Abstract

Introduction: The clinical safety and potential benefits of renin-angiotensin-aldosterone system (RAAS) inhibitors in COVID-19 remain debated, particularly in critically ill populations. Evidence on combined angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) therapy is limited, and the potential interaction with acid-base status has not been sufficiently explored. Methods: We conducted a retrospective cohort study including adults with PCR-confirmed COVID-19 admitted to the intensive care unit (ICU) at Hospital Dr. Gustavo Fricke (Chile) between March 2020 and December 2021. Patients were categorized according to RAAS therapy at admission (none, ACEI only, ARB only, ACEI + ARB) and arterial bicarbonate (HCO3-) levels (low <21 mEq/L, normal 21-27 mEq/L, high >27 mEq/L). Changes in HCO3- during the first 48 h were evaluated. The primary outcome was in-hospital mortality; secondary outcomes included ICU length of stay and duration of mechanical ventilation. Group comparisons used chi-square and non-parametric tests. Results: Of 2,838 hospitalized patients, 671 required ICU admission and 655 had complete data for analysis. Overall ICU mortality was 34.2%. Combined ACEI + ARB therapy was associated with lower mortality (16.9%) compared with no RAAS blockade (38.3%; p < 0.05), whereas ACEI or ARB monotherapy showed no significant association. Among patients with low or normal admission HCO3- levels, early increases within 48 h were associated with reduced mortality. Patients with elevated baseline HCO3- who survived experienced longer ICU stays and prolonged mechanical ventilation. Discussion: In this observational ICU cohort, dual RAAS blockade was associated with lower in-hospital mortality, although causal inference is limited by the retrospective design and incomplete pharmacologic exposure data. Early bicarbonate increase may reflect renal adaptive capacity and has potential prognostic value. Prospective controlled studies are needed to clarify the clinical relevance of RAAS modulation and metabolic biomarkers in severe COVID-19.