy in the development and deployment of the
Availability of data and materials
LSN participated in the conception and design of the study, wrote the study
protocol and designed the statistical analysis. MM participated in the writing
of the manuscript, drawing of figures, the collection of consent forms and
critical revision of the article. PE participated in the funding project, design
of the study, inclusion of patients and critical revision of the article. AB
participated in the funding project, design of the study, inclusion of patients
and critical revision of the article. J-DLK participated in the study design,
critical revision of the study protocol and application of the protocol. SA
participated in the revision of the study protocol, its application and critical
revision of the article. TW participated in the revision of the study protocol,
its application and critical revision of the article. J-MG participated in the
revision of the study protocol, its application and critical revision of the article.
HG participated in the study design, critical revision of the study protocol and
application of the protocol. PS participated in the funding project, design of the
study, inclusion of patients and critical revision of the article. All authors read
and approved the final manuscript.
Ethics approval and consent to participate
Institutional Review Board (Comité de Protection des Personnes) approval:
22 November 2016 (Hopital de Bicêtre, 78 rue du général Leclerc, 94275 Le
Kremlin Bicetre). Declared on ClinicalTrials.gov under NCT03098524. Every
patient was clearly informed and was required to sign to consent before
inclusion in the study.
Consent for publication
Approved by the co-authors.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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