Individualized Positive End-expiratory Pressure Guided by End-expiratory Lung Volume in the Acute Respiratory Distress Syndrome

Volume-control ventilation with tidal volume will be set at 6 mL/Kg of predicted body weight, respiratory rate to maintain pH\>7.30 and PaCO2\<50 mmHg and FiO2 will be set to achieve a SpO2\>88-95%. In case of hypercapnia with Ph\<7.30 despite a respiratory rate=30-35, an increase in tidal volume up to 8 ml/kg will be allowed. In both groups, the assigned ventilation protocol will be followed for a minimum of 72 hours from randomization and any time fully controlled ventilation is deemed necessary by the attending physician up to 14 days from randomization. After 14 days from randomization, PEEP will be set according to the clinical practice of each institution. After 72 hours from the study protocol, the PEEP setting protocol according to the assigned treatment will be resumed at any time within 14 days from enrolment if fully controlled ventilation is established, according to the decision of the attending physician in charge.

All patients will receive NMBA for 48 hours after the enrolment. The decision to stop NMBA administration after 48 hours will be left to the attending physician, but muscle paralysis will be strongly encouraged if PaO2/FiO2 ratio remains lower than 80-100 mmHg. NMBA administration will be resumed anytime deemed necessary by the attending physician.

Prone positioning will be used in all enrolled patients as a standard of care: the decision about the timing and the duration of prone position sessions will be left to the attending physician and the time spent by the patient in the prone and in the supine position will be recorded: PEEP will be re-set according to the protocol of the allocated treatment anytime patient's position is changed.

Assist/control and assist ventilation will be allowed after 72 hours from the enrolment if deemed appropriate by the attending physician. During spontaneous breathing, PEEP will be set according to the decision of the attending physician and the practice of each institution: however, in order to standardize the treatments, moderate PEEP (10-15 cmH2O) will be encouraged in case of moderate hypoxemia (PaO2/FiO2\<150 mmHg) in control group, while PEEP close to the value set during controlled ventilation according to the treatment protocol but \<15 cmH2O will be suggested in the intervention group. During assist/control and assisted ventilation, PEEP will never be higher than the last PEEP set according to the assigned protocol during controlled ventilation. Fully controlled mechanical ventilation will be resumed any time during the study period if the patient meets the criteria described above or any time deemed necessary by the physicians in charge

Recruitment maneuvers, extracorporeal membrane oxygenation (ECMO), extracorporeal CO2 removal (ECCO2-R) after randomization will be allowed in both groups as rescue therapies and according to the decision of attending physicians: any of these procedures will be accurately recorded on the case report form.

In order not to delay weaning from mechanical ventilation, when a patient is managed with assist/control or assist ventilation with PEEP higher than 8 cmH2O, a daily PEEP weaning trial will be performed whether PaO2/FIO2 ratio\>150 mm Hg and FIO2\<0.5: PEEP will be decreased to 8-5 cm H2O and arterial blood gas will be sampled after 20 -0 minutes. Previous ventilatory settings will be resumed if during the procedure transcutaneous oxyhemoglobin saturation decreases below 88%, PaO2/FIO2 falls below 150 mm Hg or if the patient experiences abnormal changes in respiratory rate or other clinical signs suggestive of respiratory distress. When PaO2/FIO2 is no lower than 200 mm Hg at PEEP≤8 cmH2O, the patient will be considered to have acceptable gas exchange on 8-5 cmH2O of PEEP and will be deemed capable to tolerate this setting

A 30-120-minute spontaneous breathing trial will be initiated as the following criteria are met and whether the patient tolerates fully assist ventilation with PEEP≤8 cmH2O for at least 4 hours without experiencing hypoxemia (SpO2\<88% or PaO2/FiO2\<150mmHg): * improvement or resolution of the underlying cause of acute respiratory failure * normal sensorium * correction of arterial hypoxemia (PaO2 ≥ 60 mmHg at a FiO2 ≤ 0.4 with PEEP ≤ 8 cmH2O); * absence of fever (≥ 38 °C) or sepsis; * blood hemoglobin concentration of 7 g/dL or more; * hemodynamic stability For the purpose of the study, success of the spontaneous breathing trial will be defined as presence of the following criteria: * respiratory rate \< 35/min, * arterial oxygen saturation ≥ 90%, * heart rate \< 120/min, * systolic blood pressure \> 90 and \< 160 mmHg * adequate cough. If the spontaneous breathing trial is successful, the patient will be extubated.

Each extubated patient will undergo oxygen therapy via high flow nasal cannula (maximum flows tolerated and FiO2 titrated to obtain 96%\>SpO2\>92%). Pre-emptive noninvasive ventilation (NIV) after extubation will be allowed in prolonged to wean patients (i.e. more than 3 SBT failure or more than 7 days from the first spontaneous breathing trial to being extubated) if deemed necessary by the physician in charge. In case of respiratory failure during oxygen therapy via high flow nasal cannula after extubation and, a rescue NIV trial will be allowed before intubation in both groups at the discretion of the attending physician.