Data comparing respiratory drive and effort in critically ill patients with acute respiratory distress syndrome associated to different severity of COVID-19 penumonia (CARDS) and to other risk factors are lacking. Objectives: To assess respiratory drive and effort of CARDS patients at the first transition from controlled to assisted spontaneous breathing. The second aim was the rate of a composite outcome including the need of higher level of sedation

Multicenter cohort study in four Italian ICU including adults with moderate and severe CARDS (PaO2/FiO2 <100 mmHg) at ICU admission. An historical cohort of patients with ARDS from various etiologies used for comparison. Respiratory drive (P0.1), diaphragm electrical activity (EAdi), inspiratory effort derived from EAdi (∆PmusEAdi) and from deflection in airway pressure occluded (ΔPocc) (PmusΔPocc), dynamic transpulmonary driving pressure (ΔPL,dyn, the difference between peak and end-expiratory transpulmonary pressure) measured under assisted ventilation.

The main ventilatory pattern variables:

• Airway Occlusion Pressure (P0.1): Measurement of the decrease in airway pressure during an end-expiratory occlusion.
• Pmus-EAdi-derived (∆Pmus, EAdi): Measurement of the pressure generated by the respiratory muscles during inspiration derived by electrical activity of the diaphragm measurements.
• Transpulmonary pressure EAdi-derived (∆Plung,dyn): difference between peak and end-expiratory transpulmonary pressure .
• Occlusive Pressure Difference (∆Pocc): Evaluation of the pressure difference between the initial and final airway opening during inspiration.
• Pmus-∆Pocc-derived (∆Pmus, ∆Pocc): Measurement of the pressure generated by the respiratory muscles during inspiration derived by ∆Pocc (∆Pocc*0.75)
• Transpulmonary driving pressure ∆Pocc derived (∆Plung, ∆Pocc): calculated as (Peak airway pressure -PEEP) - 2/3 * ∆Pocc
• Diaphragmatic Electrical Activity (EAdi): Recording of the electrical activity of the diaphragm.
• Peak EAdi (EAdiPEAK): Determination of the highest recorded value of diaphragmatic electrical activity.
• Pressure time product of the trans-diaphragmatic pressure per breath and per minute(PTP/min): the integral of Pmusc-EAdi-derived during inspiration per breath.
• Inspiratory Delay (ID): Assessment of the time delay between the start of neural inspiration and the onset of mechanical ventilation.
• Neuro-ventilatory Efficiency (NVE): Measurement of the efficiency of the neural drive to the respiratory muscles.
• Peak Airway Opening Pressure (PawPEAK): Measurement of the peak pressure in the airway during inspiration.
• Inspiratory Pressure-Time Product (PmusEAdi/b): Calculation of the work of breathing by integrating the product of diaphragmatic electrical activity and the change in airway pressure during inspiration.
• Tidal Volume (VT): Measurement of the volume of air inspired and expired during each breath.
• Respiratory Rate: Calculation of the number of breaths per minute delivered by the mechanical ventilator.
• Inspiratory and Expiratory Time (Ti,MECH and Te,MECH): Determination of the duration of mechanical inspiration and expiration.
• Inspiratory Duty Cycle (TI/TTOT-neur): Calculation of the ratio of inspiratory time to total respiratory cycle time based on neural inspiration.

Inclusion Criteria:

• Patients with a diagnosis of acute respiratory distress syndrome based on the Berlin criteria.
• Patients with ARDS due to confirmed COVID-19 through real-time RT-PCR on nasopharyngeal swabs or lower respiratory tract aspirates.
• Patients who had received invasive mechanical ventilation for more than 72 hours.
• Patients who were candidates for assisted ventilation.

Readiness for assisted ventilation, which was defined by the following criteria:

1. Improvement of the condition leading to acute respiratory failure.

2. Positive end-expiratory pressure lower than 10 cmH2O and inspiratory oxygen fraction lower than 0.5.

3. Richmond agitation sedation scale score between 0 and -3.

4. Ability to trigger the ventilator, i.e., decrease pressure airway opening by more than 3-4 cmH2O during a brief (5-10 seconds) end-expiratory occlusion test.

   • Hemodynamic stability without vasopressor or inotropes, except for dobutamine and norepinephrine infusion below certain thresholds (dobutamine <5 gamma/Kg/min and norepinephrine <0.3 gamma/Kg/min).
   • Normothermia.

Exclusion Criteria:

• Patients affected by neurological or neuromuscular pathology and/or known phrenic nerve dysfunction.
• Patients with any contraindication to the insertion of a nasogastric tube, such as recent upper gastrointestinal surgery or esophageal varices.
• Patients < 18 years old

Patients with diagnosis of acute respiratory distress syndrome due to confirmed (real-time RT-PCR on nasopharyngeal swabs, or lower respiratory tract aspirates) COVID-19 (CARDS), had received invasive mechanical ventilation for more than 72 hours and were candidates for assisted ventilation. The CARDS cohort divided into 'Moderate' and 'Severe' COVID groups according to P/F ratio at ICU admission.

A separate cohort of patients with ARDS by etiology different from COVID-19 (No-COVID), enrolled in previous studies and with the same inclusion and exclusion criteria.