High-flow nasal cannula versus standard oxygen therapy for adult acute hypoxemic respiratory failure: a systematic review and meta-analysis with trial sequential analysis and GRADE assessment

High-flow nasal cannula (HFNC) is widely used as an early respiratory support strategy for adults with acute hypoxemic respiratory failure (AHRF). Although HFNC may reduce the risk of endotracheal intubation, it remains uncertain whether the available evidence is sufficiently mature and whether this potential benefit translates into improved survival. We performed a systematic review and meta-analysis with trial sequential analysis (TSA) and GRADE assessment to assess HFNC versus standard oxygen therapy (SOT) in adult AHRF. PubMed, Embase, the Cochrane Library, and Web of Science were searched from inception to March 31, 2026. Randomized controlled trials (RCTs) of HFNC versus SOT in adults with AHRF were included. The primary and secondary outcomes were endotracheal intubation and all-cause mortality, respectively. For each dichotomous outcome, the risk ratio (RR) with a 95% confidence interval (CI) was pooled using a random-effects model. Prespecified subgroup analyses were performed. TSA was performed for intubation, and evidence certainty was assessed using GRADE. Ten independent RCTs reported across 11 publications were included. Compared with SOT, HFNC was associated with a lower risk of endotracheal intubation (RR, 0.85; 95% CI, 0.77–0.93; P < 0.01; I² = 40%), but did not reduce all-cause mortality (RR, 1.01; 95% CI, 0.88–1.16; P = 0.85; I² = 0%). Subgroup analyses suggested a lower intubation risk with HFNC among non-immunocompromised patients, patients with COVID-19, and those with baseline PaO₂/FiO₂ ≤ 200 mmHg, although no statistically significant subgroup interactions were observed. In the primary TSA, the accrued sample size represented only 36.8% of the diversity-adjusted required information size. The cumulative Z-curve crossed the conventional significance boundary, but not the trial sequential monitoring boundary. TSA sensitivity analyses yielded consistent findings, indicating that current evidence remains inconclusive. GRADE certainty was low for endotracheal intubation and moderate for all-cause mortality. HFNC may reduce the risk of endotracheal intubation compared with SOT in adults with AHRF, but a survival benefit has not been demonstrated.