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Objective To estimate the feasibility and the efficacy of early extubation and sequential non-invasive mechanical ventilation (MV) in chronic obstructive pulmonary disease (COPD) with exacerbated hypercapnic respiratory failure.Methods Twenty-two intubated COPD patients with severe hypercapnic respiratory failure due to pulmonary infection (pneumonia or purulent bronchitis) were involved in the study. At the time of pulmonary infection control window (PIC window) appeared, when pulmonary infection had been significantly controlled (resolution of fever and decrease in purulent sputum, radiographic infiltrations, and leukocytosis) after the antibiotic and the comprehensive therapy, the early extubation was conducted and followed by non-invasive MV via facial mask immediately in 11 cases (study group). Other 11 COPD cases with similar clinical characteristics who continuously received invasive MV after PIC window were recruited as control group.Results All patients had similar clinical characteristics and gas exchange before treatment, as well as the initiating time and all indices at the time of the PIC window. For study group and control group, the duration of invasive MV was (7.1±2.9) vs (23.0±14.0) days, respectively, P<0.01. The total duration of ventilatory support was (13±7) vs (23±14) days, respectively, P<0.05. The incidence of ventilator associated pneumonia (VAP) were 0/11 vs 6/11, respectively, P<0.01. The duration of intensive care unit (ICU) stay was (13±7) vs (26±14) days, respectively, P<0.05. Conclusions In COPD patients requiring intubation and MV for pulmonary infection and hypercapnic respiratory failure, early extubation followed by non-invasive MV initiated at the point of PIC window significantly decreases the invasive and total durations of ventilatory support, the risk of VAP, and the duration of ICU stay.