The use of positive end-expiratory pressure (PEEP) has been shown to prevent the cycling end-expiratory collapse during mechanical ventilation and to maintain alveolar recruitment, keeping lung portions open, increasing the resting end-expiratory volume. On the other hand PEEP may also overdistend the already open lung, increasing stress and strain.

Theoretically high frequency oscillatory ventilation (HFOV) could be considered an ideal strategy in patients with ARDS for the small tidal volumes, but the expected benefits have not been shown yet.

PEEP and HFOV should be tailored on individual physiology. Assuming that the esophageal pressure is a good estimation of pleural pressure, transpulmonary pressure can be estimated by the difference between airway pressure and esophageal pressure (PL= Paw - Pes). A PL of 0 cmH2O at end-expiration should keep the airways open (even if distal zones are not certainly recruited) and a PL of 15 cmH2O should produce an overall increase of lung recruitment.

The investigators want to determine whether the prevention of atelectrauma by setting PEEP and mPaw to obtain 0 cmH2O of transpulmonary pressure at end expiratory volume is less injurious than lung recruitment limiting tidal overdistension by setting PEEP and mPaw at a threshold of 15 cmH2O of transpulmonary pressure.

The comparison between conventional ventilation with tidal volume of 6 ml/Kg and HFOV enables us to understand the role of different tidal volumes on preventing atelectrauma and inducing lung recruitment.

The use of non-invasive bedside techniques such as lung ultrasound, electrical impedance tomography, and transthoracic echocardiography are becoming necessary in ICU and may allow us to distinguish between lung recruitment and tidal overdistension at different PEEP/mPaw settings, in order to limit pulmonary and hemodynamic complications during CMV and HFOV.

The absolute value of esophageal pressure (Pes), measured during an end-expiratory pause can be considered a good surrogate for pleural pressure (Ppl), and the difference between airway pressure (Paw) and Pes a valid estimation of transpulmonary pressure (PL). Although this method has not been tested in large clinical trials yet, the utility of Pes in guiding therapy of ARDS has been shown in EPVent study.

Therefore, assuming that Pes is a good estimation of Ppl, PEEP and mPaw could be targeted to obtain different value of PL. A PL of 0 cmH2O at end-expiratory pause, should keep the airways open (even if distal zones are not certainly recruited) and a PL of 15 cmH2O at end-inspiratory pause should produce an overall increase of lung recruitment, limiting tidal overdistension. The comparison of these two different ventilatory settings allows us to determine whether the prevention of atelectrauma by setting PEEP and Paw of HFOV to obtain 0 cmH2O of transpulmonary pressure at end-expiratory occlusion is less injurious than lung recruitment limiting tidal overdistension by setting PEEP and mPaw at a threshold of 15 cmH2O of transpulmonary pressure.

The use of HFOV beside conventional ventilation, enables us to understand the role of these ventilatory strategies with different end-expiratory volumes, on preventing atelectrauma and inducing lung recruitment.

In addition the use of non-invasive bedside techniques as pleural and lung ultrasonography (PLUS), electrical impedance tomography (EIT), and transthoracic echocardiography (TTE) may allow us to distinguish between lung recruitment and tidal overdistension at different PEEP/mPaw settings, in order to limit pulmonary and hemodynamic complications during CMV and HFOV, and may help in the assessment of recruitable lungs.

Primary objective:

To determine whether the prevention of atelectrauma by setting PEEP (CMV) to obtain 0 cmH2O of transpulmonary pressure at end-expiratory occlusion and mPaw (HFOV) to obtain 0 cmH2O of mean transpulmonary pressure is less injurious than lung recruitment limiting tidal overdistension by setting PEEP (CMV) and mPaw (HFOV) at a threshold of 15 cmH2O of transpulmonary pressure. Plasma cytokines will be used to define the ventilator induced lung injury.

Secondary objectives:

1. To assess lung recruitment and tidal overdistension with bedside non-invasive methods such as EIT and PLUS during CMV and HFOV, with PEEP and mPaw set to obtain a PL of 0 and a PL of 15 cmH2O.
2. To assess if the impact of PEEP and HFOV set to obtain PL of 15 cmH2O is more dangerous for right ventricular function than PEEP to obtain PLEEO and PLHFOV of 0 cmH2O. TTE will be used to evaluate the heart function.

Study management:

For this pathophysiological study we will enroll 20 patients with moderate or severe ARDS, within 72 hours of arrival in our ICU.

1. All patients will be supine, with the head of the bed elevated to 30 degrees.

2. All patients will be deeply sedated and ventilated according to clinical practice.

3. Monitoring will be provided at least with:

   • Heart rate (HR) and cardiac rhythm.
   • Mean arterial pressure (MAP) monitored by invasive blood pressure via an arterial catheter.
   • Central venous pressure (CVP).
   • Transcutaneous O2 saturation by pulse oximetry (SpO2),
   • Airflow, airway pressure (Paw), tidal volume (Vt), end-tidal partial pressure of carbon dioxide (PETCO2)

4. Immediately before the initiation of the study, the patients will be subjected to neuromuscular blockade with a cisatracurium intravenous bolus and continuous infusion titrated to achieve 0-2/4 twitches on facial nerve electrical stimulation.

5. A nasogastric catheter with esophageal and gastric balloon will be placed. Esophageal pressure (Pes) will be measured during an end-inspiratory (PesEIO) and an end-expiratory occlusion (PesEEO) of the airway. The variation of esophageal pressure during tidal inflation (ΔPes) will be calculated as the difference between PesEIO and PesEEO. Transpulmonary pressure (PL) will be calculated as the difference between Paw and Pes (PL = Paw - Pes). The intragastric pressure will be measured only during an end-expiratory occlusion of the airway (IGP).

All study data will be transcribed directly on to standardized Case Report Forms (CRF).

Patients will be randomized to start the protocol with the controlled mechanical ventilation strategy or the high frequency oscillatory ventilation. A block-randomization scheme with opaque envelopes and block size of 2 will be used.

Study protocol:

Immediately after enrolment, Pes will be measured during an end-expiratory (PesEEO) and end-inspiratory occlusion (PesEIO). PEEP to reach a PLEEO of 0 cmH2O and PEEP to reach a PLEIO of 15 cmH2O will be calculated.

CMV phase A. PLEEO = 0

1. Patients will be ventilated with CMV using the following parameters (in group 2 before starting PesEEO and PesEIO will be measured):

   1. Vt 6 ml/kg predicted body weight
   2. PEEP so that PLEEO = 0 cmH2O
   3. Respiratory Rate (RR) to reach pH 7.25-7.35
   4. FiO2 to have SpO2 ≥ 90%

2. After 40 minutes at these settings, lung ultrasound will be performed to obtain a lung ultrasound score.

3. After completing PLUS, TTE will be performed

4. After completing TTE, EIT will be positioned and recordings of global and regional time courses of impedance changes and associated EIT images will be obtained

5. Blood sample for cytokines measurement will be collected and the following parameters will be measured:

   • Arterial blood gases
   • Crs
   • Alveolar dead space.

B. PLEIO = 15

1. Patients will be ventilated with the same Vt, RR and FiO2 of phase A. PEEP will be set at the value obtained to reach a PLEIO = 15 cmH2O.
2. Same measurements will be repeated as in phase A (steps 2 to 5).

C. PLEEO = 0

1. Patients will be ventilated with the same Vt, RR and FiO2 of previous phases. PEEP will be set at the same value of phase A (PEEP so that PLEEO = 0 cmH2O).
2. Same measurements will be repeated as in phase A (steps 2 to 5). PesEEO and PesEIO will be measured so that CMV phase is completed.

HFOV phase D. PL = 0

1. Patients will be switched to HFOV. Pes will be measured and mPaw to reach a PLHFOV of 0 and of 15 will be calculated. Patients will be ventilated using the following parameters:

   1. Pressure amplitude 90 cmH2O
   2. mPaw to reach a PL of 0 cmH2O
   3. Respiratory Rate (RR) ≥ 5Hz to reach pH 7.25-7.35
   4. FiO2 to have SpO2 ≥ 90%

2. Same measurements will be performed as in phase A (steps 2 to 4). Blood sample for cytokines measurement will be collected and the following parameters will be measured:

   • Arterial blood gases.

E. PL = 15

1. Patients will be ventilated with the same HFOV setting, except for mPaw, which will be set to reach a PL of 15 cmH2O.
2. Same measurements will be performed as in phase D.

F. PL = 0

1. Patients will be ventilated with the same HFOV setting, except for mPaw, which will be set to reach a PL of 0 cmH2O.
2. Same measurements will be performed as in phase D. Then Pes will be measured and HFOV phase is completed.

Inclusion Criteria:

• Moderate or severe ARDS, defined according to the Berlin definition (2);
• Endotracheal intubation or tracheostomy

Exclusion Criteria:

• Severe heart failure/cardiogenic shock;
• Pulmonary arterial hypertension requiring systemic vasodilators;
• Contraindications to esophageal balloon: esophageal pathology (stricture, perforation, high grade of varices), recent history of esophageal or gastric surgery, upper GI tract bleeding, severe coagulopathy and nasal trauma;
• Contraindications to Electrical Impedance Tomography (EIT): a temporary or permanent pacemaker, or implantable cardioverter-defibrillator (ICD);
• Age < 16 years.