Vieira F.Schreiber A.Docci M.Rodrigues A.Phoophiboon V.Subira C.Ko M.Sousa M.L.A.Pham T.Piraino T.Coudroy R.Cavalot G.Telias I.Junhasavasdikul D.Dres M.Sklar M.C.Brochard L.Mahidol University2026-06-052026-06-052026-01-01Annals of Intensive Care Vol.16 (2026)https://repository.li.mahidol.ac.th/handle/123456789/117097Background Evidence comparing high-flow nasal cannula (HFNC) and non-invasive ventilation (NIV) in acute hypercapnic respiratory failure remains controversial. We compared their short-term effects on breathing effort, ventilation, CO<inf>2</inf> clearance, and preference. Methods A randomized, crossover, non-inferiority trial was conducted in patients with stabilized hypercapnic exacerbation requiring NIV or HFNC. Baseline oxygen therapy was followed by a randomized sequence of NIV and HFNC at 30 and 50 L.min⁻¹. The primary endpoint was to assess non-inferiority of HFNC 50 L.min⁻¹ compared to NIV. Diaphragm, parasternal intercostal, and transversus abdominis muscle activity were assessed using thickening fraction (TF) and the product of TF and respiratory rate (TF•RR). Ventilation was evaluated using electrical impedance tomography and transcutaneous partial pressure of carbon dioxide (tcCO<inf>2</inf>). Results 21 patients (mean ± SD age 69 ± 11 years, 82% COPD) were enrolled. In 17, diaphragm thickening fraction (TFdi) was available: HFNC 50 L.min⁻¹ was non-inferior to NIV in reducing TFdi (p = 0.122, 95% CI: −19.1–3.4), as was HFNC at 30 L.min⁻¹ (p = 0.413, 95% CI: −17.0–5.7). Only HFNC 50 L.min⁻¹ reduced TFdi•RR (p = 0.036) and respiratory rate compared to baseline (p = 0.001). HFNC at 50 L.min⁻¹ decreased the baseline TFdi by 18% ± 36% (p = 0.033), whereas NIV did not decrease it. HFNC and NIV reduced tcCO₂ compared to baseline. Minute ventilation and the estimated ventilatory ratio were lower with HFNC than NIV (p < 0.01). HFNC was the preferred strategy by the patients. Conclusions In stabilized hypercapnic exacerbation, HFNC and NIV reduced tcCO₂, but only HFNC lowered ventilatory ratio and minute ventilation. HFNC at 50 L.min⁻¹ reduced diaphragm activity and was non-inferior to NIV in this regard, while being preferred by patients.MedicineArticleSCOPUS10.1016/j.aicoj.2026.1000922-s2.0-10504007168321105820