Adjunctive Effects of Vitamin C and Thiamine on Inflammation, Oxidative Stress, and Clinical Outcomes in Sepsis
-
Seyed Mojtaba Marashi
,
Kamyar Dabir Ashrafi
,
Samaneh Hajy Molla Rabi
,
Mohammad Ali Haji Azizi
,
Nima Mohammadi Afrakoti
Abstract
Sepsis is known as a leading cause of morbidity, mortality, and healthcare burdened all around the globe, with imited targeted therapies beyond standard supportive care. Currently, management strategies focus mostly on controlling the infection and hemodynamic stabilization but often fail to address to pathophysiological processes of inflammation, oxidative stress, and microvascular injury. Vitamin C (ascorbic acid) is a potential antioxidant and immunomodulator, and has gained attention as an adjunctive therapy due to its role in reducing oxidative damage, inflammatory responses regulation, and supporting catecholamine synthesis. In addition, the synergistic combination of vitamin C and thiamine has been proposed to enhance cellular metabolism and organ protection in patients who are critically ill. In this study, we investigated the effects of itamin C, both alone and combination with thiamine, on clinical outcomes and biochemical markers in patients with sepsis. Our findings provide new insights into the potential role of vitamin supplementation in modulating disease progression and improving prognosis, highlighting its possible integration into sepsis management strategies.
1. Fleischmann C, Scherag A, Adhikari NK, Hartog CS, Tsaganos T, Schlattmann P, et al. Assessment of global incidence and mortality of hospital-treated sepsis: current estimates and limitations. Am J Respir Crit Care Med. 2016;193(3):259-72. https://doi.org/10.1164/rccm.201504-0781OC
2. Kumar NR, Balraj TA, Kempegowda SN, Prashant A. Multidrug-resistant sepsis: a critical healthcare challenge. Antibiotics (Basel). 2024;13(1):46. https://doi.org/10.3390/antibiotics13010046
3. Cutuli SL, Cascarano L, Lazzaro P, Tanzarella ES, Pintaudi G, Grieco DL, et al. Antimicrobial exposure in critically ill patients with sepsis-associated multi-organ dysfunction requiring extracorporeal organ support: a narrative review. Microorganisms. 2023;11(2):473. https://doi.org/10.3390/microorganisms11020473
4. Borges A, Bento L. Organ crosstalk and dysfunction in sepsis. Ann Intensive Care. 2024;14(1):147. https://doi.org/10.1186/s13613-024-01377-0
5. Liu S, Liang Q. Sepsis toxicity network reconstruction-dynamic signaling and multi-organ injury: a review. Biomol Biomed. 2025;:. https://doi.org/10.17305/bb.2025.12931
6. Wang R, Zhao J, Wei Q, Wang H, Zhao C, Hu C, et al. Potential of circulating lncRNA CASC2 as a biomarker in reflecting the inflammatory cytokines, multi-organ dysfunction, disease severity, and mortality in sepsis patients. J Clin Lab Anal. 2022;36(8):e24569. https://doi.org/10.1002/jcla.24569
7. Wang Y, Guan QN, Zhang ZJ, Zhang Y. Interaction between endothelial injury and immune response in septic shock: from basic research to clinical applications. Front Physiol. 2025;16:1627008. https://doi.org/10.3389/fphys.2025.1627008
8. Eldib AM, Mufti RE, Babikir IH, El-Gerbed MS, Khalifa HS, El-Anwar N, et al. Evaluation of the synergistic protective effects of vitamin C, N-acetylcysteine, and sodium ferulate on inflammation, oxidative stress, and nephrotoxicity in 5-fluorouracil-treated rats. Egypt J Zool. 2025;:. https://doi.org/10.21608/ejz.2025.375371.1130
9. Carr AC, Rosengrave PC, Bayer S, Chambers S, Mehrtens J, Shaw GM. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. 2017;21(1):300. https://doi.org/10.1186/s13054-017-1891-y
10. Sankar J, Manoharan A, Lodha R, Sharma H, Kabra S. Vitamin C versus placebo in pediatric septic shock (VITACiPS): a randomised controlled trial. J Intensive Care Med. 2025;:08850666251362121. https://doi.org/10.1177/08850666251362121
11. Pei H, Qu J, Chen JM, Zhang YL, Zhang M, Zhao GJ, et al. The effects of antioxidant supplementation on short-term mortality in sepsis patients. Heliyon. 2024;10(8):e. https://doi.org/10.1016/j.heliyon.2024.e29156
12. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304-77. https://doi.org/10.1007/s00134-017-4683-6
13. Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial. Chest. 2020;158(1):164-73. https://doi.org/10.1016/j.chest.2020.02.049
14. Kim J, Arnaout L, Remick D. Hydrocortisone, ascorbic acid, and thiamine (HAT) therapy decreases oxidative stress, improves cardiovascular function, and improves survival in murine sepsis. Shock. 2020;53(4):460-7. https://doi.org/10.1097/SHK.0000000000001385
15. Wang Y, Lin H, Lin BW, Lin JD. Effects of different ascorbic acid doses on the mortality of critically ill patients: a meta-analysis. Ann Intensive Care. 2019;9(1):58. https://doi.org/10.1186/s13613-019-0532-9
16. Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial. JAMA. 2020;323(5):423-31. https://doi.org/10.1001/jama.2019.22176
17. Alissa A, Alrashed MA, Alshaya AI, Al Sulaiman K, Alharbi S. Reevaluating vitamin C in sepsis and septic shock: a potential benefit in severe cases? Front Med. 2024;11:1476242. https://doi.org/10.3389/fmed.2024.1476242
18. Fujii T, Salanti G, Belletti A, Bellomo R, Carr A, Furukawa TA, et al. Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis. Intensive Care Med. 2022;48(1):16-24. https://doi.org/10.1007/s00134-021-06558-0
19. Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12(1):32. https://doi.org/10.1186/1479-5876-12-32
20. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229-38. https://doi.org/10.1016/j.chest.2016.11.036
2. Kumar NR, Balraj TA, Kempegowda SN, Prashant A. Multidrug-resistant sepsis: a critical healthcare challenge. Antibiotics (Basel). 2024;13(1):46. https://doi.org/10.3390/antibiotics13010046
3. Cutuli SL, Cascarano L, Lazzaro P, Tanzarella ES, Pintaudi G, Grieco DL, et al. Antimicrobial exposure in critically ill patients with sepsis-associated multi-organ dysfunction requiring extracorporeal organ support: a narrative review. Microorganisms. 2023;11(2):473. https://doi.org/10.3390/microorganisms11020473
4. Borges A, Bento L. Organ crosstalk and dysfunction in sepsis. Ann Intensive Care. 2024;14(1):147. https://doi.org/10.1186/s13613-024-01377-0
5. Liu S, Liang Q. Sepsis toxicity network reconstruction-dynamic signaling and multi-organ injury: a review. Biomol Biomed. 2025;:. https://doi.org/10.17305/bb.2025.12931
6. Wang R, Zhao J, Wei Q, Wang H, Zhao C, Hu C, et al. Potential of circulating lncRNA CASC2 as a biomarker in reflecting the inflammatory cytokines, multi-organ dysfunction, disease severity, and mortality in sepsis patients. J Clin Lab Anal. 2022;36(8):e24569. https://doi.org/10.1002/jcla.24569
7. Wang Y, Guan QN, Zhang ZJ, Zhang Y. Interaction between endothelial injury and immune response in septic shock: from basic research to clinical applications. Front Physiol. 2025;16:1627008. https://doi.org/10.3389/fphys.2025.1627008
8. Eldib AM, Mufti RE, Babikir IH, El-Gerbed MS, Khalifa HS, El-Anwar N, et al. Evaluation of the synergistic protective effects of vitamin C, N-acetylcysteine, and sodium ferulate on inflammation, oxidative stress, and nephrotoxicity in 5-fluorouracil-treated rats. Egypt J Zool. 2025;:. https://doi.org/10.21608/ejz.2025.375371.1130
9. Carr AC, Rosengrave PC, Bayer S, Chambers S, Mehrtens J, Shaw GM. Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes. Crit Care. 2017;21(1):300. https://doi.org/10.1186/s13054-017-1891-y
10. Sankar J, Manoharan A, Lodha R, Sharma H, Kabra S. Vitamin C versus placebo in pediatric septic shock (VITACiPS): a randomised controlled trial. J Intensive Care Med. 2025;:08850666251362121. https://doi.org/10.1177/08850666251362121
11. Pei H, Qu J, Chen JM, Zhang YL, Zhang M, Zhao GJ, et al. The effects of antioxidant supplementation on short-term mortality in sepsis patients. Heliyon. 2024;10(8):e. https://doi.org/10.1016/j.heliyon.2024.e29156
12. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304-77. https://doi.org/10.1007/s00134-017-4683-6
13. Iglesias J, Vassallo AV, Patel VV, Sullivan JB, Cavanaugh J, Elbaga Y. Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis: the ORANGES trial. Chest. 2020;158(1):164-73. https://doi.org/10.1016/j.chest.2020.02.049
14. Kim J, Arnaout L, Remick D. Hydrocortisone, ascorbic acid, and thiamine (HAT) therapy decreases oxidative stress, improves cardiovascular function, and improves survival in murine sepsis. Shock. 2020;53(4):460-7. https://doi.org/10.1097/SHK.0000000000001385
15. Wang Y, Lin H, Lin BW, Lin JD. Effects of different ascorbic acid doses on the mortality of critically ill patients: a meta-analysis. Ann Intensive Care. 2019;9(1):58. https://doi.org/10.1186/s13613-019-0532-9
16. Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: the VITAMINS randomized clinical trial. JAMA. 2020;323(5):423-31. https://doi.org/10.1001/jama.2019.22176
17. Alissa A, Alrashed MA, Alshaya AI, Al Sulaiman K, Alharbi S. Reevaluating vitamin C in sepsis and septic shock: a potential benefit in severe cases? Front Med. 2024;11:1476242. https://doi.org/10.3389/fmed.2024.1476242
18. Fujii T, Salanti G, Belletti A, Bellomo R, Carr A, Furukawa TA, et al. Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis. Intensive Care Med. 2022;48(1):16-24. https://doi.org/10.1007/s00134-021-06558-0
19. Fowler AA 3rd, Syed AA, Knowlson S, Sculthorpe R, Farthing D, DeWilde C, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014;12(1):32. https://doi.org/10.1186/1479-5876-12-32
20. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest. 2017;151(6):1229-38. https://doi.org/10.1016/j.chest.2016.11.036
| Files | ||
| Issue | Vol 8 No 4 (2025) | |
| Section | Original Article(s) | |
| Keywords | ||
| Sepsis Vitamin C Thiamine Oxidative Stress Adjunctive Therapy | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Marashi SM, Dabir Ashrafi K, Hajy Molla Rabi S, Haji Azizi MA, Mohammadi Afrakoti N. Adjunctive Effects of Vitamin C and Thiamine on Inflammation, Oxidative Stress, and Clinical Outcomes in Sepsis. AJS. 2025;8(4):137-145.
