Therapeutic potential of megadose vitamin C to reverse organ dysfunction in sepsis and COVID‐19
Clive N May, Rinaldo Bellomo, Yugeesh R Lankadeva
British Journal of Pharmacology, doi:10.1111/bph.15579
Sepsis induced by bacteria or viruses can result in multiorgan dysfunction, which is a major cause of death in intensive care units. Current treatments are only supportive, and there are no treatments that reverse the pathophysiological effects of sepsis. Vitamin C has antioxidant, anti-inflammatory, anticoagulant and immune modulatory actions, so it is a rational treatment for sepsis. Here, we summarise data that support the use of megadose vitamin C as a treatment for sepsis and COVID-19. Megadose intravenous sodium ascorbate (150 g per 40 kg over 7 h) dramatically improved the clinical state and cardiovascular, pulmonary, hepatic and renal function and decreased body temperature, in a clinically relevant ovine model of Gram-negative bacteriainduced sepsis. In a critically ill COVID-19 patient, intravenous sodium ascorbate (60 g) restored arterial pressure, improved renal function and increased arterial blood oxygen levels. These findings suggest that megadose vitamin C should be trialled as a treatment for sepsis and COVID-19.
CONFLICT OF INTEREST YRL, RB and CNM have a provisional patent on vitamin C use in sepsis (2020901120).
References
Alexander, Fabbro, Kelly, Mathie, Peters et al., The concise guide to PHARMACOLOGY 2019/20: Catalytic receptors, British Journal of Pharmacology,
doi:10.1111/bph.14751Alexander, Fabbro, Kelly, Mathie, Peters et al., The concise guide to PHARMACOLOGY 2019/20: Enzymes, British Journal of Pharmacology,
doi:10.1111/bph.14752Alexander, Kelly, Mathie, Peters, Veale et al., The concise guide to PHARMACOLOGY 2019/20: Transporters, British Journal of Pharmacology,
doi:10.1111/bph.14753Annane, Bellissant, Sebille, Lesieur, Mathieu et al., Impaired pressor sensitivity to noradrenaline in septic shock patients with and without impaired adrenal function reserve, British Journal of Clinical Pharmacology,
doi:10.1046/j.1365-2125.1998.00833.xCalzavacca, Evans, Bailey, Bellomo, May, Cortical and medullary tissue perfusion and oxygenation in experimental septic acute kidney injury, Critical Care Medicine,
doi:10.1097/CCM.0000000000001198Chen, Espey, Sun, Pooput, Kirk et al., Pharmacologic doses of ascorbate act as a prooxidant and decrease growth of aggressive tumor xenografts in mice, Proceedings of the National Academy of Sciences of the United States of America,
doi:10.1073/pnas.0804226105Chertoff, N-Acetylcysteine's role in sepsis and potential benefit in patients with microcirculatory derangements, Journal of Intensive Care Medicine,
doi:10.1177/0885066617696850Chiscano-Camon, Ruiz-Rodriguez, Ruiz-Sanmartin, Roca, Ferrer, Vitamin C levels in patients with SARS-CoV-2-associated acute respiratory distress syndrome, Critical Care,
doi:10.1186/s13054-020-03249-yFowler, Syed, Knowlson, Sculthorpe, Farthing et al., Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis, Journal of Translational Medicine,
doi:10.1186/1479-5876-12-32Fowler, Truwit, Hite, Morris, Dewilde et al., 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: The Journal of the American Medical Association,
doi:10.1001/jama.2019.11825Fujii, Luethi, Young, Frei, Eastwood 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: The Journal of the American Medical Association,
doi:10.1001/jama.2019.22176Holford, Carr, Jovic, Ali, Whitaker et al., Vitamin C-An adjunctive therapy for respiratory infection, sepsis and COVID-19, Nutrients,
doi:10.3390/nu12123760Hwang, Ryoo, Park, Jo, Jang et al., Combination therapy of vitamin C and thiamine for septic shock: A multi-Centre, double-blinded randomized, controlled study, Intensive Care Medicine,
doi:10.1007/s00134-020-06191-3Ivanov, Goc, Ivanova, Niedzwiecki, Rath, Inhibition of ACE2 expression by ascorbic acid alone and its combinations with other natural compounds, Infectious Diseases: Research and Treatment
Jamalimoghadamsiahkali, Zarezade, Koolaji, Seyedalinaghi, Zendehdel et al., Safety and effectiveness of high-dose vitamin C in patients with COVID-19: A randomized open-label clinical trial, European Journal of Medical Research,
doi:10.1186/s40001-021-00490-1Joffre, Hellman, Oxidative stress and endothelial dysfunction in sepsis and acute inflammation, Antioxidants & Redox Signaling,
doi:10.1089/ars.2021.0027Ladurner, Schmitt, Schachner, Atanasov, Werner et al., Ascorbate stimulates endothelial nitric oxide synthase enzyme activity by rapid modulation of its phosphorylation status, Free Radical Biology & Medicine,
doi:10.1016/j.freeradbiomed.2012.03.022Langenberg, Bagshaw, May, Bellomo, The histopathology of septic acute kidney injury: A systematic review, Critical Care,
doi:10.1186/cc6823Lankadeva, Okazaki, Evans, Bellomo, May, Renal medullary hypoxia: A new therapeutic target for septic acute kidney injury?, Seminars in Nephrology,
doi:10.1016/j.semnephrol.2019.10.004Lankadeva, Peiris, Okazaki, Birchall, Trask-Marino et al., Reversal of the pathophysiological responses to gram-negative sepsis by megadose vitamin C, Critical Care Medicine,
doi:10.1097/CCM.0000000000004770Marik, Khangoora, Rivera, Hooper, Catravas, Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: A retrospective before-after study, Chest,
doi:10.1016/j.chest.2016.11.036Matejovic, Krouzecky, Martinkova, Rokyta, Radej et al., Effects of tempol, a free radical scavenger, on long-term hyperdynamic porcine bacteremia, Critical Care Medicine,
doi:10.1097/01.CCM.0000162927.94753.63May, Bellomo, Lankadeva, Therapeutic potential of megadose vitamin C to reverse organ dysfunction in sepsis and COVID-19, British Journal of Pharmacology
Moskowitz, Huang, Hou, Gong, Doshi et al., Effect of ascorbic acid, corticosteroids, and thiamine on organ injury in septic shock: The ACTS randomized clinical trial, JAMA: The Journal of the American Medical Association,
doi:10.1001/jama.2020.11946Nourbakhsh, Singh, Role of renal oxygenation and mitochondrial function in the pathophysiology of acute kidney injury. Nephron, Clinical Practice,
doi:10.1159/000363545Rhodes, Evans, Alhazzani, Levy, Antonelli et al., Surviving sepsis campaign: International guidelines for management of sepsis and septic shock: 2016, Critical Care Medicine,
doi:10.1097/CCM.0000000000002255Rudd, Johnson, Agesa, Shackelford, Tsoi et al., Global, regional, and national sepsis incidence and mortality, 1990-2017: Analysis for the global burden of disease study, Lancet,
doi:10.1016/S0140-6736(19)32989-7Salama, Han, Yau, Reiss, Kramer et al., Tocilizumab in patients hospitalized with Covid-19 pneumonia, The New England Journal of Medicine,
doi:10.1056/NEJMoa2030340Schorah, Downing, Piripitsi, Gallivan, Al-Hazaa et al., Total vitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients, The American Journal of Clinical Nutrition,
doi:10.1093/ajcn/63.5.760Singer, Deutschman, Seymour, Shankar-Hari, Annane et al., The third international consensus definitions for sepsis and septic shock (Sepsis-3), JAMA: The Journal of the American Medical Association,
doi:10.1001/jama.2016.0287Subramanian, Sabui, Moradi, Marchant, Said, Inhibition of intestinal ascorbic acid uptake by lipopolysaccharide is mediated via transcriptional mechanisms, Biochimica et Biophysica Acta -Biomembranes,
doi:10.1016/j.bbamem.2017.10.010Yanase, Fujii, Naorungroj, Belletti, Luethi et al., Harm of intravenous high dose vitamin C therapy in adult patients: A scoping review, Critical Care Medicine,
doi:10.1097/CCM.0000000000004396Zabet, Mohammadi, Ramezani, Khalili, Effect of high-dose ascorbic acid on vasopressor's requirement in septic shock, Journal of Research in Pharmacy Practice,
doi:10.4103/2279-042X.179569Zhao, Ling, Li, Peng, Huang et al., Beneficial aspects of high dose intravenous vitamin C on patients with COVID-19 pneumonia in severe condition: A retrospective case series study, Annals of Palliative Medicine,
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'abstract': '<jats:p>Sepsis induced by bacteria or viruses can result in multiorgan dysfunction, which is '
'a major cause of death in intensive care units. Current treatments are only supportive, and '
'there are no treatments that reverse the pathophysiological effects of sepsis. Vitamin C has '
'antioxidant, anti‐inflammatory, anticoagulant and immune modulatory actions, so it is a '
'rational treatment for sepsis. Here, we summarise data that support the use of megadose '
'vitamin C as a treatment for sepsis and COVID‐19. Megadose intravenous sodium ascorbate '
'(150\u2009g per 40\u2009kg over 7\xa0h) dramatically improved the clinical state and '
'cardiovascular, pulmonary, hepatic and renal function and decreased body temperature, in a '
'clinically relevant ovine model of Gram‐negative bacteria‐induced sepsis. In a critically ill '
'COVID‐19 patient, intravenous sodium ascorbate (60\u2009g) restored arterial pressure, '
'improved renal function and increased arterial blood oxygen levels. These findings suggest '
'that megadose vitamin C should be trialled as a treatment for sepsis and COVID‐19.</jats:p>',
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