Right ventricular failure may be associated with mortality in patients with acute respiratory distress syndrome (ARDS). Mechanical ventilation may promote right ventricular failure by inducing alveolar overdistention and atelectasis. Electrical impedance tomography (EIT) is a bedside non-invasive technique assessing the regional distribution of lung ventilation, thus helping titrating positive end-expiratory pressure (PEEP) to target the minimum levels of alveolar overdistension and atelectasis. The aim of this physiologic randomized crossover trial is to assess right ventricular size and function with transthoracic echocardiography with different levels of PEEP in adult patients with moderate-to-severe ARDS undergoing controlled invasive mechanical ventilation: the level of PEEP determined according to the ARDS Network low PEEP-FiO2 table, the PEEP value that minimizes the risk of alveolar overdistension and atelectasis (as determined by EIT), the highest PEEP value minimizing the risk of alveolar overdistension (as determined by EIT), and the lowest PEEP level that minimizes the risk of alveolar atelectasis (as determined by EIT). Our findings may offer valuable insights into the level of PEEP favoring right ventricular protection during mechanical ventilation in patients with ARDS.

Acute respiratory distress syndrome (ARDS) is a diffuse pulmonary inflammatory disease with multifactorial etiology that is very common in patients admitted to the intensive care unit (ICU) and is associated with unsatisfactory short- and long-term prognosis. Patients with ARDS can develop right ventricular (RV) failure, which occurs in 22-50% of patients despite lung protective ventilation and is associated with increased mortality. Despite being required to ensure survival of patients with ARDS, mechanical ventilation itself may have injurious effects on RV function. First, high transpulmonary pressure, secondary to the use of high tidal volume, plateau pressure or positive end-expiratory pressure (PEEP), can cause alveolar overdistension, especially in the aerated parenchymal regions, and collapse of alveolar vessels. The consequent increase in pulmonary arterial pressure may lead to excessively high RV afterload and reduced systolic function. Second, the development of parenchymal atelectasis potentially secondary to the application of low tidal volumes and/or PEEP may increase pulmonary vascular resistance because of extra-alveolar vascular collapse. Finally, mechanical ventilation can have indirect effects on pulmonary circulation and RV function, mediated by alveolar oxygenation, acidosis, and hypercapnia.

The application of PEEP can prevent cyclic opening and closing of the alveoli (i.e., atelectrauma) and improve oxygenation. Ideally, PEEP should maintain lung recruitment and optimize oxygenation and dead space, while at the same time avoiding alveolar overdistension and hemodynamic complications. However, the PEEP titration strategy in patients with ARDS is still widely debated, due to the variability of the effects of PEEP in different patients and different lung parenchymal regions in the same patient. Depending on the extent of potentially recruitable lung parenchyma and the distribution of lung damage, the application of PEEP can cause alveolar overdistension and promote RV failure and/or favor alveolar recruitment and improve RV function. Therefore, it is stil unclear what level of PEEP is associated with the optimization of RV function in patients with ARDS. We may hypothesize that the level of PEEP able to reduce alveolar collapse without increasing overdistension may improve RV function.

Several strategies have been suggested to assess lung recruitability and PEEP responsiveness in patients with ARDS. Electrical impedance tomography (EIT) is a bedside non-invasive technique that monitors the regional distribution of lung ventilation. The choice of the PEEP value that minimizes the extent of overdistension and atelectasis, as assessed with EIT, was associated with better respiratory mechanics and survival in patients with severe ARDS in some pilot studies.

The aim of this prospective pathophysiological interventional study is to evaluate the variation of RV size and function with transthoracic echocardiography in adult patients requiring invasive controlled mechanical ventilation for moderate-to-severe ARDS with four different PEEP values applied according to a randomized sequence in each patient:

• The level of PEEP determined according to the ARDS Network low PEEP-fraction of inspired oxygen (FiO2) table;
• The PEEP value that minimizes the risk of overdistension and atelectasis, as determined by EIT;
• The highest PEEP value that minimizes the risk of overdistension, as determined by EIT;
• The lowest PEEP level that minimizes the risk of atelectasis, as determined by EIT.

The primary hypothesis of the study is that the level of PEEP that simultaneously minimizes alveolar overdistension and collapse is associated with better RV function than the PEEP level selected based on the low PEEP-FiO2 table and PEEP levels that minimize overdistension and collapse, separately. The secondary hypotheses of the study are that: 1) the level of PEEP that minimizes overdistension is associated with better RV function than the level of PEEP that minimizes collapse; 2) the PEEP level that minimizes alveolar collapse is associated with greater pulmonary air content, as assessed by lung ultrasound, compared to the PEEP levels chosen based on the low PEEP-FiO2 table, the PEEP level that minimizes overdistension and collapse simultaneously, and the PEEP level that minimizes overdistension.

The physiological data obtained from this study may offer valuable insights into the right ventricular-protective level of PEEP in patients with ARDS and support future large randomized studies investigating PEEP levels associated with improved patient survival.

Inclusion criteria:

1. Moderate to severe acute respiratory distress syndrome
2. Inclusion within 72 hours of acute respiratory distress syndrome diagnosis
3. Endotracheal intubation or tracheostomy

Exclusion criteria:

1. Age lower than 18 years old
2. Pregnancy
3. Absence of informed consent
4. Thoracic surgery or lung transplant during the admission
5. Contraindications to recruitment maneuvers (mean arterial pressure lower than 65 mmHg despite administration of fluids or vasopressors, active air leaks through a chest tube, pneumothorax or subcutaneous or mediastinal emphysema in absence of chest drainage)
6. Contraindications to electrical impedance tomography (contraindication to recruitment maneuvers, presence of pacemakers or other electronic devices in the chest, injuries or burns in the electrode placement area)
7. ACEP quality < 4

Being sedated and paralyzed, included patients will not be aware of the study phase.

The investigators performing the echocardiographic exams will be blinded to the experimental setting because the PEEP level set at the ventilator will be covered.

The echocardiographic measurement will be performed offline with no information on the experimental settings.