Background: Acute hypoxemic respiratory failure (AHRF) remains a major cause of critical care admission, with timely selection of respiratory support crucial for reducing morbidity and mortality. High-flow nasal cannula (HFNC) therapy has emerged as an effective alternative to conventional oxygen therapy and non-invasive ventilation; however, real-world evidence from Indian clinical settings remains limited. This study evaluated the efficacy of HFNC in AHRF and identified predictors of treatment success and failure.

Methods: This prospective observational study included 296 adult patients with AHRF managed with HFNC in a tertiary care ICU. Baseline demographic and clinical variables, oxygenation indices, early physiological responses (including ROX index at 1 and 6 hours), and HFNC settings were recorded. Patients were categorized into HFNC success (no escalation to invasive mechanical ventilation) and HFNC failure (required intubation). Outcomes included ICU length of stay, ventilator days, and hospital mortality. Statistical comparisons were performed using appropriate parametric and non-parametric tests, with p < 0.05 considered significant.

Results: HFNC was successful in 184 patients (62.2%) and failed in 112 (37.8%). Failure was associated with older age (61.1 ± 13.7 vs. 57.7 ± 11.4 years; p = 0.003), male predominance (81.3% vs. 58.7%; p < 0.001), and a higher prevalence of ARDS (22.3% vs. 12.5%; p = 0.008). Baseline severity indicators—including lower PaO₂/FiO₂ ratio (152.6 ± 51.3 vs. 181.4 ± 42.4; p < 0.001), higher respiratory rate, and higher SOFA scores—were significantly associated with HFNC failure. Early physiological response strongly predicted outcomes: ROX index values at 1 and 6 hours and 24-hour improvement in oxygenation were significantly higher in the success group (p < 0.001 for all). HFNC failure resulted in longer ICU stay (10.5 vs. 5.1 days; p < 0.001) and higher hospital mortality (28.6% vs. 8.7%; p < 0.001). HFNC-related adverse events were infrequent and comparable across groups.

Conclusion: HFNC is an effective and well-tolerated first-line respiratory support modality for AHRF. Early improvements in oxygenation and higher ROX index values are strong predictors of treatment success, whereas older age, ARDS etiology, and greater baseline illness severity are associated with failure. Timely recognition of HFNC non-response is essential to reduce mortality and optimize clinical outcomes.