IV vitamin C article courtesy of Tim Ewer, Gerald Lewis and ACNEM

This article on use of IV vitamin C was originally published in The Journal of the Australian College of Nutritional and Environmental Medicine, Volume 30 No 1, April 2011.

"INTRAVENOUS VITAMIN C AND THE TREATMENT OF INFECTIONS'

Tim Ewer, MBChB, MSc, MRCP(UK), FRACP, FRNZCGP
Gerald Lewis, MBChB, FRCP(UK), FRACP, MD(Otago)

The use of intravenous vitamin C (IVC) is controversial and, as yet, mainstream medicine has not accepted it as a standard treatment for infections. The following article sets out some of the scientific information regarding the mechanisms of action, efficacy and potential risks of IVC.

BACKGROUND IV vitamin C

Historically, high doses were advocated almost immediately after ascorbic acid was isolated (Szent-Gyorgyi received the Nobel Prize for ascorbate-related work in 1937). In an overview of vitamin C use, Dr Andrew Saul¹ (assistant editor of the Journal of Orthomolecular Medicine) highlights the early medical pioneers of high-dose vitamin C therapy including Claus Washington Jungeblut (1898-1976); William J. McCormick (1880-1968), and Frederick R. Klenner (1907-1984.)

Jungeblut first published on ascorbate as a prevention and treatment for polio in 1935², which was also reproduced in later experiments^3-5. He went on to show that vitamin C inactivated diphtheria toxin⁶ and tetanus toxin⁷.

Between 1943 and 1947, Klenner, a specialist in diseases of the chest, cured 41 cases of viral pneumonia with vitamin C⁸.

By 1946, McCormick showed how vitamin C prevents and also cures kidney stones⁹; by 1957, how it fights cardiovascular disease and that smoking of one cigarette neutralizes inthe body approximately 25 mg of ascorbic acid¹⁰.

Beginning in the 1960s, Robert F. Cathcart, M.D. used large doses of vitamin C to treat pneumonia, hepatitis, and eventually AIDS¹¹ and Hugh D. Riordan (1932-2005) published on a variety of uses of IVC¹².

MECHANISM IV vitamin C

There is impelling evidence from animal models of sepsis that intravenous ascorbate injection increases survival and protects several microvascular functions, including capillary bloodflow, microvascular permeability barrier, and arteriolar responsiveness to vasoconstrictors and vasodilators¹³.

These effects are both rapid and persistent as ascorbate quickly accumulates in microvascular endothelial cells, scavenges reactive oxygen species, and acts through tetrahydrobiopterin to stimulate nitric oxide production by endothelial nitric oxide synthase. A major reason for the long duration of the improvement in microvascular function is that cells retain high levels of ascorbate, which alter redox sensitive signaling pathways to diminish septic induction of NADPH oxidase and inducible nitric oxide synthase.

In addition to the antimicrobial effects of being a potent antioxidant, vitamin C has a number of other mechanisms which contribute to its antimicrobial activity, as collated by Dr Thomas Levy¹⁴. They include the following:

• Enhancement of interferon production - references 15-19
• Enhancement of phagocytic function ref - 20-38
• Selective concentration of vitamin C in white blood cells 39-43
• Enhancement of cell-mediated immune response 44
• Enhancement of cytokine production by white blood cells 45
• Inhibition of T-lymphocyte apoptosis 46
• Enhancement of nitric oxide production by phagocytes 47
• Enhancement of T-lymphocyte proliferation 48-50
• Enhancement of B-lymphocyte proliferation 51
• Inhibition of neuraminidase 52
• Enhancement of antibody production and complement activity 50, 53-62
• Enhancement of natural killer cell activity 63
• Enhancement of prostaglandin formation 64-66
• Enhancement of cyclic GMP levels in lymphocytes 67, 68
• Enhanced localized generation of hydrogen peroxide 69-71
• Vitamin C and hydrogen peroxide can dissolve the protective capsules of some bacteria, such as pneumococci 72
• Detoxification of histamine 73, 74
• Neutralization of the oxidative stress that can otherwise enhance the infective process 75
• Nonspecific immunopotentiation and improvement of the vaccination effect 50, 76, 77
• Mucolytic effect of vitamin C 78
• Possible alteration of bacteria cell surface qualities 79

The importance of vitamin C in seriously ill patients has been highlighted by research showing that plasma vitamin C levels become abnormally low within 24 hours of acute injury⁸⁰ and are especially low in patients going into multiple organ failure⁸¹ andsepsis⁸². Cases of scurvy are described with low documented plasma ascorbate levels even with supplementation of 130mg/day⁸³.

The microcirculation is particularly susceptible to oxidative stress which leads to the systemic inflammatory response syndrome, hemodynamic instability, and multiple organ failure⁸⁴.

Restoring antioxidant and endothelial functions in the critically ill patient requires supraphysiologic concentrations of ascorbate⁸⁵, and such concentrations can only be achieved by parenteral administration⁸⁶.

CLINICAL EVIDENCE IV vitamin C

In addition to substantial worldwide clinical experience of IV vitamin C use^{14, 87}, there have been a variety of studies in critically ill patients in ICU’s which have shown improved outcomes from infections when intravenous Vitamin C is used.

• A study in Italian ICUs, reviewed adding 500mg Vitamin Cand 800iu vitamin E to enteric feeding in 105 critically ill patients who were septic or at risk of becoming septic, significantly reduced the 28 day mortality compared with 111 controls (45.7% cf 67.5% in the normally fed controls P<.05).⁸⁸
The authors state: “The lack of adverse effects, coupled withthe minimal expense, supports the use of AOX in critically ill patients.”

• A randomised prospective trial in 595 critically ill patients (91% victims of trauma) gave 1000iu of vitamin E orally and1 gram of IV Vitamin C 8 hourly for the duration of ICU stay or 28 days. Multiple organ failure was significantly less (RR 0.43), and less pulmonary morbidity (RR 0.81) in those receiving antioxidants.⁸⁹

• Vitamin C 1 gram IV 8 hourly plus oral vitamin E and selenium for 7 days was given to 4294 patients acutely admitted to their trauma centre⁹⁰. In the antioxidant groups, hospital stay was significantly reduced (3 vs 4 days, P<0.001), and ICU stay (2 vs 3 days, P<0.001). Mortality was lower (6.1 vs 8.5%, P<0.001), and patients with an expected survival of less than 50% survived best (odds ratio 0.24).

• In a European study of patients admitted to ICU with organ failure after cardiac surgery, major trauma or subarachnoid haemorrhage, were given an intravenous antioxidant cocktail of selenium, zinc, vitamin B1 and vitamin C 1.1 grams daily (double doses on days 1 and 3)⁹¹. Most endpoints did not change although the antioxidant group had lower inflammatory markers, and the trauma survivors had 10 days shorter hospital stay (P<0.045). The authors state the reduced inflammatory response may prove beneficial in conditions with an intense inflammation.

• A study from The University of Michigan in critically illtrauma patients, gave 2272 patients selenium, 3000iu vitaminE and 3 grams of IV vitamin C for 7 days, and compared them with 2022 patients with similar conditions admitted in the previous year⁹². Those receiving antioxidants had less abdominal compartment syndrome (0.7 vs 2.9%, P<0.001), surgical site infections (1.3 vs 2.7, P<0.002), ventilator respiratory failure (7.1 vs 10.8, P<0.001), pulmonary failure(17.4 vs 27.6%, P< 0.001). Multivariate regression showed a 53% odds reduction in abdominal wall complications and 38% odds reduction in respiratory failure.

• 84 patients with pancreatitis were randomised to give half 6 grams of IV vitamin C daily for 5 days and the controls received 1 gram daily⁹³. To quote the authors of the study, “Fever and vomiting disappeared, and leukocyte counts and amylase in urine and blood became normal quicker in the treatment group than in the control group. Moreover, patients in the treatment group also had a higher cure rate, a lower complication rate and less in-ward days compared with those in the control group”. Note the control patients also received vitamin C (1 gram), so the additional benefits could be attributed to the higher doses.

INDICATIONS IV vitamin C

In a survey⁹⁴ of IVC use from 2006 and 2008, Padayatty and colleagues reviewed 172 practitioners who had given IVC to a total of 11,233 patients (average dose 28g every 4 days). They found that the indications for use varied considerably as shown in the graph.

Although tens of millions of infusions have been given, only ahandful of clinical reports can be found in the medical Literature relating to possible serious harm from IVC.

Most of these are poorly documented letters to the editor and in most there are other possible aggravating factors, including pre-existing renal disease^95-102.

No trial specifically looking at vitamin C hasreported renal failure or an increased incidence of renal stones.There has also been research countering the theory of increasedoxalate production with vitamin C^{103, 104}.

Two cases of haemolysis have been documented in patients with glucose-6-phosphate dehydrogenase deficiency^{105, 106} and in paroxysmal nocturnal haemoglobinuria^{107, 108} related to vitamin C use.

A recent phase one study of high dose IV vitamin C in patients with advanced cancer did not find any serious side effects¹⁰⁹.

In Padayatty’s study they found evidence of very few reportedside-effects and most of those were minor.

DISCUSSION IV vitamin C

Vitamin C appears to have an important role in preventing andfighting infection. The need for an effective agent for treatingviruses has been highlighted in recent times by the rapid spreadof flu epidemics, including ‘bird flu’ and ‘swine flu’, which can be extremely difficult to treat (and 49 people died in NZ in 2010 of H1N1 flu)¹¹⁰.

Neuraminidase inhibitors like Tamiflu may help to reduce the symptoms and complications of flu if taken early after exposure. However, a recent Cochrane review states that, “doubts remain about the effectiveness and safety of the drug because its evaluation has been limited to manufacturer sponsoredtrials. There is clear evidence of publication bias" ¹¹¹.

In an article called, ‘Ascorbic Acid Role in Containment of theWorld Avian Flu Pandemic’, Ely states that, “the apparent failureof ‘medicine’ to provide a completely understood and logicallybased biochemical prevention and treatment for all influenzas(and many other viral diseases) may be an unavoidable result ofthe evolving complexity of the H5N1 virus”.

However, clinical experience cited in all accounts, including the 2003 to 2006 period, suggest that ascorbic acid is not being administered to humans infected or at risk for influenza and ...proper use of ascorbic acid as described here could provide effective containment for the flu pandemic¹¹².

Of interest recently has been the media coverage of cases inNew Zealand and Australia where IVC has been used in anattempt to salvage the lives of two critically ill patients resulting from flu infections, with an apparent life-saving success in one of them.

There have been critical responses from the medicalcommunity^113-116 which do not appear to have examined the scientific evidence in any depth and have focussed on the very small number of reported cases of renal complications.

CONCLUSION IV vitamin C

• There is strong data that adequate vitamin C levels are essential to mount a maximal response to infections or any form of trauma, and that levels measured in patients in these situations are almost all uniformly low (it is surprising that it is not measured routinely given that it is not a difficult assay).

• High doses are often required parenterally to ‘normalise’ theseplasma levels

• While many of the ‘mega dose’ controlled trials gave between1 and 3 grams per day, the most spectacular results from thecase studies involved giving patients much higher doses 25-50grams.

• Controlled trials from reputable institutions published inquality journals support the benefits of high antioxidanttherapy (especially vitamin C) in critically ill patients. Whilenot only vitamin C was used in a number of the studies,perhaps intensivists should consider giving both Vitamins Cand E if they are not convinced on the efficacy of Vitamin Calone.

• Although there is little evidence that high dose IV vitamin Cis nephrotoxic or causes renal stones in patients with normalrenal function, it should be very carefully monitored in patientswith mild to moderate renal failure and probably avoided insevere renal failure unless potentially life-saving. IVC shouldnot be used in patients with G6PD deficiency or paroxysmalnocturnal haemoglobinuria.

• There is a pressing need for further high-quality research intothe use of high-dose vitamin C in the treatment of infections,such as influenza, and other inflammatory conditions. Howto encourage researchers and funders to work with appropriateclinicians to achieve this requires urgent attention. Withthe ongoing risk from global epidemics of life-threateningviral illnesses it is important that low-cost and low-riskinterventions such as IVC are fully examined for their potentialbenefits.

• In the interim, there appears to be sufficient good data that the therapy is effective and safe, and its use should be considered in seriously ill patients, especially if the plasma vitamin C levels are measured to be low.

Intravenous vitamin C as cancer therapy

Vit C in food and oral supplements

REFERENCES IV vitamin C

ACNEM Journal Vol 30 No 1 – April 2011

1. Saul AW. High-Dose Vitamin C Therapy for Major Diseases, 2008.
2. Jungeblut CW. Inactivation of poliomyelitis virus by crystalline vitamin C (ascorbic acid). J ExperMed 1935;62:317-321.
3. Jungeblut CW. Vitamin C therapy and prophylaxis in experimental poliomyelitis. J Exp Med1937;65:127-146.
4. Jungeblut CW. Further observations on vitamin C therapy in experimental poliomyelitis. J ExperMed 1937;66:459-477.
5. Jungeblut CW. A further contribution to vitamin C therapy in experimental poliomyelitis. JExper Med 1939;70:315-332.
6. Jungeblut CW, Zwemer RL. Inactivation of diphtheria toxin in vivo and in vitro by crystallinevitamin C (ascorbic acid). Proc Soc Exper Biol Med 1935;32:1229-34.
7. Jungeblut CW. Inactivation of tetanus toxin by crystalline vitamin C (l-ascorbic acid). J Immunol1937;33:203-214.
8. Klenner FR. Observations on the dose of administration of ascorbic acid when employed beyondthe range of a vitamin in human pathology. Journal of Applied Nutrition 1971;23(3 and 4):61-68.
9. McCormick WJ. Lithogenesis and hypovitaminosis. Medical Record 1946;159(7): 410-413.
10. McCormick W. Intervertebral-disc lesions: a new etiological concept. Arch Pediatr.1954;71(1):29-32.
11. Cathcart R. Vitamin C, Titrating to Bowel Tolerance, Anascorbemia, and Acute InducedScurvy. Medical Hypotheses 1981;7:1359-1376.
12. Riordan HD, Hunninghake R.E, Riordan NH, et al. Intravenous Ascorbic Acid: Protocol forits Application and Use. Puerto Rico Health Sciences Journal 2003;22(3).
13. Wilson JX. Mechanism of action of vitamin C in sepsis: Ascorbate modulates redox signaling inendothelium. Biofactors 2009;35(1):5-13.
14. Levy TE. Curing the incurable. Henderson, NV: LivOn Books, 2009.
15. Dahl H, Degre M. The effect of ascorbic acid on production of human interferon and theantiviral activity in vitro. Acta Pathologica et Microbiologica Scandinavica. Section B, Microbiology1976;84(5):280-284.
16. Geber W, Lefkowitz S, Hung C. Effect of ascorbic acid, sodium salicylate, and caffeine on theserum interferon level in response to viral infection. Pharmacology 1975;13(3):228-233.
17. Karpinska T, Kawecki Z, Kandefer-Szerszen M. The influence of ultraviolet irradiation,L-ascorbic acid and calcium chloride on the induction of interferon in human embryo fibroblasts.Archivum Immunologiae et Therapiae Experimentalis 1982;30(1):33-37.
18. Siegel B. Enhanced interferon response to murine leukemia virus by ascorbic acid. Infection andImmunity 1974;10(2):409-410.
19. Siegel B. Enhancement of interferon production by poly(rI)- poly(rC) in mouse cell cultures byascorbic acid. Nature 1975;254(5500):531-532.
20. Anderson R, Theron A. Effects of ascorbate on leucocytes. Part III. In vitro and in vivostimulation of abnormal neutrophil motility by ascorbate. South African Medical Journal1979;56(11):429-433.
21. Anderson R, Dittrich O. South African Medical Journal. 56 1979 Effects of ascorbate onleucocytes. Part IV. Increased neutrophil function and clinical improvement after oral ascorbate in 2patients with chronic granulomatous disease;12(476-480).
22. Anderson R, et al. The effects of increasing weekly doses of ascorbate on certain cellular andhumoral immune functions in normal volunteers. The American Journal of Clinical Nutrition1980;33(1):71-76.
23. Anderson R, Hay I, van Wyk H, Oosthuizen R, Theron A. The effect of ascorbate on cellularhumoral immunity in asthmatic children. South African Medical Journal 1980;58(24):974-977.
24. Boxer L, et al. Correction of leukocyte function in Chediak-Higashi syndrome by ascorbate. TheNew England Journal of Medicine 1976;295(19):1041-1045.
25. Boxer L, et al. Enhancement of chemotactic response and microtubule assembly in humanleukocytes by ascorbic acid. Journal of Cellular Physiology 1979;100(1):119-126.
26. Ciocoiu M, Lupusoru E, Coley V, Badescu M, Paduraru I. [The involvement of vitamins Cand E in changing the immune response]. Article in Romanian. Revista Medico-Chirurgicala aSocietatii de Medici si Naturalisti din Iasi 1998;102(1-2):93-96.
27. Corberand J, Nguyen F, Fraysse B, Enjalbert L. Malignant external otitis andpolymorphonuclear leukocyte migration impairment. Improvement with ascorbic acid. Archives ofOtolaryngology 1982;108(2):122-124.
28. Cunningham-Rundles S. Effects of nutritional status on immunological function. The AmericanJournal of Clinical Nutrition 35(5 Suppl):1202-1210. 1982.
29. Dallegri F, Lanzi G, Patrone F. Effects of ascorbic acid on neutrophil locomotion. InternationalArchives of Allergy and Applied Immunology 1980;61(1):40-45.
30. De la Fuente M, et al. Immune function in aged women is improved by ingestion of vitamins Cand E. Canadian Journal of Physiology and Pharmacology 1998;76(4):373-380.
31. Ganguly R, Durieux M, Waldman R. Macrophage function in vitamin C -deficient guineapigs. The American Journal of Clinical Nutrition 1976;29(7):762-765.
32. Goetz! E, Wasserman S, Gigli I, Austen K. Enhancement of random migration andchemotactic response of human leukocytes by ascorbic acid. The Journal of Clinical Investigation1974;53(3):813-818.
33. Levy R, Schlaeffer F. Successful treatment of a patient with recurrent furunculosis by vitaminC : improvement of clinical course and of impaired neutrophil functions. International Journal ofDermatology 1993;32(11):832-834.
34. Levy R, Shriker O, Porath A, Riesenberg K, SchlaefferF. Vitamin C for the treatment ofrecurrent furunculosis in patients with impaired neutrophil functions. The Journal of InfectiousDiseases 1996;173(6):1502-1505.
35. Nungester W, Ames A. The relationship between ascorbic acid and phagocytic activity. Journalof Infectious Diseases 1948;83:50-54.
36. Oberritter H, Glatthaar B, Moser U, Schmidt K. Effect of functional stimulation on ascorbatecontent in phagocytes under physiological and pathological conditions. International Archives ofAllergy and Applied Immunology 1986;81(1):46-50.
37. Patrone F, Dallegri F, Bonvini E, Minervini F SC. Effects of ascorbic acid on neutrophilfunction. Studies on normal and chronic granulomatous disease neutrophils. Acta Vitaminologica etEnzymologica 1982;4(1-2):163-168.
38. Sandler J, Gallin J, Vaughan M. Effects of serotonin, carbamylcholine, and ascorbic acid onleukocyte cyclic GMP and chemotaxis. The Journal of Cell Biology 1975;67(2):480-484.
39. Evans R, Currie L, Campbell A. The distribution of ascorbic acid between various cellularcomponents of blood, in normal individuals, and its relation to the plasma concentration. TheBritish Journal of Nutrition 1982;47(3):473-482.
40. Glick D, Hosoda S. Histochemistry. LXXViii. Ascorbic acid in normal mast cells andmacrophages and neoplastic mast cells. Proceedings of the Society for Experimental Biology andMedicine 1965;119:52-56.
41. Goldschmidt M. Reduced bactericidal activity in neutrophils from scorbutic animals and theeffect of ascorbic acid on these target bacteria in vivo and in vitro. The American Journal of ClinicalNutrition 1991;54(6):12145-12205.
42. Thomas W, Holt P. Vitamin C and immunity: an assessment of the evidence. Clinical andExperimental Immunology 1978;32(2):370-379.
43. Washko R, Wang Y, Levine M. Ascorbic acid recycling in human neutrophils. The Journal ofBiological Chemistry 1993;268(21):15531-15535.
44. Siegel B, Morton J. Vitamin C and immunity: influence of ascorbate on prostaglandin E2synthesis and implications for natural killer cell activity. International Journal for Vitamin andNutrition Research 1984;54(4):339-342.
45. Jeng K, Yang C, Siu W, Tsai Y, Liao W, Kuo J. Supplementation with vitamins C andE enhances cytokine production by peripheral blood mononuclear cells in healthy adults. TheAmerican Journal of Clinical Nutrition 1996;64(6):960-965.
46. Campbell J, Cole M, Bunditrutavorn B, Vella A. Ascorbic acid is a potent inhibitor of variousforms of T cell apoptosis. Cellular Immunology 1999;194(1):1-5.
47. Mizutani A, Maki H, Tohi Y, Hitomi K, Tsukagoshi N. Ascorbate-dependent enhancementof nitric oxide formation in activated macrophages. Nitric Oxide: Biology and Chemistry1998;2(4):235-241.
48. Fraser R, Pavlovic S, Kurahara C, Murata A, Peterson N, Taylor K, et al. The effect ofvariations in vitamin C intake on the cellular immune response of guinea pigs. The AmericanJournal of Clinical Nutrition 1980;33(4):839-847.
49. Kennes B, Dumont I, Brohee D, C H, Neve P. Effect of vitamin C supplements on cellmediatedimmunity in old people. Gerontology 1983;29(5):305-310.
50. Wu C, Dorairajan T, Lin T. Effect of ascorbic acid supplementation on the immune response ofchickens vaccinated and challenged with infectious bursa) disease virus. Veterinary Immunology andImmunopathology 2000;74(1-2):145-152.
51. Schwager J, Schulze J. Influence of ascorbic acid on the response to mitogens and interleukinproduction of porcine lymphocytes. International Journal for Vitamin and Nutrition Research1997;67(1):10-16.
52. Rotman D. Sialoresponsin and an antiviral action of ascorbic acid. Medical Hypotheses1978;4(1):40-43.
53. Bourne G. Vitamin C and immunity. The British Journal of Nutrition 1949;2:342.
54. Ecker E, Pillemer L. Vitamin C requirement of the guinea pig. Proceedings of the Society forExperimental Biology and Medicine 1940;44:262.
55. Feigen G, et al. Enhancement of antibody production and protection against systemicanaphylaxis by large doses of vitamin C. Research Communications in Chemical Pathology andPharmacology 1982;38(2):313-333.
56. Haskell B, Johnston C. Complement component Clq activity and ascorbic acid nutriture inguinea pigs. The American Journal of Clinical Nutrition 1991;54(6):12286-12305.
57. Johnston C, Kolb W, Haskell B. The effect of vitamin C nutriture on complement componentClq concentrations in guinea pig plasma. The Journal of Nutrition 1987;117(4):764-768.
58. Li Y, Lovell T. Elevated levels of dietary ascorbic acid increase immune responses in channelcatfish. The Journal of Nutrition 1985;115(1):123-131.
59. Prinz W, Bartz R, Bregin B, Hersch M. The effect of ascorbic acid supplementation on someparameters of the human immunological defence system. International Journal for Vitamin andNutrition Research 1977;47(3):248-257.
60. Sakamoto M, Kobayashi S, Ishii S, Katoo K, Shimazono N. The effect of vitamin Cdeficiency on complement systems and complement components. Journal of Nutritional Science andVitaminology 1881;27(4):367-378.
61. Valiance S. Relationships between ascorbic acid and serum proteins of the immune system.British Medical Journal 1977;2(6084):437-438.
62. Wahli T, Meier W, Pfister K. Ascorbic acid induced immune-mediated decrease in mortality inIchthyophthirius multifliis rainbow-trout (Salmo gairdneri). Acta Tropica 1986;43(3):287-289.
63. Heuser G, Vojdani A. Enhancement of natural killer cell activity and T and B cell functionby buffered vitamin C in patients exposed to toxic chemicals: the role of protein kinase-C.Immunopharmacology and Immunotoxicology 1997;19(3):291-312.
64. Horrobin D, et al. The nutritional regulation of T lymphocyte function. Medical Hypotheses1979;5(9):969-985.65. Scott J. On the biochemical similarities of ascorbic acid and interferon. Journal of TheoreticalBiology 1982;98(2):235-238.
66. Siegel B, Morton J. Vitamin C and the immune response. Experientia 1977;33(3):393-395.67. Atkinson J, Weiss A, Ito M, Kelly J, Parker C. Effects of ascorbic acid and sodium ascorbateon cyclic nucleotide metabolism in human lymphocytes. Journal of Cyclic Nucleotide Reseprch1979;5(2):107-123.
68. Panush R, Delafuente J, Katz R, J. J. Modulation of certain immunologic responses by vitaminC. III. Potentiation of in vitro and in vivo lymphocyte responses. International Journal for Vitaminand Nutrition Research. 1982;Supplement 23:35-47.
69. Kraut E, Metz E, A. S. In vitro effects of ascorbate on white cell metabolism and thechemiluminescence response. Journal of the Reticuloendothelial Society 1980;27(4):359-366.
70. Miller T. Killing and lysis of gram-negative bacteria through the synergistic effect of hydrogenperoxide, ascorbic acid, and lysozyme. Journal of Bacteriology 1969;98(3):949-955.
71. Tappel A. Lipid peroxidation damage to cell components. Federation Proceedings1973;32(8):1870-1874.
72. Robertson W, Ropes M, W. B. The degradation of mucins and polysaccharides by ascorbic acidand hydrogen peroxide. The Biochemical Journal 1941;35:903.
73. Johnston C, Martin L, X. C. Antihistamine effect of supplemental ascorbic acid and neutrophilchemotaxis. Journal of the American College of Nutrition 1992;11(2):172-176.
74. Nandi B, Subramanian N, Majumder A, I. C. Effect of ascorbic acid on detoxification ofhistamine under stress conditions. Biochemical Pharmacology 1974;23(3):643-647.
75. Kastenbauer S, Koedel U, Becker B, H. P. Oxidative stress in bacterial meningitis in humans.Neurology 2002;58(2):186-191.
76. Banic S. Immunostimulation by vitamin C. International Journal for Vitamin and NutritionResearch. 1982;Supplement 23:49-52.
77. Versteeg J. Investigations on the effect of ascorbic acid on antibody production in rabbitsafter injection of bacterial and viral antigens by different routes. Proceedings of the KoninklijkeNederlandse Akademie van Wetenschappen. Series C. Biological and Medical Sciences1970;73(5):494-501.
78. Ericsson Y. The effect of ascorbic acid oxidation on mucoids and bacteria in body secretions.Acta Pathologica et Microbiologica Scandinavica 1954;35:573-583.
79. Rawal B. Chemotherapy. 24 Bactericidal action of ascorbic acid on Pseudomonas aeruginosa:alteration of cell surface as a possible mechanism;3(166-171).
80. Schorah CJ, Downing C, Piripitsi A, Gallivan L, Al-Hazaa AH, Sanderson MJ, et al. Totalvitamin C, ascorbic acid, and dehydroascorbic acid concentrations in plasma of critically ill patients.Am J Clin Nutr 1996;63:760-5.
81. Borrelli E, Roux-Lombard P, Grau GE, Girardin E, Ricou B, Dayer J, et al. Plasmaconcentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict thedevelopment of multiple organ failure in patients at risk. Crit Care Med 1996;24:392-7.
82. Galley HF, Davies MJ, NR W. Ascorbyl radical formation in patients with sepsis: effect ofascorbate loading. Free Radic Biol Med 1996;20:139-43.
83. Perret JL, Lagauche D, Favier JC, Rey P, Bigois L, F. A. Scurvy in intensive care despitevitamin supplementation. Presse Med 2004;33:170-1.
84. Biesalski H K. Parenteral ascorbic acid as a key for regulating microcirculation in critically ill.Critical Care Medicine 2008;36(8):2466-2468.
85. McGregor GP, Biesalski HK. Rationale and impact of vitamin C in clinical nutrition. CurrOpin Clin Nutr Metab Care 2006;9:697-703.
86. Long CL, Maull KI, Krishnan RS, et al. Ascorbic acid dynamics in the seriously ill andinjured. Journal of surgical research 2003;109(2):144-148.
87. Riordan N, Riordan H, Casciari J. Clinical and Experimental Experiences with IntravenousVitamin C. J Orthomolecular Med 2000;15(4):201-213.
88. Crimi E, et al. The Beneficial Effects of Antioxidant Supplementation in Enteral Feeding inCritically Ill Patients: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial. AnesthAnalg 2004;99:857–63.
89. Nathens A, Neff N. Randomized, Prospective Trial of Antioxidant Supplementation inCritically Ill Surgical Patients. Ann Surg 2002;236(6):814-822.
90. Collier B, Giladi A, Dossett LA, Dyer L, Fleming SB, Cotton BA. Impact of highdoseantioxidants on outcomes in acutely injured patients. JPEN J Parenter Enteral Nutr2008;32(4):384-8.
91. Berger M, et al. Influence of early antioxidant supplements on clinical evolution and organfunction in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients. CritCare 2008;12(4):R101.
92. Giladi AM, Dossett LA, Fleming SB, Abumrad NN, BA. C. High-dose antioxidantadministration is associated with a reduction in post-injury complications in critically ill traumapatients. Injury 2010;41(7):857-61.
93. Du WD, Yuan ZR, Sun J, Tang JX, Cheng AQ, Shen DM, et al. Therapeutic efficacy ofhigh-dose vitamin C on acute pancreatitis and its potential mechanisms. World J Gastroenterol.2003;9(11):2565-9.
94. Padayatty SJ, Sun AY, Chen Q, Espey MG, Drisko J, Levine M. Vitamin C: IntravenousUse by Complementary and Alternative Medicine Practitioners and Adverse Effects. PLoS ONE2010;5(7):e11414.
95. Bromley J, Hughes BG, Leong DC, NA. B. Life-threatening interaction betweencomplementary medicines: cyanide toxicity following ingestion of amygdalin and vitamin C. AnnPharmacother 2005;39:1566–69.
96. Lawton JM, Conway LT, Crosson JT, al. e. Acute oxalate nephropathy after massive ascorbicacid administration. Arch Intern Med 1985;145:950–951.
97. Mashour S, Turner Jr JF, Merrell R. Acute Renal Failure, Oxalosis, and Vitamin CSupplementation - A Case Report and Review of the Literature. CHEST 2000;118:561-563.
98. Massey LK, Liebman M, Kynast-Gales SA. Ascorbate Increases Human Oxaluria andKidney Stone Risk. J. Nutr. 2005;135:1673-1677.
99. McAllister CJ, Scowden EB, Dewberry FL, A. R. Renal failure secondary to massive infusionof vitamin C. JAMA 1984(252:1684).
100. McHugh GJ, Graber ML, Freebairn RC. Fatal vitamin C-associated acute renal failure.Anaesthesia and Intensive Care 2008;36(4):585-8.
101. Swartz RD, Wesley JR, Somermeyer MG, K. L. Hyperoxaluria and renal insufficiency dueto ascorbic acid administration during total parenteral nutrition. Ann Intern Med 1984;100:530–531.
102. Wong K, Thomson C, Bailey RR, al. e. Acute oxalate nephropathy after a massiveintravenous dose of vitamin C. Aust N Z J Med 1994;24:410– 411.
103. Gerster H. No Contribution of Ascorbic Acid to Renal Calcium Oxalate Stones. Ann NutrMetab 1997;41:269-282.
104. Hickey S, Roberts H. Vitamin C Does Not Cause Kidney Stones. Orthomolecular MedicineNews Service 2005;July 5.
105. Campbell GD Jr, Steinberg MH, JD. B. Ascorbic acid induced hemolysis in G-6-PDdeficiency. Ann Intern Med 1975:82:810.
106. Rees DC, Kelsey H, JDM. R. Acute haemolysis induced by high dose ascorbic acid in glucose-6-phosphate dehydrogenase deficiency. BMJ 1993;306:841–842.
107. Iwamoto N, Kawaguchi T, Horikawa K, Nagakura S, Hidaka M, Kagimoto T, etal. Haemolysis induced by ascorbic acid in paroxysmal nocturnal haemoglobinuria. Lancet1994;343:357.
108. Iwamoto N, Nakakuma H, Ota N, Shimokado H, K. T. Ascorbic acid-induced hemolysis ofparoxysmal nocturnal hemoglobinuria erythrocytes. Am J Hematol 1994;47:337–38.
109. Hoffer LJ, Levine M, Assouline S, Melnychuk D, Padayatty SJ, Rosadiuk K, et al. Phase Iclinical trial of i.v. ascorbic acid in advanced malignancy. Ann Oncol 2008;19:1969–74.
110. NZPA. 49 NZers died of swine flu last year. NZ Herald 2010 Oct 15, 2010.
111. Jefferson T, ones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treatinginfluenza in healthy adults and children - a review of unpublished data - Cochrane review. CochraneDatabase of Systematic Reviews 2010(A159).
112. Ely JTA. Ascorbic Acid Role in Containment of the World Avian Flu Pandemic. Exp. Biol.Med. 2007;232:847-851.
113. Auckland District Health Board. High-Dosage Vitamin C Therapy. Auckland: ADHBMedia Release, 2010.
114. College of Intensive Care Medicine of Australia and New Zealand. High Dose IntravenousVitamin C Treatment in Critically Ill Patients in New Zealand: College of Intensive Care Medicineof Australia and New Zealand, 2010.
115. Gillett G. Doctor Does Not Always Know Best. Otago Daily Times 2010.
116. Holt S. Hype around high-dose vitamin C is unjustified. Journal of the New Zealand MedicalAssociation 2010;123(1324).

From IV vitamin C article back to home page