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HOME > Acute Crit Care > Volume 37(4); 2022 > Article
Letter to the Editor
Infection Meta-analysis assessing the effectiveness of intravenous vitamin C in patients with sepsis and septic shock
Muhammad Ali Tariq1orcid, Hamza Amin2orcid, Uzair Ali1orcid
Acute and Critical Care 2022;37(4):674-677.
DOI: https://doi.org/10.4266/acc.2022.01088
Published online: October 21, 2022

1Department of Medicine, Dow University Hospital, Dow International Medical College, Karachi, Pakistan

2Department of Medicine, Dr. Ruth KM Pfau Civil Hospital, Dow University of Health Sciences, Karachi, Pakistan

Corresponding author: Muhammad Ali Tariq Department of Medicine, Dow University Hospital, Dow International Medical College, Gulzar-e-Hijri Scheme 33, Suparco Rd, Karachi, Pakistan Tel: +92-312-2319607 Fax: +92-342-88454 E-mail: m.alitariqpk@gmail.com
• Received: August 10, 2022   • Revised: September 1, 2022   • Accepted: September 2, 2022

Copyright © 2022 The Korean Society of Critical Care Medicine

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Dear Editor:
Sepsis continues to be leading cause of mortality among patients admitted to intensive care unit (ICU), with about 48.9 million cases of sepsis diagnosed and 11 million deaths worldwide in 2017 [1]. Despite significant advances in the understanding of the pathophysiology of sepsis, the mainstay management still relies on active fluid resuscitation for hemodynamic support, early administration of antibiotics, and identification of source and infection control [2]. Vitamin C has been suggested as a possible therapy that attenuates the pathophysiology of sepsis [2]. Multiple randomized controlled trials (RCTs) addressing effectiveness and safety of vitamin C have reported varied conclusions [3]. Previously, published meta-analysis were limited by the sample size and highlighted the need of further studies with a larger number of patients to provide further evidence [3]. The recent publication of results from LOVIT (Lessening Organ Dysfunction with Vitamin C), the largest trial to date addressing this question, justifies re-examination of the evidence [4].
PubMed and Scopus databases were searched for relevant studies by two investigators (MAT, UA) using the following keywords: “ascorbic,” “Vitamin C,” “ascorbic acid,” “sepsis,” “septic shock.” Studies were included if they were: (1) RCT (2) comprised of adult patients with Sepsis or septic shock (3) treatment arm: high-dose intravenous (IV) vitamin C (≥1.5 g every 6 hours or 25 mg/kg every 6 hours) either as monotherapy or combination therapy with thiamine and hydrocortisone, (4) control arm: placebo or standard regiment. Outcomes of interest were ICU mortality, 30-day and 90-day mortality, change in Sequential Organ Failure Assessment score (delta SOFA) within 72 hours. Subgroup analyses were conducted for vitamin C as monotherapy versus combination therapy. Review articles, non-randomized studies, conference abstracts and studies published prior to 2010 were excluded. Odds ratios (ORs) or weighted mean difference (WMD) with 95% confidence intervals (CI) were calculated using random effects model. Statistical heterogeneity in studies was assessed by I2 statistics. A P<0.05 was considered significant.
The initial literature search identified 854 unique studies, 14 trials with 2,793 patients met the eligibility criteria [3-5]. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) flowchart of the study selection is shown in Supplementary Figure 1. Baseline study characteristics are shown in Supplementary Table 1. IV vitamin C in combination with thiamine and hydrocortisone significantly reduced SOFA score at 72 hours (7 RCTs, 1,318 patients; WMD: –0.52, 95% CI: –1.01 to –0.03, P=0.037, I2=53%) (Figure 1D). For other outcomes, IV vitamin C was not statistically significant in reducing the ICU mortality (6 RCTs, 1,284 patients; OR: 0.98, 95% CI: 0.74 to 1.30, P=0.91, I2=0.0%) (Figure 1A), 30-day mortality (14 RCTs, 2,783 patients; OR: 0.87, 95% CI: 0.69 to 1.09, P=0.22, I2=32.0%) (Figure 1B), 90-day mortality (5 RCTs, 1,740 patients; OR: 1.10, 95% CI: 0.91 to 1.34, P=0.33, I2=0.0%) (Figure 1C). The results were consistent across the subgroups.
In this meta-analysis we analyzed IV vitamin C therapy in sepsis summarizing the most recent available clinical data. Overall meta-analysis results indicate use of IV high dose vitamin C in combination with thiamine and hydrocortisone is associated with significantly improved SOFA score at 72 hours but has no effect on ICU stay and mortality. However, the clinical significance of reduction in SOFA score is still unclear and caution should be exercised when utilizing surrogate outcomes instead of patient centered outcomes such as mortality. In conclusion, this systematic review and meta-analysis provide conclusive evidence into the effects of IV vitamin C in sepsis. With marginal improvement in delta SOFA among septic patients there no mortality benefit. Little evidence exists to support the routine use of vitamin C in sepsis patients.

CONFLICT OF INTEREST

No potential conflict of interest relevant to this article was reported.

FUNDING

None.

ACKNOWLEDGMENTS

None.

AUTHOR CONTRIBUTIONS

Conceptualization: MAT. Formal analysis: all authors. Methodology: all authors. Writing–original draft: HA, UA. Writing–review & editing: all authors.

Supplementary materials can be found via https://doi.org/10.4266/acc.2021.01088.
Supplementary Figre 1.
Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flowchart of the study selection process. Vit, vitamin; RCT, randomized controlled trial.
acc-2022-01088-suppl1.pdf
Supplementary Table 1.
Baseline characteristics of trials included in analysis
acc-2022-01088-suppl2.pdf
Figure 1.
Forest plot showing the effect of intravenous vitamin C compared with control on (A) intensive care unit (ICU) mortality, (B) 30-day mortality, (C) 90-day mortality, and (D) change in Sequential Organ Failure Assessment (SOFA) score at 72 hours. Vit: vitamin; MH: Mantel-Haenszel; CI: confidence interval; HAT: hydrocortisone, ascorbic acid, and thiamine. A list of articles indicated in Figure 1 can be found in the online Supplementary Table 1.
acc-2022-01088f1.jpg
  • 1. Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the Global Burden of Disease Study. Lancet 2020;395:200-11.ArticlePubMedPMC
  • 2. Thompson K, Venkatesh B, Finfer S. Sepsis and septic shock: current approaches to management. Intern Med J 2019;49:160-70.ArticlePubMedPDF
  • 3. Sato R, Hasegawa D, Prasitlumkum N, Ueoka M, Nishida K, Takahashi K, et al. Effect of IV high-dose vitamin C on mortality in patients with sepsis: a systematic review and meta-analysis of randomized controlled trials. Crit Care Med 2021;49:2121-30.ArticlePubMed
  • 4. Lamontagne F, Masse MH, Menard J, Sprague S, Pinto R, Heyland DK, et al. Intravenous vitamin C in adults with sepsis in the intensive care unit. N Engl J Med 2022;386:2387-98.ArticlePubMed
  • 5. Agarwal A, Basmaji J, Fernando SM, Ge FG, Xiao Y, Faisal H, et al. Parenteral vitamin C in patients with severe infection: a systematic review. NEJM Evid 2022;1.Article

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    • Randomized Clinical Trial of Antioxidant Therapy Patients with Septic Shock and Organ Dysfunction in the ICU: SOFA Score Reduction by Improvement of the Enzymatic and Non-Enzymatic Antioxidant System
      Alfredo Aisa-Álvarez, Israel Pérez-Torres, Verónica Guarner-Lans, Linaloe Manzano-Pech, Randall Cruz-Soto, Ricardo Márquez-Velasco, Sergio Casarez-Alvarado, Juvenal Franco-Granillo, Marcela Elizabeth Núñez-Martínez, María Elena Soto
      Cells.2023; 12(9): 1330.     CrossRef

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      Meta-analysis assessing the effectiveness of intravenous vitamin C in patients with sepsis and septic shock
      Acute Crit Care. 2022;37(4):674-677.   Published online October 21, 2022
      DOI: https://doi.org/10.4266/acc.2022.01088
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    Meta-analysis assessing the effectiveness of intravenous vitamin C in patients with sepsis and septic shock
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    Figure 1. Forest plot showing the effect of intravenous vitamin C compared with control on (A) intensive care unit (ICU) mortality, (B) 30-day mortality, (C) 90-day mortality, and (D) change in Sequential Organ Failure Assessment (SOFA) score at 72 hours. Vit: vitamin; MH: Mantel-Haenszel; CI: confidence interval; HAT: hydrocortisone, ascorbic acid, and thiamine. A list of articles indicated in Figure 1 can be found in the online Supplementary Table 1.

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    Meta-analysis assessing the effectiveness of intravenous vitamin C in patients with sepsis and septic shock
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