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0 0.5 1 1.5 2+ Mortality 49% Improvement Relative Risk Alkalinization  Calonico et al.  LATE TREATMENT Is late treatment with alkalinization + sodium ibuprofenate beneficial for COVID-19? Retrospective 5,416 patients in Argentina (March 2020 - September 2021) Lower mortality with alkalinization + sodium ibuprofenate (p=0.01) Calonico et al., National Bureau of Ec.., May 2022 Favors alkalinization Favors control

Causal Inference During a Pandemic: Evidence on the Effectiveness of Nebulized Ibuprofen as an Unproven Treatment for COVID-19 in Argentina

Calonico et al., National Bureau of Economic Research, doi:10.3386/w30084
May 2022  
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27th treatment shown to reduce risk in November 2021
*, now known with p = 0.0000000056 from 14 studies.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
4,100+ studies for 60+ treatments.
Retrospective 5,146 hospitalized COVID-19 patients in Argentina, showing lower mortality associated with nebulized ibuprofen (NaIHS) treatment. Doubly robust inverse probability weighting estimators were used to control for confounding. Authors emphasize the need for randomized controlled trials.
The treatment appears to be the same as detailed in Kalayan, which reports a pH of 8.5. Kreutzberger et al. showed that SARS-CoV-2 requires an acidic pH (between 6.2-6.8) for membrane fusion and cell entry, even when the viral spike protein is primed by proteases like TMPRSS2. Efficacy seen here may be more due to alkalinization, which shows more consistent higher efficacy than ibuprofen in studies to date.
Study covers ibuprofen and alkalinization.
risk of death, 48.7% lower, RR 0.51, p = 0.01, treatment 1,019, control 3,303.
Effect extraction follows pre-specified rules prioritizing more serious outcomes. Submit updates
Calonico et al., 31 May 2022, retrospective, Argentina, peer-reviewed, 3 authors, study period March 2020 - September 2021, this trial uses multiple treatments in the treatment arm (combined with sodium ibuprofenate) - results of individual treatments may vary. Contact:,,
This PaperAlkalinizationAll
Sebastian Calonico, Rafael Di, Tella Juan, Cruz Lopez, Del Valle, Vincent Pons, Amitabh Chandra, Matias Cattaneo, Asim Khwaja, Ariel Stern, Robert Lieli, Pedro Degiovanni, Rafael Di Tella, Juan Cruz, Lopez Del, Juan Cruz Lopez
Many medical decisions during the pandemic were made without the support of causal evidence obtained in clinical trials. We study the case of nebulized ibuprofen (NaIHS), a drug that was extensively used on COVID-19 patients in Argentina amidst wild claims about its effectiveness and without regulatory approval. We study data on 5,146 patients hospitalized in 11 health centers spread over 4 provinces, of which a total of 1,019 (19.8%) received the treatment. We find a large, negative and statistically significant correlation between NaIHS treatment and mortality using inverse probability weighting estimators. We consider several threats to identification, including the selection of "low" risks into NaIHS, spillovers affecting patients in the control group, and differences in the quality of care in centers that use NaIHS. While the negative correlation appears to be, broadly, robust, our results are best interpreted as emphasizing the benefits of running a randomized controlled trial and the challenges of incorporating information produced in other, less rigorous circumstances.
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Late treatment
is less effective
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