Despite best supportive care, mortality of the Acute Respiratory Distress Syndrom (ARDS) remains high. In the absence of specific treatments, providing safe and efficient mechanical ventilation (MV) is key to survival.

The use of low tidal volumes (VT) and plateau pressures (PPLAT) improves survival in randomized controlled trials (RCTs), but the safest VT to be applied for each patient remains unknown. Whether targeting low ∆P instead of a 6 mL/kg VT improves outcome has not been tested prospectively. The optimal method to set PEEP is also a matter of debate. As the amount of potentially recruitable lung vary widely among patients and is strongly associated with the response to PEEP, it may be necessary to tailor PEEP settings based on the response to a PEEP trial.

The first aim is to test a personalized approach to set PEEP widely supported by the literature. The first hypothesis is that i) patients with greater amounts of recruitable lung may benefit from higher PEEP levels, provided that attention is paid to maintain ∆P below 14 cmH2O, ii) setting PEEP based on results of a PEEP-responsiveness test improves survival as compared to low- and high-PEEP strategies applied independently of the patient response.

Apart from VT reduction and PPLAT control below 30 cmH2O, only 2 interventions demonstrated a reduction of mortality in large RCTs: a 48-hour continuous infusion of neuromuscular blocking agents (NMBAs) at the acute phase of ARDS6 and the use of prone positioning (PP). Whereas there is little doubt on the utility of PP in patients with PaO2/FiO2 ratio < 150 mmHg, there is more controversy on the impact of NMBAs on survival. Despite a strong rationale and a very widespread use in clinical practice, no current guidelines answer the question of the best timing of muscle relaxation in moderate to severe ARDS patients treated with PP.

As a second aim, the hypothesis is that the early systematic and combined use of NMBAs improved survival of patients with moderate to severe ARDS requiring prone positioning after optimization of PEEP settings.

Inclusion Criteria:

• Invasive mechanical ventilation within 96 hours of ICU admission and within 72 hours of tracheal intubation for first randomization and then within 72 hours of the first randomization for the second randomization

• Patients meeting the Berlin ARDS definition criteria with hypoxemia characterized as

  • for first randomization: PaO2/FiO2 ≤150 mmHg on a PEEP ≥5 cmH2O with FiO2≥0.6 while VT is 6 ml/kg Predicted Body Weight (PBW) and adequate sedation level to adjust mechanical ventilation settings
  • for second randomization: PaO2/FiO2 ≤150 mmHg on optimized ventilatory settings according to the first randomization, confirmed by two Arterial blood gas (ABG) analyses separated by an interval time of 4 hours and observed within 72 hours of the first randomization

• Informed consent signed:

  • by the patient
  • Or informed consent signed by a family members/trustworthy person if his condition does not allow him to express his consent by written as per L. 1111-6
  • Or in a situation urgently and in the absence of family members/trustworthy person, the patient can be enrolled. The consent to participate to the research will be requested as soon as the condition of the patient will allow him to consent.

• Health insurance coverage

Exclusion Criteria:

• Age < 18 years
• Known pregnancy or breastfeeding
• Participation in another interventional studies as long as these studies do not interfere with the primary endpoint and the secondary safety objectives of PEPER, or being in the exclusion period at the end of a previous study.
• Intracranial pressure > 30 mm Hg or cerebral perfusion pressure < 60 mmHg
• Severe chronic respiratory disease requiring long-term O2 therapy or home mechanical ventilation (except Continuous positive arway pressure (CPAP)/ Bilevel positive airway pressure (BIPAP) used for sleep apnea syndrome)
• Chronic interstitial lung disease
• Continuous neuromuscular blockade infusion at enrolment
• Previous hypersensitivity or anaphylactic reaction to any NMBA
• Neuromuscular disease that may potentiate neuromuscular blockade or impair spontaneous ventilation: amyotrophic lateral sclerosis, Guillain-Barré syndrome, myasthenia gravis, upper spinal injury at level C5 or above
• Patients on ECMO or any technique of extracorporeal CO2 removal
• Sickle cell disease
• Actual body weight >1 kg/cm of height
• Severe chronic liver disease defined as a Child-Pugh score of 12-15
• Pneumothorax at randomization
• Expected duration of mechanical ventilation <48 hours
• Simplified acute physiology score SAPS II score >75 at the time of enrolment or suffering from a disease with an estimated survival time of less than two months
• Decision to withhold life-sustaining treatment
• Patients deprived of freedom or under legal authority
• Unstable spine fracture

Medical team blinded for first randomization. The second randomization is open label.