Ascorbic Acid as an Adjunctive Therapy in Critically Ill Patients with COVID-19: A Multicenter Propensity Score Matched Study
Khalid Al Sulaiman, Ohoud Al Juhani, Khalid Bin Salah, Hisham A Badreldin, Abdullah Al Harthi, Mohammed Alenazi, Aisha Alharbi, Rahmah Algarni, Shmeylan Al Harbi, Abdullah Alhammad, Ramesh Vishwakarma, Sarah Aldekhyl
doi:10.21203/rs.3.rs-354711/v1
Background: Ascorbic acid represents an appealing option for clinicians to utilize in the context of a global health pandemic of COVID-19 patients due to its proposed clinical e cacy, relative safety, and low cost.
Objectives: The aim of this study was to evaluate the e cacy and safety of using ascorbic acid in supplemental dose as adjunctive therapy in critically ill patients with COVID-19.
Methods: This was a multi-center, non-interventional, retrospective cohort study. All critically ill adult patients admitted to ICU with a con rmed COVID-19 between March 1st to December 31 st , 2020 were included in the nal analysis. The study was conducted at two large governmental tertiary hospitals in Saudi Arabia. The purpose was to investigate the association between clinical outcomes with ascorbic acid use as an adjunctive therapy in COVID-19 after propensity score matching using baseline severity scores, systemic use of corticosteroids and study centers.
Results: A 739 patients were included in this study; 296 patients were included after propensity score matching. There was no association between the administration of ascorbic acid and in-hospital mortality nor 30day ICU mortality (OR (95%CI): 0.77 (0.476, 1.234), p-value=0.2738 and OR (95%CI): 0.73 (0.438 ,1.204), p-value=0.215 respectively). Using ascorbic acid was associated with lower incidence of thrombosis compared with the non-ascorbic acid group (6.1% vs. 13% respectively); OR (95%CI): 0.42 (0.184, 0.937), p-value=0.0342).
Conclusion: Supplemental dose of ascorbic acid as an adjunctive therapy in COVID19 critically ill patients was not associated with mortality bene ts; but associated with lower incidence of thrombosis. Further studies are required to con rm these ndings.
Conclusion The use of ascorbic acid was not assosiated with in-hospital nor 30-days ICU mortality reduction. Using supplemental ascorbic acid doses as an adjunctive therapy in critically ill patients with COVID-19 was associated with lower incidence of thrombosis. Further studies are warranted to con rm these ndings.
Abbreviations Intensive care units (ICUs), Coronavirus disease (COVID-19), Mechanical ventilation (MV), Length of Stay (LOS).
Declarations Author contributions All authors contributed to data collections, analysis, drafted, revised, and approved the nal version of the manuscript.
Funding None.
Ethics approval and consent to participate The study was approved November 19th, 2020, by King Abdullah International Medical Research Center (KAIMRC)-Institutional Review Board (IRB), Riyadh, Saudi Arabia (Reference No: RC20/589/R). All methods were performed in accordance with relevant guidelines and regulations. Participants' con dentiality was strictly observed throughout the study by using anonymous unique serial number for each subject and restricting data only to the investigators. KAIMRC-IRB committee waived the informed consent due to its retrospective nature.
Consent for publication Not applicable.
Competing interests No author has a con ict of interest in this study. This is a list of supplementary les associated with this preprint. Click to download. Additional le1DemographyandBaselinecharacteristics.docx Additional le2Coexistingillness.docx
References
Borrelli, Roux-Lombard, Grau, Giradin, Ricou et al., Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development of multiple organ failure in patients at risk, Crit. Care Med
Carr, Maggini, Vitamin C and Immune Function, Nutrients
Carr, Rosengrave, Bayer, Chambers, Mehrtens et al., Hypovitaminosis C and vitamin C de ciency in critically ill patients despite recommended enteral and parenteral intakes, Crit Care
Cheng, Can early and high intravenous dose of vitamin C prevent and treat coronavirus disease 2019 (COVID-19)?, Medicine in Drug Discovery,
doi:10.1016/j.medidd.2020.100028Dey, Bishayi, Killing of S. aureus in murine peritoneal macrophages by Ascorbic acid along with antibiotics Chloramphenicol or O oxacin: correlation with in ammation, Microb Pathog
Donnino, Andersen, Chase, Double-Blind, Placebo-Controlled Trial of Thiamine as a Metabolic Resuscitator in Septic Shock: A Pilot Study, Crit Care Med,
doi:10.1097/CCM.0000000000001572Fisher, Seropian, Kraskauskas, Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury, Crit Care Med
Fowler, Syed, Knowlson, Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis, J Transl Med
Fowler, Truwit, Hite, Effect of vitamin C infusion on organ failure and biomarkers of in ammation and vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS-ALI randomized clinical trial, JAMA
Fujii, Luethi, Young, Frei, Eastwood et al., Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vaso-pressor support among patients with septic shock, JAMA
Gorton, Jarvis, The effectiveness of vitamin C in preventing and relieving the symptoms of virus-induced respiratory infections, J Manipulative Physiol Ther
Grooth, Spoelstra-De Man, Oudemans-Van Straaten, Early plasma vitamin C concentration, organ dysfunction and ICU mortality, Intensive Care Med
Habib, Ahmed, Early adjuvant intravenous vitamin C treatment in septic shock may resolve the vasopressor depend-ence, Int J Microbiol Adv Immunol
Hemilä, Chalker, Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis, Nutrients
Horby, Lim, Dexamethasone in hospitalized patients with COVID-19 -preliminary report, N Engl J Med
Huang, Wang, Li, Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China, Lancet
Hunt, Chakravorty, Annan, Habibzadeh, Schorah, The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections, Int J Vitam Nutr Res
Kim, Jo, Eom, Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: propensity score-based analysis of a before-after cohort study, J Crit Care
Kim, Lim, Byun, Vitamin C supplementation reduces the odds of developing a common cold in Republic of Korea Army recruits: randomized controlled trial, BMJ Mil Health Published Online First,
doi:10.1136/bmjmilitary-2019-001384Leibovitz, Siegel, Ascorbic acid and the immune response, Adv Exp Med Biol
Li, Guo, Li, Qin, Huang, Therapeutic targets and signaling mechanisms of vitamin C activity against sepsis: a bioinformatics study, Brief Bioinform
Lin, Chen, Acute kidney injury classi cation: AKIN and RIFLE criteria in critical patients, World J Crit Care Med,
doi:10.5492/wjccm.v1.i2.40Marik, Khangoora, Rivera, Hooper, Catravas, Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study, Chest
Marik, Khangoora, Rivera, Hooper, Catravas, Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study, Chest
Nathens, Neff, Jurkovich, Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients, Ann Surg
Peters, Goetzsche, Grobbelaar, Noakes, Vitamin C supplementation reduces the incidence of postrace symptoms of upper-respiratory-tract infection in ultramarathon runners, Am J Clin Nutr
Sulaiman, Juhani, Eljaaly, Clinical Features and Outcomes of Critically Ill Patients with Coronavirus Disease 2019 (COVID-19): A Multicenter Cohort Study, International Journal of Infectious Diseases,
doi:10.1016/j.ijid.2021.02.037Thomas, Patel, Bittel, Effect of High-Dose Zinc and Ascorbic Acid Supplementation vs Usual Care on Symptom Length and Reduction Among Ambulatory Patients With SARS-CoV-2 Infection: The COVID A to Z Randomized Clinical Trial, JAMA Netw Open
Wei, Wang, Liao, E cacy of vitamin C in patients with sepsis: an updated metaanalysis, Eur J Pharmacol
Yoo, Kim, Ju, Lee, Cho et al., Clinical impact of supplementation of vitamins B1 and C on patients with sepsis-related acute respiratory distress syndrome, Tuberc Respir Dis
Zabet, Mohammadi, Ramezani, Khalili, Effect of high-dose Ascorbic acid on vasopressor's requirement in septic shock, J Res Pharm Pract
Zhang, Rao, Li, Pilot trial of high-dose vitamin C in critically ill COVID-19 patients, Ann Intensive Care
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"abstract": "<jats:title>Abstract</jats:title>\n <jats:p><jats:bold>Background:</jats:bold> Ascorbic acid represents an appealing option for clinicians to utilize in the context of a global health pandemic of COVID-19 patients due to its proposed clinical efficacy, relative safety, and low cost.<jats:bold>Objectives:</jats:bold>The aim of this study was to evaluate the efficacy and safety of using ascorbic acid in supplemental dose as adjunctive therapy in critically ill patients with COVID-19. <jats:bold>Methods: </jats:bold>This was a multi-center, non-interventional, retrospective cohort study. All critically ill adult patients admitted to ICU with a confirmed COVID-19 between March 1st to December 31<jats:sup>st</jats:sup>, 2020 were included in the final analysis. The study was conducted at two large governmental tertiary hospitals in Saudi Arabia. The purpose was to investigate the association between clinical outcomes with ascorbic acid use as an adjunctive therapy in COVID-19 after propensity score matching using baseline severity scores, systemic use of corticosteroids and study centers. <jats:bold>Results:</jats:bold>A 739 patients were included in this study; 296 patients were included after propensity score matching. There was no association between the administration of ascorbic acid and in-hospital mortality nor 30-day ICU mortality (OR (95%CI): 0.77 (0.476, 1.234), p-value=0.2738 and OR (95%CI): 0.73 (0.438 ,1.204), p-value=0.215 respectively). Using ascorbic acid was associated with lower incidence of thrombosis compared with the non-ascorbic acid group (6.1% vs. 13% respectively); OR (95%CI): 0.42 (0.184, 0.937), p-value=0.0342).<jats:bold>Conclusion:</jats:bold>Supplemental dose of ascorbic acid as an adjunctive therapy in COVID19 critically ill patients was not associated with mortality benefits; but associated with lower incidence of thrombosis. Further studies are required to confirm these findings.</jats:p>",
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