Abstract: Investigational medications in 9,638 hospitalized patients with severe COVID-19: lessons from the “fail-and-learn” strategy during the first two waves of the pandemic in 2020 Adam C. Delgado Sky Ridge Medical Center Brendon Cornett HCA Healthcare Continental Division Ye Ji Choi HCA Healthcare Continental Division Christina Colosimo Sky Ridge Medical Center Vincent P. Stahel University of Colorado Oliwier Dziadkowiec HCA Healthcare Continental Division Philip F. Stahel (  stahelp23@ecu.edu ) East Carolina University Research Article Keywords: COVID-19, corticosteroids, remdesivir, azithromycin, hydroxychloroquine, tocilizumab, mechanical ventilation, mortality Posted Date: February 20th, 2023 DOI: https://doi.org/10.21203/rs.3.rs-2596201/v1 License:   This work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License Page 1/14 Abstract Background: The early surge of the novel coronavirus disease 2019 (COVID-19) pandemic introduced a significant clinical challenge due to the high case-fatality rate in absence of evidence-based treatment recommendations. The empirical modalities were relegated to historical expertise from the traditional management of acute respiratory distress syndrome (ARDS) in conjunction with off-label pharmaceutical agents endorsed under the “emergency use authorization” paradigm by regulatory agencies. This study was designed to evaluate the insights from the “fail-and-learn” strategy in 2020 before the availability of COVID-19 vaccines and access to reliable insights from high-quality randomized controlled trials. Methods: A retrospective, multicenter, propensity-matched, case-control study was performed on a data registry comprising 186 hospitals from a national health care system in the United States, designed to investigate the efficacy of empirical treatment modalities during the early surge of the COVID-19 pandemic in 2020. Reflective of the time-windows of the initial two surges of the pandemic in 2020, patients were stratified into “early” (March 1–June 30) versus “late” (July 1–December 31) study cohorts. Logistic regression was applied to determine the efficacy of prevalent medications (remdesivir, azithromycin, hydroxychloroquine, corticosteroids, tocilizumab) and supplemental oxygen delivery modalities (invasive vs. non-invasive ventilation) on patient outcomes. The primary outcome measure was in-hospital mortality. Group comparisons were adjusted for covariates related to age, gender, ethnicity, body weight, comorbidities, and treatment modalities pertinent to organ failure replacement. Results: From a total of 87,788 patients in the multicenter data registry screened in this study, 9,638 patients were included who received 19,763 COVID-19 medications during the first two waves of the 2020 pandemic.The results showed inconclusive variable results pertinent to the impact of empirical medications on patient outcomes. In contrast, the necessity for oxygen supply showed significantly increased odds of mortality beyond the effect of the investigational medications. Of all the covariates associated with increased mortality, invasive mechanical ventilation had the highest odds ratios of 8.34 in the first surge and 9.46 in in the second surge of the pandemic (P<0.01). Conclusion: This retrospective multicenter observational cohort study on 9,638 hospitalized patients with severe COVID-19 during revealed that the necessity for invasive ventilation had the highest odds of..