ECMO has emerged as a promising intervention that may provide more efficacious supportive care to patients with refractory severe acute respiratory distress syndrome (ARDS). The largest randomized trial of ECMO for severe forms of ARDS was recently published and demonstrated no significant benefit from early initiation of ECMO with respect to 60-day mortality, when compared with a strategy of conventional mechanical ventilation (MV) (ref EOLIA). However, a rescue ECMO option was used by 28% of the controls, which is likely to have diluted the potential positive effect of ECMO. One may argue that a less restrictive primary endpoint, such as death or rescue ECMO, would have yielded positive findings.

Meanwhile, improvements in technology have made ECMO safer and easier to use, allowing for the potential of more widespread application in patients with ARDS. VV-ECMO can be used as a life-saving rescue therapy in patients with ARDS when MV cannot maintain adequate oxygenation or CO2 elimination. Alternatively, VV-ECMO may be used in patients who remain hypoxemic during MV (i.e., PaO2/FiO2<80 mmHg) despite optimization of MV (including the application of high levels of positive end-expiratory pressure (PEEP), neuromuscular blockers, and prone positioning) and allow "lung rest" by lowering airway pressures and tidal volume to ameliorate ventilator-induced lung injury (VILI).

Prone positioning (PP) has been used for more than 30 years in patients with acute hypoxemic respiratory failure and in particular with ARDS. Initially, PP in ARDS patients was proposed as an efficient mean to improve oxygenation, sometimes dramatically, in a large number of patients. In addition, it is now clear, and data are still accumulating, that PP is also able to prevent VILI which is as important as maintaining safe gas exchange in mechanical ventilation. Therefore, PP is a strategy that covers the two major goals of ventilator support in ARDS patients, maintaining safe oxygenation and preventing VILI and reducing mortality at the end. This latter objective makes sense on ECMO as one of the main objective of this device is to markedly reduce VILI by resting the lung.

Considering that PP is a valuable and safe therapy to reduce VILI, its combination with ECMO could enhance VILI prevention. In recent preliminary studies, it was reported that the combination of VV-ECMO and PP was associated with a dramatic improvement in oxygenation, in pulmonary and thoracic compliance and in chest X-ray findings. It may thus facilitate the weaning of ECMO and can be performed without compromising the safety of the patients. Lung recruitment and improvement in ventilation/perfusion mismatch on prone position may both contribute to improve oxygenation. PP may therefore be efficient to hasten the weaning of VV-ECMO when atelectasis and ventilation/perfusion mismatch occur under ultra-protective ventilation even in patients in whom pre-ECMO PP failed. In addition, it could also enhance ventilator induced lung injury prevention on ECMO.

Inclusion Criteria:

1. Severe ARDS refractory to conventional therapy placed on VV-ECMO support in the preceding 48h.

2. Obtain informed consent from a close relative or surrogate. According to the specifications of emergency consent, randomization without the close relative or surrogate consent could be performed.

   Close relative/surrogate/family consent will be asked as soon as possible. The patient will be asked to give his/her consent for the continuation of the trial when his/her condition will allow.

3. Social security registration

Exclusion Criteria:

1. Age <18 and >75
2. Pregnancy and breastfeeding woman
3. Initiation of VV-ECMO >48 h
4. Resuscitation >10 minutes before ECMO
5. Irreversible neurological pathology
6. End-stage chronic lung disease
7. ARDS secondary to an abdominal surgery
8. Contraindications for PP
9. Irreversible ARDS with no hope for lung function recovery
10. Patient moribund on the day of randomization, SAPS II >90
11. Liver cirrhosis (Child B or C)
12. Chronic renal failure requiring hemodialysis
13. Lung transplantation
14. Burns on more than 20 % of the body surface