The aim of this multicenter, randomized, controlled, open-label trial is to investigate the efficacy of early treatment with HFNO compared with SOT in preventing early deterioration of patients admitted to the ER because of acute hypoxemic respiratory failure.

Inclusion Criteria:

• Age ≥ 18 years;
• PaO2/FiO2 ratio between 250 and 150 mmHg or SpO2/FiO2 ratio between 190 and 274, after at least 15 minutes of spontaneous breathing through a Venturi mask (VM), with a FiO2 targeted at a SpO2 94-97%;
• Respiratory rate(RR)≤35breaths/min,afteratleast15minutesofspontaneous breathing through a VM, with a FiO2 targeted at a SpO2 94-97%;
• PaCO2 ≤ 45 mmHg;
• Unilateral or bilateral infiltrate(s), as detected with chest radiography and/or computed tomography and/or with lung ultrasound not fully explained by effusions, atelectasis, or nodules/masses. Infiltrates at lung ultrasound are defined as presence of focal B-lines, consolidations (with irregular marginal contour, air bronchogram, air trapping sign) and irregularity of the pleural line.

Exclusion Criteria:

• Respiratory failure due to:

  • Acute asthma or COPD exacerbation,
  • Cardiac failure or fluid overload as primary cause of respiratory failure;

• Unstable angina or ongoing acute myocardial infarction;

• Acute respiratory acidosis with pH < 7.35 and PaCO2 > 45 mmHg;

• Hemodynamic instability and/or use of vasopressors/inotropes;

• Altered mental status (Kelly >3), see Figure 1;(18)

• Contraindications to NIV (high risk of aspiration pneumonia, impaired airways protection, head-facial trauma and/or burns, uncooperative patient, cranial/thoracic/abdominal open wounds);

• Indications to urgent intubation performed according to the clinician in charge;

• Body Mass Index > 35 kg/m2;

• Pregnancy;

• Patient's refusal to participate.