The variability and disparities in the recommended targets across different international guidelines suggest the optimal oxygen saturation (SpO2) target for acute respiratory failure (ARF) patients be further explored. To explore the association between SpO2 and in-hospital mortality of ARF patients, as well as to determine the optimum SpO2 for ARF patients. In this cohort study, 3,225 ARF patients were included at the end of the follow-up; among them, and 1,249 patients survived and 1,976 died. The restricted cubic spline (RCS) was drawn to show the nonlinear association between the median SpO2 and the risk of in-hospital mortality of ARF patients and to identify the optimal range of SpO2. Cox regression was applied to identify the association between the median SpO2 and the risk of in-hospital mortality in ARF patients. Kaplan-Meier curves were plotted to identify the in-hospital mortality of ARF patients. The in-hospital mortality rate was 61.2% in all ARF patients at the end of the follow-up. The median SpO2 was associated with decreased risk of in-hospital mortality of ARF patients after adjusting for confounders (hazard ratio (HR) = 0.95, 95% confidence interval (95% CI): 0.93-0.97). The median SpO2 was non-linearly correlated with the in-hospital mortality of ARF patients. The overall survival (OS) was higher in the 96-98% group. A median SpO2 ≤ 96% was associated with an increased risk of in-hospital mortality in ARF patients accompanied by malignant cancer (HR = 1.55, 95% CI: 1.24-1.94), renal failure (HR = 1.45, 95% CI: 1.24-1.70), chronic obstructive pulmonary disease (COPD; HR = 1.70, 95% CI: 1.27-2.28) and atrial fibrillation (AF; HR = 1.25, 95% CI: 1.02-1.53). The median SpO2 > 98% was associated with an elevated risk of in-hospital mortality in ARF patients accompanied by AF (HR = 1.22, 95% CI: 1.04-1.44). The median SpO2 was linked to a decreased risk of in-hospital mortality in ARF patients.
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