• In-ICU mortality [ Time Frame: 90 days ]
  Mortality at ICU discharge
• In-Hospital mortality [ Time Frame: 90 days ]
  Mortality at hospital discharge
• 90-day mortality [ Time Frame: 90 days ]
  Mortality at 90 days from randomization
• 28-day Ventilator free days [ Time Frame: 28 days ]
  The days spent without ventilator assistance within 28 days from randomization
• 60-day Ventilator free days [ Time Frame: 28 days ]
  The days spent without ventilator assistance within 60 days from randomization
• Time to successful weaning [ Time Frame: 90 days ]
  The time from enrolment to successful liberation from mechanical ventilation
• Time spent on assisted ventilation after the enrolment [ Time Frame: 28 days ]
  The time spent on assisted ventilation on 28-day basis
• AUC IL-6 [ Time Frame: 72 hours ]
  Area under the curve (AUC) of serum interleukin 6 in the initial 72 hours of treatment
• AUC IL-8 [ Time Frame: 72 hours ]
  Area under the curve (AUC) of serum interleukin 8 in the initial 72 hours of treatment
• AUC TNF [ Time Frame: 72 hours ]
  Area under the curve (AUC) of serum tumor necrosis factor in the initial 72 hours of treatment
• Plateau pressure [ Time Frame: 72 hours ]
  Plateau pressure during the assigned treatment
• Total Lung stress-End-inspiratory transpulmonary pressure derived from elastance ratio [ Time Frame: 72 hours ]
  Total increase in transpulmonary pressure due to tidal volume and PEEP during the assigned treatment
• Static stress [ Time Frame: 72 hours ]
  Total increase in transpulmonary pressure due to PEEP during the assigned treatment
• Set PEEP [ Time Frame: 72 hours ]
  Set PEEP during the assigned treatment
• Set PEEP variability [ Time Frame: 72 hours ]
  Ratio of standard deviation to mean PEEP during the assigned treatment
• End-expiratory transpulmonary pressure [ Time Frame: 72 hours ]
  Directly measured end-expiratory transpulmonary pressure during the assigned treatment
• Dynamic stress-Transpulmonary driving pressure [ Time Frame: 72 hours ]
  Total increase in transpulmonary pressure due to tidal volume during the assigned treatment
• Respiratory system driving pressure [ Time Frame: 72 hours ]
  The difference between Plateau Pressure and total PEEP during the assigned treatment
• Respiratory system compliance [ Time Frame: 72 hours ]
  Ratio of tidal volume to respiratory system driving pressure during the assigned treatment
• Respiratory system compliance normalized to predicted body weight [ Time Frame: 72 hours ]
  Ratio of respiratory system compliance and predicted body weight during the assigned treatment
• Lung compliance [ Time Frame: 72 hours ]
  Ratio of tidal volume to transpulmonary driving pressure during the assigned treatment
• Dynamic strain [ Time Frame: 30 minutes ]
  Ratio of tidal volume to end-expiratory aerated volume (end-expiratory lung volume plus PEEP-induced alveolar recruitment) at study start
• Static strain [ Time Frame: 30 minutes ]
  Ratio of PEEP-induced overdistension volume to end-expiratory aerated volume (end-expiratory lung volume plus PEEP-induced alveolar recruitment) at study start
• Oxygenation [ Time Frame: 72 hours ]
  Ratio of PaO2 to FiO2 during the assigned treatment
• Oxygenation stretch index [ Time Frame: 72 hours ]
  Ratio of PaO2/FiO2 to respiratory system driving pressure during the assigned treatment
• Carbon dioxide [ Time Frame: 72 hours ]
  Arterial pressure of CO2 during the assigned treatment
• Heart rate [ Time Frame: 72 hours ]
  Heart rate during the assigned treatment
• Arterial pressure [ Time Frame: 72 hours ]
  Mean arterial pressure during the assigned treatment
• Simplified organ failure assessment [ Time Frame: 28 days ]
  Simplified organ failure assessment (SOFA) after randomization
• Catecholamine requirements per day [ Time Frame: 72 hours ]
  Catecholamin administration ad dosage during the assigned treatment
• Organ failure [ Time Frame: 28 days ]
  Organ failure free days on a 28-day basis, as defined by the simplified organ failure assessment (SOFA)
• Need for rescue recruitment maneuvers [ Time Frame: 72 hours ]
  The proportion of patients needing rescue recruitment maneuvers during the assigned treatment
• Nedd for rescue extra-corporeal membrane oxygenation [ Time Frame: 90 days ]
  The proportion of patients needing rescue extra-corporeal membrane oxygenation due to persistent hypoxemia
• Nedd for tracheostomy [ Time Frame: 90 days ]
  The proportion of patients needing tracheostomy to enhance the weaning process

During the acute respiratory distress syndrome (ARDS), patients' response to positive end-expiratory pressure (PEEP) is variable according to different degrees of lung recruitability. The search for a tool to individualize PEEP on the basis of patients' individual response is warranted.

Measurement of end-expiratory lung volume (EELV) by the nitrogen washin-washout technique, bedside available from recent ICU ventilators, has been shown to reliably estimate PEEP-induced alveolar recruitment and may therefore help titrate PEEP on patient's individual requirements.

The authors designed an open-label, multicenter, randomized trial to test whether an individualized PEEP setting protocol driven by EELV may improve a composite clinical outcome in patients with moderate-to-severe ARDS.

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.

Prespecified subgroup analysis will be conducted according to:

• [(Express PEEP EELV)-(EELV PEEP 5 cmH2O)]/Functional residual capacity (FRC) ≥ and < 73% during the PEEP trial
• Rec ≥ 19 ml/cmH2O and Rec < 19 ml/cmH2O across the range between the lowest and highest PEEP tested during the PEEP trial
• P/F ratio≥ and <100 mmHg at study inclusion
• IL-6≥ and <400 pg/ml at study inclusion

• Device: Invasive Mechanical ventilation

  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.

• Drug: Neuromuscular Blocking Agents
  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.
• Procedure: Prone positioning
  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.
• Procedure: Resume of spontaneous breathing

  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

• Procedure: Rescue treatments
  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.
• Procedure: Weaning from PEEP

  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

• Procedure: Weaning from mechanical ventilation

  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.
• Procedure: Extubation

  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.

• Experimental: IPERPEEP

  End expiratory lung volume (EELV) will be measured at each step during a 5-step decremental PEEP trial.

  Set PEEP will be ≥5 cmH2O and chosen to ensure the maximum recruitment, with a maximum plateau pressure of 30 cmH2O. Recruitment across two adjacent PEEP levels will be normalized to the changes in applied PEEP: Recruitment/cmH2O (Rec) will be computed as the ratio of recruitment and PEEP difference.

  • Rec ≥ 19 ml/cmH2O will lead to the higher PEEP value.
  • Rec< 7 ml/cmH2O will lead to lower PEEP value.
  • 19 ml/cmH2O >Rec≥7ml/cmH2O: the choice among two adjacent PEEP levels will be left to the attending physician.

  In patients with airway closure, no PEEP lower than airway opening pressure will be tested or used (due to interferences with EELV measurement) for the whole duration of treatment. A 5-step PEEP trial will re-assess EELV at different PEEP levels every 12-24 hours,after body position or ventilator settings changes.

  Interventions:

  • Device: Invasive Mechanical ventilation
  • Drug: Neuromuscular Blocking Agents
  • Procedure: Prone positioning
  • Procedure: Resume of spontaneous breathing
  • Procedure: Rescue treatments
  • Procedure: Weaning from PEEP
  • Procedure: Weaning from mechanical ventilation
  • Procedure: Extubation
• Active Comparator: EXPRESS
  PEEP set so that the plateau pressure is within the following limits: 28 cmH2O≤Pplat≤ 30 cmH2O
  Interventions:

  • Device: Invasive Mechanical ventilation
  • Drug: Neuromuscular Blocking Agents
  • Procedure: Prone positioning
  • Procedure: Resume of spontaneous breathing
  • Procedure: Rescue treatments
  • Procedure: Weaning from PEEP
  • Procedure: Weaning from mechanical ventilation
  • Procedure: Extubation

Eligibility inclusion criteria, according to the ARDS Berlin definition, will be assessed within the first 24 hours from the initiation of invasive mechanical ventilation:

1. Acute respiratory failure within 1 week of a known clinical insult or new or worsening respiratory symptoms;
2. Bilateral infiltrates at the chest x-ray or CT scan, not fully explained by effusions, lobar/lung collapse, or nodules;
3. Respiratory failure not fully explained by cardiac failure or fluid overload; objective assessment required to exclude hydrostatic edema if no risk factor present.
4. PaO2/FiO2 ratio≤150 mmHg after 30 mins - 1 hour of mechanical ventilation with PEEP=5 cmH2O.
5. Written informed consent.

Exclusion Criteria:

1. Pregnancy;
2. Pneumothorax;
3. Acute brain injury;
4. Clinical signs of history of decompensated heart failure (New York Heart Association class 3-4 before the acute phase of the disease or documented ejection fraction<35% or pulmonary capillary wedge pressure>18 mmHg) or acute coronary syndrome;
5. Intubation as a result of an acute exacerbation of chronic pulmonary disease: chronic obstructive pulmonary disease, asthma, cystic fibrosis, etc;
6. Clinically evident intrinsic PEEP (≥2 cmH2O) during screening visit (End-expiratory pause to achieve Flow=0);
7. BMI>35;
8. BMI<15 or body weight<35 Kg;
9. Any chronic disease requiring long-term oxygen therapy or mechanical ventilation at home;
10. Neuromuscular disease of any kind;
11. Severe chronic liver disease (Child-Pugh C or worse);
12. Bone marrow transplantation or chemotherapy-induced neutropenia;
13. History of liver or lung transplant;
14. Decision to withhold life-sustaining treatment;
15. Need for therapy with inhaled nitric oxide due to documented pulmonary arterial hypertension;
16. Life-threatening hypoxemia deemed to require extracorporeal membrane oxygenation (ECMO);
17. Presence of documented barotrauma;
18. High risk of mortality within 3 months from other than ARDS (severe neurological damage, age >85 years and cancer patients in terminal stages of the disease).
19. Persistent hemodynamic instability, intractable shock (norepinephrine>1 mcg/kg/h and/or blood lactate>5 mmol/L and/or considered too hemodynamically unstable for enrolment in the study by the patient's managing physician).
20. More than 24 hours from endotracheal intubation to the time of the screening visit.

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