High-Flow Nasal Cannula Outcomes in COVID-19-Associated Acute Hypoxemic Respiratory Failure: Illness Severity, Awake Prone Positioning, and Risk of Intubation in a Single-Center ICU Cohort

Background and Objectives: High-flow nasal cannula (HFNC) is widely used in acute hypoxemic respiratory failure, yet predictors of successful noninvasive support and the role of awake prone positioning remain incompletely defined, and observational analyses are vulnerable to immortal-time bias. We evaluated factors associated with HFNC success and the association of awake prone positioning with HFNC outcomes in critically ill adults with COVID-19-associated acute hypoxemic respiratory failure, using analyses designed to reduce time-related and indication-related bias. Materials and Methods: In this retrospective, single-center intensive care unit (ICU) cohort study, adults with virologically confirmed COVID-19 who received HFNC, with awake prone positioning considered as part of the initial HFNC strategy, between April 2020 and December 2021 were followed from HFNC initiation until endotracheal intubation or ICU discharge. HFNC success was defined as avoidance of intubation during the index ICU stay. Multivariable logistic regression with multiple imputation of missing covariates, propensity score-based inverse probability of treatment weighting (IPTW), and landmark time-to-event analyses were used to assess the association between awake prone positioning and HFNC failure. Results: Among 222 patients, HFNC was successful in 72 (32.4%) and unsuccessful in 150 (67.6%). Failure was associated with lower PaO2/FiO2 ratios, higher FiO2 requirements, and higher APACHE II and SOFA scores at ICU admission (all p ≤ 0.011). In the imputed multivariable model, awake prone positioning was associated with lower HFNC failure (odds ratio [OR] 0.23; 95% CI 0.10–0.53; p < 0.001), whereas higher APACHE II score (OR 1.09 per point; 95% CI 1.02–1.17; p = 0.012), higher HFNC FiO2 (OR 1.41 per 10%; 95% CI 1.15–1.73; p < 0.001), and lower PaO2/FiO2 ratio (p = 0.037) were independently associated with failure. IPTW yielded a consistent estimate (OR 0.22; 95% CI 0.10–0.47). In time-to-event analyses, the unadjusted association was strong but likely influenced by early deterioration; after a day-1 landmark it attenuated yet remained significant (hazard ratio [HR] 0.52; 95% CI 0.34–0.79; p = 0.002), and at a day-2 landmark it was non-significant unadjusted (HR 0.66; 95% CI 0.39–1.11) but significant after adjustment for illness severity (HR 0.47; 95% CI 0.25–0.88; p = 0.019). Conclusions: Patients undergoing awake prone positioning during HFNC had a lower observed incidence of intubation, although the difference was more modest than crude analyses suggested and sensitive to landmark timing, whereas greater illness severity and more severe hypoxemia at ICU admission were independently associated with failure. These findings support severity-informed monitoring and timely escalation during HFNC. Causality cannot be inferred because of the retrospective design and residual confounding, particularly confounding related to the ability to tolerate prone positioning.