This multicenter, cross-over study aims to investigate the effects of two different respiratory strategies, the use of high flow nasal cannula (NHF) and the use of home mechanic ventilation (HMV), both associated with standard oxygen therapy, in patients with COPD and persistent hypercapnia following a severe acute exacerbation.

The purpose is to evaluate whether the clinical benefits, in terms of reduction in PaCO2 levels, resulting from the use of NHF are non-inferior to those obtained from the use of HMV.

Partecipants will be randomized at 1:1 ratio into two groups:

group 1: will start the respiratory strategy under study (NHF + standard oxygen therapy) as first treatment group 2 will start the control respiratory strategy (HMV + standard oxygen therapy) as first treatment.

The study has a crossover design: each patient will undergo treatment with the two different respiratory strategies, NHF and HMV, each lasting for 3 months

This multicenter, cross-over study aims to investigate the effects of two different respiratory strategies, the use of high flow nasal cannula (NHF) and the use of home mechanic ventilation (HMV) both associated with standard oxygen therapy, in patients with COPD and persistent hypercapnia following a severe acute exacerbation. The purpose of this study is to evaluate whether the clinical benefits, in terms of reduction in PaCO2 levels, resulting from the use of NHF are non-inferior to those obtained from the use of HMV.

Patients will be randomly assigned through a simple randomization list, stratified by recruiting center, generated by the Stata statistical software. Based on this list, patients will be divided into two groups: group 1 will start as the first treatment with the respiratory strategy under study (NHF + standard oxygen therapy) and group 2 will start as the first treatment with the control respiratory strategy (HMV + standard oxygen therapy). Randomization will occur at a 1:1 ratio. The study has a crossover design; each patient will undergo treatment with the two different respiratory strategies, NHF and HMV, each lasting for 3 months. To minimize the carry-over effect, a washout period of 7 days between respiratory supports will be scheduled. Therefore, considering the washout period, the total treatment duration is 25 weeks.

Inclusion Criteria:

• Age ≥18 years
• Acquisition of informed consent form
• Patients with COPD
• Persistent hypercapnia (PaCO2 >53 mmHg) 2-4 weeks after an acute hypercapnic exacerbation of COPD requiring NIV.
• pH value >7.35.
• Chronic hypoxemia (PaO2 <55mmHg or <60mmHg if at least one of the following criteria is present: polycythemia, pulmonary hypertension or Chronic Pulmonary Heart Disease, >30% of sleep time with SpO2 < 90% measured with a pulse oximeter)

Exclusion Criteria:

• BMI >30 kg/m2
• Clinically significant obstructive sleep apnea syndrome (patients in whom there was a clinical suspicion of OSA syndrome based on clinical review or overnight oximetry will go further testing with limited respiratory polygraphy)
• Neuromuscular or chest wall diseases
• Need for intubation and invasive mechanical ventilation during exacerbation
• Use of home non-invasive mechanical ventilation or CPAP
• Contraindications for NIV
• Presence of cognitive impairment that would prevent informed consent into the trial
• Patients with active and unstable coronary artery syndrome
• Patients suffering from malignancies