IPERPEEPIndividualized Positive End-expiRatory Pressure Guided by End-Expiratory Lung Volume in Moderate-to-severe Acute resPiratory Distress Syndrome.The IPERPEEP Study

ARDS patients with a PaO2/FiO2 ratio equal or below 150 mmHg (during mechanical ventilation with PEEP 5 cmH2O) will be enrolled within 24 hours from endo-tracheal intubation. To standardize lung volumes at study initiation, all patients will undergo mechanical ventilation with tidal volume set at 6 ml/kg of predicted body weight and PEEP set to obtain a plateau pressure within 28 and 30 cmH2O for thirty minutes (Express PEEP). Afterwards, a 5-step decremental PEEP trial will be conducted (Express PEEP to PEEP 5 cmH2O), and EELV will be measured at each step. PEEP-induced alveolar recruitment will be calculated for each PEEP range as the difference between PEEP-induced change EELV and the predicted increase in lung volume due to PEEP (PEEP-induced overdistension, equal to the product of respiratory system compliance and PEEP change). Patients will be then randomized to receive mechanical ventilation with PEEP set according to the optimal recruitment observed in the PEEP trial (IPERPEEP arm) trial or according to the Express strategy (Control arm, PEEP set to achieve a plateau pressure of 28-30 cmH2O). In both groups, tidal volume size, the use of prone positioning and neuromuscular blocking agents will be standardized. Primary endpoint of the study is a composite clinical outcome incorporating in-ICU mortality, 60-day ventilator free days and the area under the curve of serum Interleukin 6 over the course of the initial 72 hours. Primary and secondary endpoints will also be analyzed in subgroups, as defined below: * ∆EELV5-16/FRC ≥ 73% \[18\] during the PEEP trial * ∆EELV5-16/FRC < 73%\[23\] during the PEEP trial * Recruitment-to-inflation ratio (RI) ≥ 1 and <1 across the range between the lowest and highest PEEP tested during the PEEP trial * P/F ratio<100 mmHg at study inclusion * IL-6>400 pg/ml at study inclusion