Display options
Cite
Medeiros PMC, Schjalm C, Christiansen D, et al. Vitamin C, Hydrocortisone, and the Combination Thereof Significantly Inhibited Two of Nine Inflammatory Markers Induced by Escherichia Coli But Not by Staphylococcus Aureus - When Incubated in Human Whole Blood. Shock. 2022;57(1):72-80doi: 10.1097/SHK.0000000000001834.
Medeiros, P. M. C., Schjalm, C., Christiansen, D., Sokolova, M., Pischke, S. E., Würzner, R., Mollnes, T. E., & Barratt-Due, A. (2022). Vitamin C, Hydrocortisone, and the Combination Thereof Significantly Inhibited Two of Nine Inflammatory Markers Induced by Escherichia Coli But Not by Staphylococcus Aureus - When Incubated in Human Whole Blood. Shock (Augusta, Ga.), 57(1), 72-80. https://doi.org/10.1097/SHK.0000000000001834
Medeiros, Pedro Miguel Coelho, et al. "Vitamin C, Hydrocortisone, and the Combination Thereof Significantly Inhibited Two of Nine Inflammatory Markers Induced by Escherichia Coli But Not by Staphylococcus Aureus - When Incubated in Human Whole Blood." Shock (Augusta, Ga.) vol. 57,1 (2022): 72-80. doi: https://doi.org/10.1097/SHK.0000000000001834
Medeiros PMC, Schjalm C, Christiansen D, Sokolova M, Pischke SE, Würzner R, Mollnes TE, Barratt-Due A. Vitamin C, Hydrocortisone, and the Combination Thereof Significantly Inhibited Two of Nine Inflammatory Markers Induced by Escherichia Coli But Not by Staphylococcus Aureus - When Incubated in Human Whole Blood. Shock. 2022 Jan 01;57(1):72-80. doi: 10.1097/SHK.0000000000001834. PMID: 34265830.
Copy Download .nbib Format: NLM
Share it on

Shock. 2022 Jan 01;57(1):72-80. doi: 10.1097/SHK.0000000000001834.

Vitamin C, Hydrocortisone, and the Combination Thereof Significantly Inhibited Two of Nine Inflammatory Markers Induced by Escherichia Coli But Not by Staphylococcus Aureus - When Incubated in Human Whole Blood.

Shock (Augusta, Ga.)

Pedro Miguel Coelho Medeiros, Camilla Schjalm, Dorte Christiansen, Marina Sokolova, Soeren Erik Pischke, Reinhard Würzner, Tom Eirik Mollnes, Andreas Barratt-Due

Affiliations

  1. Department of Immunology, Oslo University Hospital and University of Oslo, Oslo, Norway.
  2. Research Laboratory, Nordland Hospital, Bodø and Faculty of Health Sciences, K. G. Jebsen Center, University of Tromsø, Norway.
  3. Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway.
  4. Institute of Hygiene and Medical Microbiology, Medical University of Innsbruck, Innsbruck, Austria.
  5. Center of Molecular Inflammation Research, Norwegian University of Science and Technology, Trondheim, Norway.

PMID: 34265830 DOI: 10.1097/SHK.0000000000001834

Abstract

ABSTRACT: Vitamin C combined with hydrocortisone is increasingly being used to treat septic patients, even though this treatment regimen is based on questionable evidence. When used, a marked effect on key players of innate immunity would be expected, as sepsis is featured by a dysregulated immune response.Here, we explored the effect of vitamin C and hydrocortisone alone and combined, in an ex vivo human whole-blood model of Escherichia coli- or Staphylococcus aureus-induced inflammation. Inflammatory markers for activation of complement (terminal C5b-9 complement complex [TCC]), granulocytes (myeloperoxidase), platelets (β-thromboglobulin), cytokines (tumor necrosis factor [TNF], IL-1β, IL6, and IL-8), and leukocytes (CD11b and oxidative burst) were quantified, by enzyme-linked immunosorbent assay, multiplex technology, and flow cytometry.In E. coli- and S. aureus-stimulated whole blood, a broad dose-titration of vitamin C and hydrocortisone alone did not lead to dose-response effects for the central innate immune mediators TCC and IL-6. Hence, the clinically relevant doses were used further. Compared to the untreated control sample, two of the nine biomarkers induced by E. coli were reduced by hydrocortisone and/or vitamin C. TNF was reduced by hydrocortisone alone (19%, P = 0.01) and by the combination (31%, P = 0.01). The oxidative burst of monocytes and granulocytes was reduced for both drugs alone and their combination, (ranging 8-19%, P < 0.05). Using S. aureus, neither of the drugs, alone nor in combination, had any effects on the nine biomarkers.In conclusion, despite the limitation of the ex vivo model, the effect of vitamin C and hydrocortisone on bacteria-induced inflammatory response in human whole blood is limited and following the clinical data.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Shock Society.

Conflict of interest statement

The authors report no conflicts of interest.

References

  1. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315 (8):801–810, 2016. - PubMed
  2. Rhodes A, Evans LE, Alhazzani W, Levy MM, Antonelli M, Ferrer R, Kumar A, Sevransky JE, Sprung CL, Nunnally ME, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med 43 (3):304–377, 2017. - PubMed
  3. Sevransky JE, Nour S, Susla GM, Needham DM, Hollenberg S, Pronovost S. Hemodynamic goals in randomized clinical trials in patients with sepsis: a systematic review of the literature. Crit Care 11 (3):R67, 2007. - PubMed
  4. Macias WL, Nelson DR, Williams M, Garg R, Janes J, Sashegyi A. Lack of evidence for qualitative treatment by disease severity interactions in clinical studies of severe sepsis. Crit Care 9 (6):R607–R622, 2005. - PubMed
  5. Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet 392 (10141):75–87, 2018. - PubMed
  6. Kashiouris MG, L’Heureux M, Cable CA, Fisher BJ, Leichtle SW, Fowler AA. The emerging role of vitamin C as a treatment for sepsis. Nutrients 12 (2):292, 2020. - PubMed
  7. Pohanka M, Pejchal J, Snopkova S, Havlickova K, Karasova JZ, Bostik P, Pikula J. Ascorbic acid: an old player with a broad impact on body physiology including oxidative stress suppression and immunomodulation: a review. Mini Rev Med Chem 12 (1):35–43, 2012. - PubMed
  8. Kaźmierczak-Barańska J, Boguszewska K, Adamus-Grabicka A, Karwowski BT. Two faces of vitamin C-antioxidative and pro-oxidative agent. Nutrients 12 (5):1501, 2020. - PubMed
  9. Cárcamo JM, Pedraza A, Bórquez-Ojeda O, Golde DW. Vitamin C suppresses TNF alpha-induced NF kappa B activation by inhibiting I kappa B alpha phosphorylation. Biochemistry 41 (43):12995–13002, 2002. - PubMed
  10. Qing Z, Xiao-Hui W, Xi-Mei W, Chao-Chun Z. Vitamin C deficiency aggravates tumor necrosis factor α-induced insulin resistance. Eur J Pharmacol 829:1–11, 2018. - PubMed
  11. Fisher BJ, Kraskauskas D, Martin EJ, Farkas D, Wegelin JA, Brophy D, Ward KR, Voelkel NF, Fowler AA 3rd, Natarajan R. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. Am J Physiol Lung Cell Mol Physiol 303 (1):L20–L32, 2012. - PubMed
  12. Hagel AF, Layritz CM, Hagel WH, Hagel HJ, Hagel E, Dauth W, Kressel J, Regnet T, Rosenberg A, Neurath MF, et al. Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases. Naunyn Schmiedebergs Arch Pharmacol 386 (9):789–793, 2013. - PubMed
  13. Kim SR, Ha YM, Kim YM, Park EJ, Kim JW, Park SW, Kim HJ, Chung HT, Chang KC. Ascorbic acid reduces HMGB1 secretion in lipopolysaccharide-activated RAW 264.7 cells and improves survival rate in septic mice by activation of Nrf2/HO-1 signals. Biochem Pharmacol 95 (4):279–289, 2015. - PubMed
  14. Manning J, Mitchell B, Appadurai A, Shakya A, Pierce LJ, Wang H, Nganga V, Swanson PC, May JM, Tantin D, et al. Vitamin C promotes maturation of T-cells. Antioxid Redox Signal 19 (17):2054–2067, 2013. - PubMed
  15. Thomas WR, Holt PG. Vitamin C and immunity: an assessment of the evidence. Clin Exp Immunol 32 (2):370–379, 1978. - PubMed
  16. Dey S, Bishayi B. Killing of S. aureus in murine peritoneal macrophages by Ascorbic acid along with antibiotics chloramphenicol or ofloxacin: correlation with inflammation. Microb Pathog 115:239–250, 2018. - PubMed
  17. Kallio J, Jaakkola M, Mäki M, Kilpeläinen P, Virtanen V. Vitamin C inhibits Staphylococcus aureus growth and enhances the inhibitory effect of quercetin on growth of Escherichia coli in vitro. Planta Med 78 (17):1824–1830, 2012. - PubMed
  18. Colunga Biancatelli RML, Berrill M, Catravas JD, Marik PE. Quercetin and vitamin C: an experimental, synergistic therapy for the prevention and treatment of SARS-CoV-2 related disease (COVID-19). Front Immunol 11:1451, 2020. - PubMed
  19. Carr AC, Rowe S. The emerging role of vitamin C in the prevention and treatment of COVID-19. Nutrients 12 (11):3286, 2020. - PubMed
  20. Marik PE, Kory P, Varon J, Iglesias J, Meduri GU. MATH+ protocol for the treatment of SARS-CoV-2 infection: the scientific rationale. Expert Rev Anti Infect Ther 19 (2):129–135, 2021. - PubMed
  21. Rygård SL, Butler E, Granholm A, Møller MH, Cohen J, Finfer S, Perner A, Myburgh J, Venkatesh B, Delaney A. Low-dose corticosteroids for adult patients with septic shock: a systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 44 (7):1003–1016, 2018. - PubMed
  22. Marik PE. Hydrocortisone, ascorbic acid and thiamine (HAT therapy) for the treatment of sepsis. Focus on ascorbic acid. Nutrients 10 (11):1762, 2018. - PubMed
  23. 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 151 (6):1229–1238, 2017. - PubMed
  24. Zabet MH, Mohammadi M, Ramezani M, Khalili H. Effect of high-dose ascorbic acid on vasopressor's requirement in septic shock. J Res Pharm Pract 5 (2):94–100, 2016. - PubMed
  25. Fowler AA 3rd, Truwit JD, Hite RD, Morris PE, DeWilde C, Priday A, Fisher B, Thacker LR 2nd, Natarajan R, Brophy DF, et al. The CITRIS-ALI randomized clinical trial. JAMA 322 (13):1261–1270, 2019. - PubMed
  26. Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, Deane AM, Shehabi Y, Hajjar LA, Oliveira G, 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 323 (5):423–431, 2020. - PubMed
  27. Chang P, Liao Y, Guan J, Guo Y, Zhao M, Hu J, Zhou J, Wang H, Cen Z, Tang Y, et al. Combined treatment with hydrocortisone, vitamin C, and thiamine for sepsis and septic shock: a randomized controlled trial. Chest 158 (1):174–182, 2020. - PubMed
  28. 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 158 (1):164–173, 2020. - PubMed
  29. Sevransky JE, Rothman RE, Hager DN, Bernard GR, Brown SM, Buchman TG, Busse LW, Coopersmith CM, DeWilde C, Ely EW, et al. Effect of vitamin C, thiamine, and hydrocortisone on ventilator- and vasopressor-free days in patients with sepsis: the VICTAS randomized clinical trial. JAMA 325 (8):742–750, 2021. - PubMed
  30. Kumar V. Sepsis roadmap: what we know, what we learned, and where we are going. Clin Immunol 210:108264, 2020. - PubMed
  31. Barratt-Due A, Pischke SE, Nilsson PE, Espevik T, Mollnes TE. Dual inhibition of complement and Toll-like receptors as a novel approach to treat inflammatory diseases – C3 or C5 emerge together with CD14 as promising targets. J Leukoc Biol 101 (1):193–204, 2017. - PubMed
  32. Barratt-Due A, Pischke SE, Brekke OL, Thorgersen EB, Nielsen EW, Espevik T, Huber-Lang M, Mollnes TE. Bride and groom in systemic inflammation – the bells ring for complement and Toll in cooperation. Immunobiology 217 (11):1047–1056, 2012. - PubMed
  33. Bar-Or D, Carrick MM, Mains CW, Rael LT, Slone D, Brody EN. Sepsis, oxidative stress, and hypoxia: are there clues to better treatment? Redox Rep 20 (5):193–197, 2015. - PubMed
  34. Skjeflo EW, Christiansen D, Landsem A, Stenvik J, Woodruff TM, Espevik T, Nielsen EW, Mollnes TE. Phagocytosis of live and dead Escherichia coli and Staphylococcus aureus in human whole blood is markedly reduced by combined inhibition of C5aR1 and CD14. Mol Immunol 112:131–139, 2019. - PubMed
  35. Mollnes TE, Lea T, Frøland SS, Harboe M. Quantification of the terminal complement complex in human plasma by an enzyme-linked immunosorbent assay based on monoclonal antibodies against a neoantigen of the complex. Scand J Immunol 22 (2):197–202, 1985. - PubMed
  36. Mollnes TE, Redl H, Høgåsen K, Bengtsson A, Garred P, Speilberg L, Lea T, Oppermann M, Götze O, Schlag G. Complement activation in septic baboons detected by neoepitope-specific assays for C3b/iC3b/C3c, C5a and the terminal C5b-9 complement complex (TCC). Clin Exp Immunol 91 (2):295–300, 1993. - PubMed
  37. Bergseth G, Ludviksen JK, Kirschfink M, Giclas PC, Nilsson B, Mollnes TE. An international serum standard for application in assays to detect human complement activation products. Mol Immunol 56 (3):232–239, 2013. - PubMed
  38. Mollnes TE, Brekke OL, Fung M, Fure H, Christiansen D, Bergseth G, Videm V, Lappegård KT, Köhl J, Lambris JD. Essential role of the C5a receptor in E coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation. Blood 100 (5):1869–1877, 2002. - PubMed
  39. Ricklin D, Barratt-Due A, Mollnes TE. Complement in clinical medicine: clinical trials, case reports and therapy monitoring. Mol Immunol 89:10–21, 2017. - PubMed
  40. Ward PA. The harmful role of c5a on innate immunity in sepsis. J Innate Immun 2 (5):439–445, 2010. - PubMed
  41. Khan AA, Alsahli MA, Rahmani AH. Myeloperoxidase as an active disease biomarker: recent biochemical and pathological perspectives. Med Sci (Basel) 6 (2):33, 2018. - PubMed
  42. Xu X, Sun B. Platelet granule secretion mechanisms: are they modified in sepsis? Thromb Res 136 (5):845–850, 2015. - PubMed
  43. Waage A, Bakke O. Glucocorticoids suppress the production of tumour necrosis factor by lipopolysaccharide-stimulated human monocytes. Immunology 63 (2):299–302, 1988. - PubMed
  44. El-Benna J, Hurtado-Nedelec M, Marzaioli V, Marie JC, Gougerot-Pocidalo MA, Dang PM. Priming of the neutrophil respiratory burst: role in host defense and inflammation. Immunol Rev 273 (1):180–193, 2016. - PubMed
  45. Gonzalez-Perilli L, Prolo C, Álvarez MN. Arachidonic acid and nitroarachidonic: effects on NADPH oxidase activity. Adv Exp Med Biol 1127:85–95, 2019. - PubMed
  46. Brekke OL, Christiansen D, Fure H, Fung M, Mollnes TE. The role of complement C3 opsonization, C5a receptor, and CD14 in E. coli-induced up-regulation of granulocyte and monocyte CD11b/CD18 (CR3), phagocytosis, and oxidative burst in human whole blood. J Leukoc Biol 81 (6):1404–1413, 2007. - PubMed
  47. Brekke OL, Christiansen D, Fure H, Pharo A, Fung M, Riesenfeld J, Mollnes TE. Combined inhibition of complement and CD14 abolish E. coli-induced cytokine-, chemokine- and growth factor-synthesis in human whole blood. Mol Immunol 45 (14):3804–3813, 2008. - PubMed
  48. Skjeflo EW, Christiansen D, Espevik T, Nielsen EW, Mollnes TE. Combined inhibition of complement and CD14 efficiently attenuated the inflammatory response induced by Staphylococcus aureus in a human whole blood model. J Immunol 192 (6):2857–2864, 2014. - PubMed
  49. Huber-Lang M, Barratt-Due A, Pischke SE, Sandanger Ø, Nilsson PH, Nunn MA, Denk S, Gaus W, Espevik T, Mollnes TE. Double blockade of CD14 and complement C5 abolishes the cytokine storm and improves morbidity and survival in polymicrobial sepsis in mice. J Immunol 192 (11):5324–5331, 2014. - PubMed
  50. Skjeflo EW, Sagatun C, Dybwik K, Aam S, Urving SH, Nunn MA, Fure H, Lau C, Brekke OL, Huber-Lang M, et al. Combined inhibition of complement and CD14 improved outcome in porcine polymicrobial sepsis. Crit Care 19:415, 2015. - PubMed

Publication Types