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Assessing gas exchange, diaphragm function, respiratory rate, and patient comfort during high-flow oxygen therapy and standard oxygen at the time of noninvasive ventilation discontinuation.Randomized crossover physiologic study.Two ICUs.Thirty chronic obstructive pulmonary disease patients with hypercapnic acute respiratory failure receiving noninvasive ventilation greater than 24 hours.All patients underwent five 30-minute trials, the first, third, and fifth trial in noninvasive ventilation, whereas the second and fourth were randomly conducted with either standard oxygen and high-flow oxygen therapy.Diaphragm displacement and thickening fraction were determined by sonographic evaluation at the end of each trial. Arterial blood gases, respiratory rate, and patient comfort were also assessed. PaCO2 (p = 0.153) and pH (p = 0.114) were not different among trials, while PaO2 was greater in noninvasive ventilation than with both standard oxygen (p ≤ 0.005) and high-flow oxygen therapy (p ≤ 0.001). The diaphragm displacement was no different among trials (p = 0.875), while its thickening fraction was greater with standard oxygen, compared with high-flow oxygen therapy and all noninvasive ventilation trials (p < 0.001 for all comparisons), without differences between high-flow oxygen therapy and noninvasive ventilation. Respiratory rate also increased with standard oxygen, compared with both high-flow oxygen therapy (p < 0.001) and noninvasive ventilation (p < 0.01). High-flow oxygen therapy improved comfort, compared with standard oxygen (p = 0.004) and noninvasive ventilation (p < 0.001).At the time of noninvasive ventilation interruption, PaCO2 and diaphragm displacement remained unchanged regardless of the modality of oxygen administration. However, although standard oxygen resulted in a remarkable increase in diaphragm thickening fraction, high-flow oxygen therapy allowed maintaining it unchanged, while improving patient comfort.