Vitamin C in critical conditions: from bench to bedside (part 1)




vitamin C, pharmacokinetics, physiological role, sepsis, shock, trauma, burns


Vitamin C (ascorbic acid) plays an important physiological role in numerous metabolic functions. It is also a cofactor in the synthesis of important substances, in particular catecholamines and vasopressin. A decrease in the level of ascorbic acid has been noted in various diseases, often accompanying the severity of the patient’s state. The aim of this article is to review the current knowledge on the physiological role of vitamin C and the experimental evidences of its use in critically ill surgical patients. The pharmacodynamics of ascorbic acid, the possibility of using high doses of vitamin C are also considered. MEDLINE database on the PubMed platform was used to search for the literature sources with key words: vitamin C, sepsis, shock, trauma, burns.


Drouin G, Godin J.‐R. Pagé B. The genetics of vitamin C loss in vertebrates. Curr Genom. 2011;12:371–378. doi: 10.2174/138920211796429736.

Lachapelle MY, Drouin G. Inactivation dates of the human and guinea pig vitamin C genes. Genetica. 2011;139:199–207. doi: 10.1007/s10709-010-9537-x.

Pauling L. Evolution and the need for ascorbic acid. Proc Natl Acad Sci USA. 1970;67:1643–1648. doi: 10.1073/pnas.67.4.1643.

May J M, Harrison FE. Role of vitamin C in the function of the vascular endothelium. Antioxid Redox Signal. 2013;19:2068–2083. doi: 10.1089/ars.2013.5205.

Granger M., Eck P. Dietary vitamin C in human health. Adv. Food Nutr. Res. 2018;83:281–310. doi: 10.1016/bs.afnr.2017.11.006.

Daruwala R, Song J, Koh WS, Rumsey SC, Levine M. Cloning and functional characterization of the human sodium‐dependent vitamin C transporters hSVCT1 and hSVCT2. FEBS Lett. 1999;460:480–484. doi: 10.1016/s0014-5793(99)01393-9.

Tsukaguchi H, Tokui T, Mackenzie B, et al. A family of mammalian Na+‐dependent L‐ascorbic acid transporters. Nature. 1999;399:70–75. doi: 10.1038/19986.

Corpe CP, Eck P, Wang J, Al‐Hasani H, Levine M. Intestinal dehydroascorbic acid (DHA) transport mediated by the facilitative sugar transporters, GLUT2 and GLUT8. J Biol Chem. 2013;288:9092–9101. doi: 10.1074/jbc.M112.436790.

Kuhn, V, Diederich L, Keller TCS, et al. Red blood cell function and dysfunction: Redox regulation, nitric oxide metabolism, anemia. Antioxid Redox Signal. 2017;26:718–742. doi: 10.1089/ars.2016.6954.

Berger MM, Oudemans-van Straaten HM. Vitamin C supplementation in the critically ill patient. Curr Opin Clin Nutr Metab Care 2015;18:193-201. doi: 10.1097/MCO.0000000000000148.

Savini I, Rossi A, Pierro C, Avigliano L, Catani MV. SVCT1 and SVCT2: key proteins for vitamin C uptake. Amino Acids. 2008;34:347-355 doi: 10.1007/s00726-007-0555-7.

Levine M, Conry‐Cantilena C, Wang Y, et al. Vitamin C pharmacokinetics in healthy volunteers: Evidence for a recommended dietary allowance. Proc Natl Acad Sci USA. 1996;93: 3704–3709. doi: 10.1073/pnas.93.8.3704.

Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: Implications for oral and intravenous use. Ann Intern Med. 2004;140:533–537. doi: 10.7326/0003-4819-140-7-200404060-00010.

Hager DN, Martin GS, Sevransky JE, Hooper MH. Glucometry when using vitamin C in sepsis: A note of caution. Chest. 2018;154:228–229. doi: 10.1016/j.chest.2018.03.018.

Cho J, Ahn S, Yim J, et al. Influence of vitamin C and maltose on the accuracy of three models of glucose meters. Ann Lab Med. 2016;36:271–274. doi: 10.3343/alm.2016.36.3.271.

Meng QH, Irwin WC, Fesser J, Massey KL. Interference of ascorbic acid with chemical analytes. Ann Clin Biochem. 2005;42(Pt 6):475–477. doi: 10.1258/000456305774538274.

Smith KE, Brown CS, Manning BM, et al. Accuracy of Point of Care Blood Glucose Level Measurements in Critically Ill Patients with Sepsis Receiving High-Dose Intravenous Vitamin C. Pharmacotherapy. 2018;38:1155–1161. doi: 10.1002/phar.2182.

Moskowitz A, Andersen LW, Huang DT, et al. Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation. Crit Care. 2018;22(1):283. doi: 10.1186/s13054-018-2217-4.

Lowes DA, Webster NR, Galley HF. Dehydroascorbic acid as pre-conditioner: Protection from lipopolysaccharide induced mitochondrial damage. Free Radic Res. 2010;44:283–292. doi: 10.3109/10715760903468766.

Yimcharoen M, Kittikunnathum S, Suknikorn C, et al. Effects of ascorbic acid supplementation on oxidative stress markers in healthy women following a single bout of exercise. J Int Soc Sports Nutr. 2019;16:2. doi: 10.1186/s12970-019-0269-8.

Marik PE. Hydrocortisone, Ascorbic Acid and Thiamine (HAT therapy) for the treatment of sepsis. Focus on ascorbic acid. Nutrients. 2018;10:1762. doi: 10.3390/nu10111762.

Marik PE. Vitamin C for the treatment of sepsis: The scientific rationale. Pharmacol Ther. 2018;189:63–70. doi: 10.1016/j.pharmthera.2018.04.007.

Carr AC, Maggini S. Vitamin C and Immune Function. Nutrients 2017;9:1211. doi: 10.3390/nu9111211.

Padayatty SJ, Levine M. Vitamin C physiology: the known and the unknown and Goldilocks. Oral Dis. 2016;22(6):463–493. doi: 10.1111/odi.12446.

van Gorkom GNY, Klein Wolterink RGJ, Van Elssen CHMJ, Wieten L, Germeraad WTV, Bos GMJ. Influence of Vitamin C on Lymphocytes: An Overview. Antioxidants. 2018;7:E41. doi: 10.3390/antiox7030041.

Tanaka M, Muto N, Gohda E, Yamamoto I. Enhancement by ascorbic acid 2-glucoside or repeated additions of ascorbate of mitogen-induced IgM and IgG productions by human peripheral blood lymphocytes. Jpn J Pharmacol. 1994;66:451–456. doi: 10.1254/jjp.66.451.

Gao YL, Lu B, Zhai JH, et al. The parenteral vitamin C improves sepsis and sepsis-induced multiple organ dysfunction syndrome via preventing cellular immunosuppression. Mediators Inflamm. 2017;2017:4024672. doi: 10.1155/2017/4024672.

Nusgens BV, Humbert P, Rougier A, Richard A, Lapière CM. Stimulation of collagen biosynthesis by topically applied vitamin C. Eur J Dermatol. 2002;12:XXXII–XXXIV. PMID: 12120619.

Teuwen LA, Draoui N, Dubois C, Carmeliet P. Endothelial cell metabolism: an update anno 2017. Curr Opin Hematol. 2017;24:240–247 doi 10.1097/MOH.0000000000000335.

Wang ZY, Liu YY, Liu GH, Lu HB, Mao CY. l-Carnitine and heart disease. Life Sci. 2018;194:88–97. doi: 10.1016/j.lfs.2017.12.015.

Puskarich M.A, Kline JA, Krabill V, Claremont H, Jones AE. Preliminary safety and efficacy of L-carnitine infusion for the treatment of vasopressor-dependent septic shock: A randomized control trial. JPEN J Parenter Enteral Nutr. 2014;38:736–743. doi: 10.1177/0148607113495414.

Oudemans-van Straaten HM, Spoelstra-de Man A, de Waard MC. Vitamin C revisited. Crit Care. 2014;18(4):460. doi: 10.1186/s13054-014-0460-x.

Carr AC, Shaw G, Fowler AA, Natarajan R. Ascorbate-dependent vasopressor synthesis- a rationale for vitamin C administration in severe sepsis and septic shock? Crit Care. 2015;19:418. doi: 10.1186/s13054-015-1131-2.

Bornstein SR, Yoshida-Hiroi M, Sotiriou S, et al. Impaired adrenal catecholamine system function in mice with deficiency of the ascorbic acid transporter (SVCT2). FASEB J. 2003;17:1928–1930. doi: 10.1096/fj.02-1167fje.

Dillon PF, Root-Bernstein R, Robinson NE, Abraham WM, Berney C. Receptor-mediated enhancement of beta adrenergic drug activity by ascorbate in vitro and in vivo. PloS One. 2010;5:e15130. doi: 10.1371/journal.pone.0015130.

May JM, Qu ZC, Meredith ME. Mechanisms of ascorbic acid stimulation of norepinephrine synthesis in neuronal cells. Biochem Biophys Res Commun 2012;426:148–152. doi: 10.1016/j.bbrc.2012.08.054.

Wilson JX. Evaluation of vitamin C for adjuvant sepsis therapy. Antioxid Redox Signal. 2013;19:2129–2140. doi: 10.1089/ars.2013.5401.

Kim SR, Kim YM, Park EJ, Kim JW, Park SW, Kim HJ. 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. 2015;95:279–289. doi: 10.1016/j.bcp.2015.04.007..

Hagel AF, Layritz CM, Hagel WH, et al. Intravenous infusion of ascorbic acid decreases serum histamine concentrations in patients with allergic and non-allergic diseases. Naunyn-Schmiedebergs Arch Pharmacol. 2013;386:789–793. doi: 10.1007/s00210-013-0880-1.

Hattori M, Yamazaki M, Ohashi W, et al. Critical role of endogenous histamine in promoting end-organ tissue injury in sepsis. Intensive Care Med Exp. 2016;4:36. doi: 10.1186/s40635-016-0109-y.

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. 2020;12(2):292. doi: 10.3390/nu12020292.

Langlois PL, Lamontagne FL. Vitamin C for the critically ill: Is the evidence strong enough? Nutrition. 2019;60:185–190. doi: 10.1016/j.nut.2018.10.009.

Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J. 1999;13:1007–1024. doi: 10.1096/fasebj.13.9.1007.

Larsen R, Gozzelino R, Jeney V, et al. A central role for free heme in the pathogenesis of severe sepsis. Sci Transl Med. 2010;2:51ra71. doi: 10.1126/scitranslmed.3001118.

Seo MY, Lee SM. Protective effect of low dose of ascorbic acid on hepatobiliary function in hepatic ischemia/reperfusion in rats. J Hepatol. 2002;36:72–77. doi: 10.1016/s0168-8278(01)00236-7.

Park SW, Lee SM. Antioxidant and prooxidant properties of ascorbic acid on hepatic dysfunction induced by cold ischemia/reperfusion. Eur J Pharmacol. 2008;580:401–406. doi: 10.1016/j.ejphar.2007.11.023.

Manzella JP, Roberts NJ. Human macrophage and lymphocyte responses to mitogen stimulation after exposure to influenza virus, ascorbic acid, and hyperthermia. J Immunol. 1979;123:1940–1944. PMID: 489966.

Siegel BV. Enhancement of interferon production by poly(rI)-poly(rC) in mouse cell cultures by ascorbic acid. Nature. 1975;254:531–532. doi: 10.1038/254531a0.

Motl J, Radhakrishnan J, Ayoub IM, Grmec S, Gazmuri RJ. Vitamin C compromises cardiac resuscitability in a rat model of ventricular fibrillation. Am J Ther. 2014;21:352–357. doi: 10.1097/MJT.0b013e31824e2b9f.

Levine M, Padayatty SJ, Espey MG. Vitamin C: A concentration-function approach yields pharmacology and therapeutic discoveries. Adv Nutr. 2011;2:78–88. doi: 10.3945/an.110.000109.

Muhlhofer A, Mrosek S, Schlegel B, et al. High-dose intravenous vitamin C is not associated with an increase of pro-oxidative biomarkers. Eur J Clin Nutr 2004;58:1151–1158. doi: 10.1038/sj.ejcn.1601943.

Dennis JM, Witting PK. Protective Role for Antioxidants in Acute Kidney Disease. Nutrients 2017;9:E718. doi: 10.3390/nu9070718.

Armour J, Tyml K, Lidington D, Wilson JX. Ascorbate prevents microvascular dysfunction in the skeletal muscle of the septic rat. J Appl Physiol. 2001;90:795–803. doi: 10.1152/jappl.2001.90.3.795.

Tyml K, Li F, Wilson JX. Delayed ascorbate bolus protects against maldistribution of microvascular blood flow in septic rat skeletal muscle. Crit Care Med. 2005;33:1823–1828. doi: 10.1097/

Fisher BJ, Seropian IM, Kraskauskas D, et al. Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury. Crit. Care Med. 2011;39:1454–1460. doi: 10.1097/CCM.0b013e3182120cb8.

Fisher BJ, Kraskauskas D, Martin EJ, et al. Mechanisms of attenuation of abdominal sepsis induced acute lung injury by ascorbic acid. Am J Physiol Lung Cell Mol Physiol. 2012;303:L20–32. doi: 10.1152/ajplung.00300.2011.

Bark BP, Grände P-O. The effect of vitamin C on plasma volume in the early stage of sepsis in the rat. Intensive Care Med Exp. 2014;2:11.

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. 2018;115:239–250. doi: 10.1016/j.micpath.2017.12.048.

Barabutis N, Khangoora V, Marik PE, Catravas JD. Hydrocortisone and Ascorbic Acid synergistically protect and repair lipopolysaccharide-induced pulmonary endothelial barrier dysfunction. Chest. 2017;152:954–962. doi: 10.1016/j.chest.2017.07.014.

Reynolds PS, Fisher BJ, McCarter J, et al. Interventional vitamin C: A strategy for attenuation of coagulopathy and inflammation in a swine multiple injuries model. J Trauma Acute Care Surg. 2018;85:S57–67 doi: 10.1097/TA.0000000000001844.

Qi MZ, Yao Y, Xie RL, et al. Intravenous Vitamin C attenuates hemorrhagic shock-related renal injury through the induction of SIRT1 in rats. Biochem Biophys Res Commun. 2018;501:358–364. doi: 10.1016/j.bbrc.2018.04.111.

Ma L, Fei J, Chen Y, Zhao B, et al. Vitamin C Attenuates Hemorrhagic Shock-induced Dendritic Cell-specific Intercellular Adhesion Molecule 3-grabbing Nonintegrin Expression in Tubular Epithelial Cells and Renal Injury in Rats. Chin Med J. 2016;129: 1731–1736. doi: 10.4103/0366-6999.185868.

Zhao B, Fei J, Chen Y, et al. Vitamin C treatment attenuates hemorrhagic shock related multi-organ injuries through the induction of heme oxygenase-1. BMC Complement Altern Med. 2014;14:442. doi: 10.1186/1472-6882-14-442.

Zhao B, Fei J, Chen Y, et al. Pharmacological preconditioning with vitamin C attenuates intestinal injury via the induction of heme oxygenase-1 after hemorrhagic shock in rats. PLoS One. 2014;9:e99134. doi: 10.1371/journal.pone.0099134.

Ekman T, Risberg B, Bagge U. Ascorbate reduces gastric bleeding after hemorrhagic shock and retransfusion in rats. Eur Surg Res. 1994;26:187–193. doi: 10.1159/000129335.

Bhandari B, Kohli SK, Lal V. Protective role of ascorbic acid in hemorrhage-induced cardiovascular depression. Indian J Physiol Pharmacol. 2014;58:371–375. PMID: 26215003.

Minor T, Niessen F, Klauke H, Isselhard W. No evidence for a protective effect of ascorbic acid on free radical generation and liver injury after hemorrhagic shock in rats. Shock. 1996;5:280–283. doi: 10.1097/00024382-199604000-00008.

Daughters K, Waxman K, Gassel A, Zommer S. Anti-oxidant treatment for shock: vitamin E but not vitamin C improves survival. Am Surg. 1996;62:789–792. PMID: 8813156.

Kremer T, Harenberg P, Hernekamp F, et al. High-dose vitamin C treatment reduces capillary leakage after burn plasma transfer in rats. J Burn Care Res. 2010;31:470–479. doi: 10.1097/BCR.0b013e3181db5199.

Matsuda T, Tanaka H, Williams S, Hanumadass M, Abcarian H, Reyes H. Reduced fluid volume requirement for resuscitation of thirddegree burns with high-dose vitamin C. J Burn Care Rehabil. 1991;12:525–532. doi: 10.1097/00004630-199111000-00007.

Dubick MA, Williams C, Elgjo GI, Kramer GC. High-dose vitamin C infusion reduces fluid requirements in the resuscitation of burn-injured sheep. Shock. 2005;24:139–144. doi: 10.1097/01. shk.0000170355.26060.e6.

Mohammed BM, Fisher BJ, Kraskauskas D, et al. Vitamin C promotes wound healing through novel pleiotropic mechanisms. Int Wound J. 2016;13:572–584. doi: 10.1111/iwj.12484.

Spoelstra-de Man AME, Elbers PWG, Oudemans-van Straaten HM. Making sense of early high-dose intravenous vitamin C in ischemia/reperfusion injury. Crit Care. 2018;22:70. doi:10.1186/s13054-018-1996-y.

Hao J, Li, WW, Du H, Zhao ZF, Liu F, Lu JC. Role of vitamin C in cardioprotection of ischemia/reperfusion injury by activation of mitochondrial KATP channel. Chem Pharm Bull. 2016;64:548–557. doi: 10.1248/cpb.c15-00693.

Okazaki T, Otani H, Shimazu T, Yoshioka K, Fujita M, Iwasaka T. Ascorbic acid and N-acetyl cysteine prevent uncoupling of nitric oxide synthase and increase tolerance to ischemia/reperfusion injury in diabetic rat heart. Free Radic Res. 2011;45:1173–1183. doi: 10.3109/10715762.2011.605361.

Klein HH, Pich S, Lindert S, Nebendahl K, Niedmann P, Kreuzer H. Combined treatment with vitamins E and C in experimental myocardial infarction in pigs. Am Heart J. 1989;118:667–673. doi: 10.1016/0002-8703(89)90577-2.

Doppelfeld IS, Parnham MJ. Experimental conditions determine effects of ascorbic acid on reperfusion injury: comparison of tissue damage with hemodynamic parameters in rat isolated hearts. Methods Find Exp Clin Pharmacol. 1992;14:419–430. PMID: 1469951.

Mickle DA, Li RK, Weisel RD, et al. Myocardial salvage with trolox and ascorbic acid for an acute evolving infarction. Ann Thorac Surg. 1989;47:553–557. doi: 10.1016/0003-4975(89)90431-1.

Chatziathanasiou GN, Nikas DN, Katsouras CS, et al. Combined intravenous treatment with ascorbic acid and desferrioxamine to reduce myocardial reperfusion injury in an experimental model resembling the clinical setting of primary PCI. Hell J Cardiol. 2012;53:195–204. PMID: 22653244.

Skyschally A, Schulz R, Gres P, Korth HG, Heusch G. Attenuation of ischemic preconditioning in pigs by scavenging of free oxyradicals with ascorbic acid. Am J Physiol Heart Circ Physiol. 2003;284:H698–703. doi: 10.1152/ajpheart.00693.2002.

Nikas DN, Chatziathanasiou G, Kotsia A, et al. Effect of intravenous administration of antioxidants alone and in combination on myocardial reperfusion injury in an experimental pig model. Curr Ther Res Clin Exp. 2008;69:423–439. doi: 10.1016/j.curtheres.2008.10.006.

Okazaki T, Otani H, Shimazu T, Yoshioka K, Fujita M, Iwasaka T. Ascorbic acid and N-acetyl cysteine prevent uncoupling of nitric oxide synthase and increase tolerance to ischemia/reperfusion injury in diabetic rat heart. Free Radic Res. 2011;45:1173–1183. doi: 10.3109/10715762.2011.605361.

Guaiquil VH, Golde DW, Beckles DL, Mascareno EJ, Siddiqui MA. Vitamin C inhibits hypoxia-induced damage and apoptotic signaling pathways in cardiomyocytes and ischemic hearts. Free Radic Biol Med. 2004;37:1419–1429. doi: 10.1016/j.freeradbiomed.2004.06.041.

Gao F, Yao CL, Gao E, et al. Enhancement of glutathione cardioprotection by ascorbic acid in myocardial reperfusion injury. J Pharmacol Exp Ther. 2002;301:543–550. doi: 10.1124/jpet.301.2.543.

Tan DX, Manchester LC, Reiter RJ, Qi W, Kim SJ, El-Sokkary GH. Ischemia/reperfusion-induced arrhythmias in the isolated rat heart: prevention by melatonin. J Pineal Res. 1998;25:184–191. doi: 10.1111/j.1600-079x.1998.tb00558.x.

Karahaliou A, Katsouras C, Koulouras V, et al. Ventricular arrhythmias and antioxidative medication: experimental study. Hell J Cardiol. 2008;49:320–328. PMID: 18846922.

Molyneux CA, Glyn MC, Ward BJ. Oxidative stress and cardiac microvascular structure in ischemia and reperfusion: the protective effect of antioxidant vitamins. Microvasc Res. 2002;64:265–277. doi: 10.1006/mvre.2002.2419.

Tsai MS, Huang CH, Tsai CY, et al. Ascorbic acid mitigates the myocardial injury after cardiac arrest and electrical shock. Intensive Care Med. 2011;37:2033–2040. doi: 10.1007/s00134-011-2362-6.

Tsai MS, Huang CH, Tsai CY, et al. Combination of intravenous ascorbic acid administration and hypothermia after resuscitation improves myocardial function and survival in a ventricular fibrillation cardiac arrest model in the rat. Acad Emerg Med. 2014;21:257–265. doi: 10.1111/acem.12335.





Scientific Review