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
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
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
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