Abstract Introduction Acute Respiratory Distress Syndrome (ARDS) is a life-threatening condition characterized by rapid-onset respiratory failure. Despite advancements in critical care, ARDS remains a major contributor to adult mortality in the United States (U.S.). Evaluating long-term mortality trends is essential for understanding evolving epidemiologic patterns and is critical for improving clinical management and public health strategies. Methods Using the CDC WONDER multiple cause of death for adults aged ≥25 years, we retrospectively analyzed age-adjusted mortality rates (AAMRs) per 100,000 for ARDS (ICD-10 codes: J80), stratified by year, gender, race/ethnicity, and geography. Joinpoint regression was used to estimate average annual percent change (AAPC) and annual percent change (APC) with 95% confidence intervals (CIs). Statistical significance was defined as p 0.05. Results From 1999-2023, 355,363 ARDS-related deaths were reported, predominantly in hospital inpatient settings. The overall AAMR declined from 7.4 in 1999 to 4.63 in 2023 (AAPC: -1.83; 95%CI: -5.28 to 1.73; p = 0.309), with a sharp surge, peaking at 21.7 in 2021 during the COVID-19 pandemic (APC: 86.97; p = 0.006). Adults aged ≥65 years experienced the highest mortality burden during this pandemic (AAMR: 112.8 in 2021). AAMRs for both genders also showed a sharp rise between 2018 and 2021, with men having higher AAMRs than women (2021 AAMR: 27.52 vs 16.63). By race, AAMRs were highest in Non-Hispanic (NH) Black or African Americans (38.39) and lowest in NH Asian or Pacific Islanders (15.0) in 2021. Rural areas (6.23) exceeded urban areas (5.49). Regionally, the highest peak in AAMR was observed in the South region at 24.0 in 2021. At the state level, Nevada and Louisiana were in the top 90th percentile during the pandemic. Conclusion Between 1999 and 2023, ARDS-related AAMRs in U.S. adults declined modestly before experiencing a significant, transient increase during the COVID-19 pandemic. Although rates have decreased since the 2021 peak, they have not returned to pre-pandemic levels, underscoring the lingering impact of COVID-19 on ARDS-related mortality. Ongoing surveillance and targeted interventions are required to reduce ARDS burden and improve outcomes in the post-pandemic era. This abstract is funded by: None
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