Combined ACEI and ARB therapy and ICU Mortality in critically ill COVID-19 patients: a retrospective cohort study

Ivanny Carolina Marchant^1,2*Gloria Balcazar^2,3Valentina Pozo^2,4Pablo Olivero^2,4Hilda Espinoza^2,5

• ¹Laboratorio de Modelamiento en Medicina, Facultad de Medicina, Universidad de Valparaíso, Valparaíso, Chile
• ²Unidad de Estudios Clínicos, Facultad de Medicina, Universidad de Valparaíso, Valparaíso, Chile
• ³Unidad de Cuidados Intensivos, Hospital Dr. Gustavo Fricke, Viña del Mar, Chile
• ⁴Laboratorio de Estructura y Función Celular, Facultad de Medicina, Valparaiso, Chile
• ⁵Escuela de Química y Farmacia, Facultad de Farmacia, Universidad de Valparaíso, Valparaiso, Chile

The safety and potential benefits of renin-angiotensin system (RAAS) blockers in COVID-19 remain controversial. While monotherapy with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been widely studied, the impact of combined ACEI+ARB therapy in critically ill patients is unknown. Acid-base balance may also influence prognosis. We conducted a retrospective cohort study of adults with PCR-confirmed COVID-19 admitted to the intensive care unit (ICU) atof Hospital Dr. Gustavo Fricke (Chile) between March 2020 and December 2021. Patients were stratified by RAAS therapy at admission (none, ACEI only, ARB only, ACEI+ARB) and by arterial bicarbonate (HCO₃-) levels: low (<21 mEq/L), normal (21–27 mEq/L), or high (>27 mEq/L). Changes in HCO₃ -during the first 48 hours were also assessed. The primary outcome was in-hospital mortality; secondary outcomes included ICU length of stay and duration of mechanical ventilation. Group comparisons used chi-square test and non-parametric statistics. Among 2838 hospitalized patients, 671 (23.6%) required ICU admission, with an overall ICU mortality of 34.2%. Mortality was significantly lower in patients receiving combined ACEI+ARB therapy (16.9%) compared with those not on RAAS inhibitors (38.3%; p<0.05). No significant mortality differences were observed with ACEI or ARB monotherapy. In patients with low or normal admission HCO₃-, an increase during the first 48 hours was associated with reduced mortality (χ²= 7.9183, p = 0.01). Patients with high baseline HCO₃-who survived required longer ICU stays and mechanical ventilation. These findings suggest a potential synergistic protective effect of dual RAAS blockade, mediated through modulation of RAAS pathways and renal acid-base homeostasis, underscoring the relevance of dynamic acid-base monitoring in the ICU. Prospective randomized trials are warranted to confirm these observations and to define personalized strategies integrating metabolic biomarkers.