Assessment of the PEEP Responsiveness to Titrate End-expiratory Pressure and of the Need for Muscle Relaxation During Prone Positioning in Moderate-to-severe Acute Respiratory Distress Syndrome: A Master Protocol

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