1. C for Sepsis
Fact or Fiction?

2. C for
Sepsis
•History
•Rationale
•RCTs

3. History

4. History

5. C for
Sepsis
•History
•Rationale
•RCTs

6. Rationale
Vitamin C Deficiency Common
15% in “Scurvy” range
Deficiency associated with
Mortality
Vasopressor requirement
SOFA
Renal Failure
De Grooth et al 2014, Intensive Care Medicine

7. Rationale
Endogenous vasopressor synthesis requires
Vitamin C
Dopamine β-monooxygenase
Peptidylglycine α-amidating monooxygenase

8. Rationale
Vitamin C inhibits NADPH Oxidase
Scavenging superoxide radicals
 Endothelial & Epithelial
 Immunomodulation
Wilson JX. (2009) Biofactors

9. Rationale
Vitamin C preserves endothelial glycocalyx
LPS
↓ Glycocalyx
LPS + Vitamin C
- Preserved glycocalyx
Purwoko (2019) Drug Intervention Today

10. Rationale
Vitamin C resolves vascular permeability
Caecal ligation and perforation
↑ PP2A activation
↓ Occludin phosphorylation
↑ Vascular permeability
Vitamin C
↓PP2A activity
- Preserved Occludin phosphorylation
- Normalised vascular permeability
Zhao et al (2012) American Journal of Physiology

11. Vitamin C restores pulmonary epithelial integrity
LPS
↓ Aquaporin 5, CFTR, ENaC
- Na/K ATPase  Intracellular
- Pulmonary oedema
Vitamin C
↑ Aquaporin 5, CFTR
- Na/K ATPase  Plasma membrane
- Restored pulmonary architecture
Natharanjan et al (2011) American Journal of Respiratory and Critical Care Medicine
Fisher et al (2011) Critical Care Medicine
Rationale

12. Rationale
Vitamin C restores pulmonary epithelial integrity
Cell Free Hb
↑ Vascular permeability
- Pulmonary oedema
Pre-treatment with Vitamin C
↓ Vascular permeability
↓ Pulmonary oedema
Bastarache (2018) Shock

13. Rationale
Vitamin C resolves pulmonary coagulopathy
IP injection of Fecal Stem Solution
↓ Clot formation, strength, stability
- Microthrombi deposition
Vitamin C injection
- Restoration of coagulation
↓ Microthombi
Natharanjan et al (2011) American Journal of Respiratory and Critical Care Medicine

14. Rationale
Vitamin C prevents NETosis
IP Injection of Fecal Stem Solution
↑ NETosis by histology and serum cf-DNA
Vitamin C
↓ NETosis
↓ Organ damage
Nataranjan et al (2013) American Journal of Respiratory and Critical Care Medicine
Mohammed et al (2013) Nutrients
Natarajan et al (2014) American Journal of Respiratory and Critical Care Medicine

15. C for
Sepsis
•History
•Rationale
•RCTs

16. CITRIS-ALI
Multicentre RCT
Primary Outcomes – No difference
• ΔSOFA
• CRP, Thrombomodulin
Secondary Outcomes
• ↓ Mortality
• ↑ Hospital and ICU free days
• Not adjusted for multiple comparisons
Fowler et al (2019) JAMA

17. VITAMINS
Multicentre Open-Labelled RCT
Primary Outcomes – No difference
• Time alive and vasopressor free
Secondary Outcomes
• No mortality difference
• No difference Vasopressor use
• Improved SOFA at D3
Fujii et al (2019) JAMA

18. HYVCTTSSS
Single Centre RCT
Primary Outcomes – No difference
• Mortality
Secondary Outcomes
• ↓Mortality
w earlier diagnosis
• Improved SOFA
at D3
Chang et (2020) Chest

19. ORANGES
Multicentre RCT
Primary Outcomes
• Reduced time
requiring
vasopressors
Secondary Outcomes
No difference
• Mortality
• LOS
• Adverse Events
Iglesias et al (2020) Chest

20. VICTOR
Single Centre RCT
Primary Outcomes – No difference
• Mortality
Secondary Outcomes
• Reduced time requiring vasopressors
• No difference in LOS
Mohamed et al (2020) Indian Journal of Critical Care Medicine

21. ACTS
Multicentre RCT
Primary Outcomes
No difference
• SOFA
Secondary Outcomes
• Increased shock free days
• No difference in mortality,
LOS, adverse events
Moskowitz et al (2020) JAMA

22. ATESS
Multicentre RCT
Primary Outcomes
No difference
• SOFA
Secondary Outcomes
• No difference in mortality,
LOS, vasopressor free
days
Hwang et al (2020) Intensive Care Medicine

23. Scholz et al
Systematic
Meta-Analysis
• No reduction in pooled
mortality
• Mortality benefit if
treated for 3~4 days
• Minimal adverse
events reported
Scholz et al (2021) Critical Care

24. Why?

25. Why?
Transcriptomic Phenotypes?
Inflammopathic
Adaptive
Coagulopathic
Sweeney et al (2019) Critical Care Medicine
Iglesias et al (2021) Journal of Personalized Medicine

26. Why?
Is timing of therapy important?
Frommelt et al (2019) Trials

27. References
• De Grooth, H. J. S., Spoelstra-De Man, A. M. E. & Oudemans-Van Straaten, H. M. (2014). Early plasma vitamin c concentration, organ dysfunction and icu mortality. Intensive Care Medicine, 40(1): S199-S200
• De Grooth, H. J. S., Spoelstra-De Man, A. M. E., De Waard, M. C. & Oudemans-Van Straaten, H. M. (2014). Plasma vitamin c in critically ill patients is related to organ dysfunction and mortality. Clinical Nutrition,
33: S2
• Wilson JX. Mechanism of action of vitamin C in sepsis: ascorbate modulates redox signaling in endothelium. Biofactors (Oxford, England). 2009 Jan-Feb;35(1):5-13. DOI: 10.1002/biof.7.
• Natarajan, R., Fisher, B. J., Kraskauskas, D. & Fowler, A. A. (2011). Induction of epithelial channels by vitamin c resolves pulmonary edema following acute lung injury. American Journal of Respiratory and Critical
Care Medicine. Conference: American Thoracic Society International Conference, ATS, 183(1 MeetingAbstracts)
• Fisher, B. J., Seropian, I. M., Kraskauskas, D., Thakkar, J. N., Voelkel, N. F., Fowler, A. A., 3rd & Natarajan, R. (2011). Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury. Critical Care Medicine,
39(6): 1454-60.
• Natarajan, R., Fisher, B. J., Kraskauskas, D., Martin, E. J., Brophy, D., Ward, K. R. & Fowler, A. A. (2012). Vitamin c attenuates sepsis induced lung injury by preventing associated coagulopathy. American Journal
of Respiratory and Critical Care Medicine. Conference: American Thoracic Society International Conference, ATS, 185(MeetingAbstracts)
• Bastarache, J. A., Shaver, C. M., Wickersham, N. E., Mcneil, J. B., May, J. M. & Ware, L. B. (2018). Vitamin c attenuates vascular permeability induced by cell-free hemoglobin in the ex vivo perfused human lung.
Shock, 49 (6 Supplement 1): 108.
• Purwoko, P. (2019). Low-dose corticosteroid and vitamin c effects on endothelial cell glycocalyx expression in sepsis model human umbilical vein endothelial cells culture. Drug Invention Today, (11): 2598-
604.
• Zhou, G., Kamenos, G., Pendem, S., Wilson, J. X. & Wu, F. (2012). Ascorbate protects against vascular leakage in cecal ligation and puncture-induced septic peritonitis. American Journal of Physiology -
Regulatory Integrative & Comparative Physiology, 302(4): R409-16.
• Natarajan, R., Fisher, B. J., Kraskauskas, D., Mohammed, B., Martin, E. J., Brophy, D., Voelkel, N. F. & Fowler, A. A. (2013). Vitamin c prevents sepsis induced organ injury by attenuating neutrophil extracellular
trap formation. American Journal of Respiratory and Critical Care Medicine. Conference: American Thoracic Society International Conference, ATS, 187(MeetingAbstracts)
• Mohammed, B. M., Fisher, B. J., Kraskauskas, D., Farkas, D., Brophy, D. F., Fowler, A. A., 3rd & Natarajan, R. (2013). Vitamin c: A novel regulator of neutrophil extracellular trap formation. Nutrients, 5(8): 3131-51.
Natarajan, R., Fisher, B. J., Syed, A. & Fowler, A. A. (2014). Cell-free and mitochondrial DNA levels in severe sepsis: Effect of intervention with parenteral vitamin c. American Journal of Respiratory and Critical
Care Medicine. Conference: American Thoracic Society International Conference, ATS, 189(MeetingAbstracts)
• Fowler, A. A., 3rd, Truwit, J. D., Hite, R. D., Morris, P. E., Dewilde, C., Priday, A., Fisher, B., Thacker, L. R., 2nd, Natarajan, R., Brophy, D. F., Sculthorpe, R., Nanchal, R., Syed, A., Sturgill, J., Martin, G. S., Sevransky, J.,
Kashiouris, M., Hamman, S., Egan, K. F., Hastings, A., Spencer, W., Tench, S., Mehkri, O., Bindas, J., Duggal, A., Graf, J., Zellner, S., Yanny, L., Mcpolin, C., Hollrith, T., Kramer, D., Ojielo, C., Damm, T., Cassity, E.,
Wieliczko, A. & Halquist, M. (2019). Effect of vitamin c infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: The citris-ali
randomized clinical trial. JAMA, 322(13): 1261-70.
• Fujii, T., Luethi, N., Young, P. J., Frei, D. R., Eastwood, G. M., French, C. J., Deane, A. M., Shehabi, Y., Hajjar, L. A., Oliveira, G., Udy, A. A., Orford, N., Edney, S. J., Hunt, A. L., Judd, H. L., Bitker, L., Cioccari, L.,
Naorungroj, T., Yanase, F., Bates, S., Mcgain, F., Hudson, E. P., Al-Bassam, W., Dwivedi, D. B., Peppin, C., Mccracken, P., Orosz, J., Bailey, M., Bellomo, R. & Investigators, V. T. (2020). 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): 423-31.
• Chang, P., Liao, Y., Guan, J., Guo, Y., Zhao, M., Hu, J., Zhou, J., Wang, H., Cen, Z., Tang, Y. & Liu, Z. (2020). Combined treatment with hydrocortisone, vitamin c, and thiamine for sepsis and septic shock: A
randomized controlled trial. Chest, 158(1): 174-82.
• Iglesias, J., Vassallo, A. V., Patel, V. V., Sullivan, J. B., Cavanaugh, J. & Elbaga, Y. (2020). Outcomes of metabolic resuscitation using ascorbic acid, thiamine, and glucocorticoids in the early treatment of sepsis:
The oranges trial. Chest, 158(1): 164-73.
• Mohamed, Z. U. (2020). Vitamin c therapy or routine care in septic shock (victor) trial. Indian Journal of Critical Care Medicine, 24 (SUPPL 2): S12.
• Moskowitz, A., Huang, D. T., Hou, P. C., Gong, J., Doshi, P. B., Grossestreuer, A. V., Andersen, L. W., Ngo, L., Sherwin, R. L., Berg, K. M., Chase, M., Cocchi, M. N., Mccannon, J. B., Hershey, M., Hilewitz, A., Korotun, M.,
Becker, L. B., Otero, R. M., Uduman, J., Sen, A., Donnino, M. W. & Investigators, A. C. T. (2020). Effect of ascorbic acid, corticosteroids, and thiamine on organ injury in septic shock: The acts randomized clinical
trial. JAMA, 324(7): 642-50.
• Hwang, S. Y., Ryoo, S. M., Park, J. E., Jo, Y. H., Jang, D. H., Suh, G. J., Kim, T., Kim, Y. J., Kim, S., Cho, H., Jo, I. J., Chung, S. P., Choi, S. H., Shin, T. G. & Kim, W. Y. (2020). Combination therapy of vitamin c and
thiamine for septic shock: A multi-centre, double-blinded randomized, controlled study. Intensive Care Medicine, 46(11): 2015-25
• Scholz, S. S., Borgstedt, R., Ebeling, N., Menzel, L. C., Jansen, G. & Rehberg, S. (2021). Mortality in septic patients treated with vitamin c: A systematic meta-analysis. Critical Care (London, England), 25(1): 17.
• Sweeney, T. E., Azad, T. D., Donato, M., Haynes, W. A., Perumal, T. M., Henao, R., Bermejo-Martin, J. F., Almansa, R., Tamayo, E., Howrylak, J. A., Choi, A., Parnell, G. P., Tang, B., Nichols, M., Woods, C. W., Ginsburg,
G. S., Kingsmore, S. F., Omberg, L., Mangravite, L. M., Wong, H. R., … Khatri, P. (2018). Unsupervised Analysis of Transcriptomics in Bacterial Sepsis Across Multiple Datasets Reveals Three Robust
Clusters. Critical care medicine, 46(6), 915–925
• Iglesias J, Vassallo AV, Liesenfeld O, Levine JS, Patel VV, Sullivan JB, Cavanaugh JB, Elbaga Y, Sweeney TE. A 33-mRNA Classifier Is Able to Produce Inflammopathic, Adaptive, and Coagulopathic Endotypes
with Prognostic Significance: The Outcomes of Metabolic Resuscitation Using Ascorbic Acid, Thiamine, and Glucocorticoids in the Early Treatment of Sepsis (ORANGES) Trial. J Pers Med. 2020 Dec
23;11(1):9.
• Frommelt, M.A., Kory, P. & Long, M.T. Letter on Update to the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) Protocol. Trials 21, 350 (2020).

28. C for Sepsis
Fact or Fiction?