Veno-arterial ExtraCorporeal Membrane Oxygenation to Reduce Morbidity and Mortality Following Lung TransPlant

Study Overview
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Brief Summary
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In patients undergoing lung transplantation (LT), the investigators hypothesize that a systematic intraoperative ECMO strategy would reduce the need for invasive mechanical ventilation in the first 28 days without increasing adverse events, as compared to an on-demand intraoperative ECMO strategy. To date, LT remains a highly hazardous procedure. Even if the surgical procedure is well established, the intraoperative support is not, and most intra-operative ECMO decisions rely on local protocols, anesthesiologists' habits, and surgeons' preference. The efficacy of applying a systematic strategy on reducing the occurrence of severe primary graft dysfunction and thus mechanical ventilation in the 28 days following LT, without increasing mortality or morbidity, would support future guidelines on the use of ECMO in the intraoperative period of LT for obstructive and restrictive lung diseases.

Detailed Description
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Lung transplantation (LT) provides the prospect of improved survival and quality of life for patients with end stage lung and pulmonary vascular diseases. Its performance carries significant adverse effects, being either intra- or postoperative. The ventilation of a diseased lung for sometimes extended periods and the risk of reperfusion oedema and primary graft dysfunction is a challenge. Moreover, significant hemodynamic instabilities episodes might occur, because of pressure on, or displacement of the heart, clamping of the pulmonary arteries and ischemia-reperfusion syndrome. veno-arterial extracorporeal membrane oxygenation (VA-ECMO) has now replaced cardiopulmonary bypass for respiratory and hemodynamic intraoperative support, carrying less side effects, and an improved early survival. Even though ECMO is a widely used technique, no precise guideline exists on the hemodynamic and respiratory indexes in LT settings to initiate intraoperative ECMO, but only experts' opinion. Besides, it has to be underlined that the rate of LT performed in the absence of any mechanical support is highly variable among centres, ranging from being exceptional up to 70%. The investigators aim at evaluating two strategies of ECMO initiation in the pre- and intraoperative periods in patients with pulmonary disease requiring LT: an on-demand strategy, in which VA-ECMO will be initiated on high hemodynamic and respiratory needs thresholds and a systematic strategy in which VA-ECMO will be pre-emptively initiated. The investigators hypothesize that a systematic strategy allows to reduce the risk of severe primary graft dysfunction and the need for mechanical ventilator in the 28 days following LT without increasing adverse events

Official Title
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Veno-arterial Extracorporeal Membrane Oxygenation to Reduce Morbidity and Mortality Following Lung Transplant: a Randomized Controlled Trial

Conditions
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The Number of Ventilator-free Days in the 28 Days Following LT

Intervention / Treatment
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* Procedure: Veno-arterial extracorporeal membrane oxygenation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years Assessed for bilateral sequential lung transplantation for obstructive or restrictive lung disease Affiliation to the French social security Written informed consent Exclusion Criteria: Preoperative severe pulmonary hypertension with hemodynamic collapse (severe dysfunction of the right ventricule - mPAP>30mmHg; Pulmonary vascular resistance>600 dyn.s.cm-5, and/or a ratio of mPAP/MAP above 50% with RV fractional area change <35%, RV ejection fraction< 20%, and/or RV myocardial performance index<0.50) LT for primary pulmonary hypertension LT for cystic fibrosis and graft-vs-host disease Re-do LT Combined multi-organ transplantation Active malignancy Pregnancy, breastfeeding Patients under guardianship (tutelle, curatelle, sauvegarde de justice)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Systematic ECMO<br>VA-ECMO will be implanted before the first pulmonary artery cross-clamp, in a systematic manner | Procedure: Veno-arterial extracorporeal membrane oxygenation<br>* Strategy would reduce the need for invasive mechanical ventilation in the first 28 days without increasing adverse events<br>|
| Active Comparator: On-demand ECMO<br>VA-ECMO will be implanted intraoperatively, in an unplanned manner if the hemodynamic and respiratory indices meet pre-planned criteria at different time-points: a PaO2/FiO2 ratio<100 mmHg or a respiratory acidosis, with pH< 7.2, PaCO2>60 mmHg, a mean pulmonary arterial pressure>50mmHg (or 2/3 of MAP) and/or an acute pulmonal core at trans-esophageal echography monitoring an acute left ventricular dysfunction at trans-esophageal echography monitoring | Procedure: Veno-arterial extracorporeal membrane oxygenation<br>* Strategy would reduce the need for invasive mechanical ventilation in the first 28 days without increasing adverse events<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The number of ventilator-free days | Assess the efficacy of a systematic, pre-operative VA-ECMO strategy on increasing ventilator-free days in the 28 days following LT | The 28 days following LT | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The occurrence of grade III PGD |  | The 72 hours following LT | 
| All-cause mortality |  | Day-90 after LT | 
| Vital status |  | Day-90 after LT | 
| Time-to-death from all causes |  | The first year after LT | 
| The occurrence of ECMO-associated adverse event ; ECMO-associated adverse event defined as cannula infection, misplacement, intra-operative or per-ECMO air-embolism, limb ischemia, vascular complications, thrombophlebitis |  | The 28 days following LT, Assessed daily from day-1 to day-90 | 
| The occurrence of ventilator associated pneumonia (VAP) ; Occurrence of VAP (microbiologically confirmed pneumonia occurring under invasive ventilation 21 and after 48 hours of invasive ventilation) |  | The 28 days following LT | 
| The occurrence of intraoperative hemodynamic failure; | Intra-operative amount of norepinephrine (dose in microg/kg of body weight) | The 28 days following LT | 
| The occurrence of post-operative hemodynamic failure ; | Norepinephrine-free days (number of days without noradrenaline administration) | The 28 days following LT | 
| The occurrence of acute renal failure; | Renal failure KDIGO stage 3 | The 28 days following LT | 
| The need of red blood cell transfusion | Number of red blood cell packs administered | The 28 days following LT | 
| ECMO-free days ; VV or VA-ECMO-free days |  | The 28 days following LT | 
| The length of intensive care unit stay | Length of ICU stay in days | at day 90 | 
| The length of hospital stay; Length of hospital stay in days |  | at day 90 | 
| The occurrence of bronchial complication requiring a bronchoscopic intervention ; Bronchial complications requiring a bronchoscopic intervention |  | From LT to 1-year | 
| Forced expiratory volume during the first second (FEV1) |  | At 1-year |