This article on use of intravenous 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 experiments³-5. 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 in the body approximately 25 mg of ascorbic acid(10.)
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 blood flow, 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 injury(80) and are especially low in patients going into multiple organ failure⁸¹ and sepsis⁸². 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 (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 C
and 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 with the 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 and 1 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 centre (90.) 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 ill trauma patients, gave 2272 patients selenium, 3000iu vitamin E 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.
SIDE-EFFECTS AND TOXICITY IV vitamin C
Although tens of millions of infusions have been given, only a handful 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 has reported renal failure or an increased incidence of renal stones. There has also been research countering the theory of increased oxalate 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 effects (109.)
In Padayatty’s study they found evidence of very few reported side-effects and most of those were minor.
Padayatty concluded that “other than the known complications
of IV vitamin C in those with renal impairment or glucose 6
phosphate dehydrogenase deficiency, high dose intravenous
vitamin C appears to be remarkably safe.”
DISCUSSION IV vitamin C
Vitamin C appears to have an important role in preventing and fighting infection. The need for an effective agent for treating viruses has been highlighted in recent times by the rapid spread of 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 sponsored trials. There is clear evidence of publication bias" ¹¹¹.
In an article called, ‘Ascorbic Acid Role in Containment of the World Avian Flu Pandemic’, Ely states that, “the apparent failure of ‘medicine’ to provide a completely understood and logically based biochemical prevention and treatment for all influenzas (and many other viral diseases) may be an unavoidable result of the 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 in New Zealand and Australia where IVC has been used in an attempt 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 medical
community¹¹³<span style='font-size: 50%'>-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’ these plasma levels
• While many of the ‘mega dose’ controlled trials gave between 1 and 3 grams per day, the most spectacular results from the case studies involved giving patients much higher doses 25-50 grams.
• Controlled trials from reputable institutions published in quality journals support the benefits of high antioxidant therapy (especially vitamin C) in critically ill patients. While not only vitamin C was used in a number of the studies, perhaps intensivists should consider giving both Vitamins C and E if they are not convinced on the efficacy of Vitamin C alone.
• Although there is little evidence that high dose IV vitamin C is nephrotoxic or causes renal stones in patients with normal renal function, it should be very carefully monitored in patients with mild to moderate renal failure and probably avoided in severe renal failure unless potentially life-saving. IVC should not be used in patients with G6PD deficiency or paroxysmal nocturnal haemoglobinuria.
• There is a pressing need for further high-quality research into the use of high-dose vitamin C in the treatment of infections, such as influenza, and other inflammatory conditions. How to encourage researchers and funders to work with appropriate clinicians to achieve this requires urgent attention. With the ongoing risk from global epidemics of life-threatening viral illnesses it is important that low-cost and low-risk interventions such as IVC are fully examined for their potential benefits.
• 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.
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 Exper Med 1935;62:317-321.
3. Jungeblut CW. Vitamin C therapy and prophylaxis in experimental poliomyelitis. J Exp Med 1937;65:127-146.
4. Jungeblut CW. Further observations on vitamin C therapy in experimental poliomyelitis. J Exper Med 1937;66:459-477.
5. Jungeblut CW. A further contribution to vitamin C therapy in experimental poliomyelitis. J Exper Med 1939;70:315-332.
6. Jungeblut CW, Zwemer RL. Inactivation of diphtheria toxin in vivo and in vitro by crystalline vitamin 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 Immunol 1937;33:203-214.
8. Klenner FR. Observations on the dose of administration of ascorbic acid when employed beyond the 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 Induced Scurvy. Medical Hypotheses 1981;7:1359-1376.
12. Riordan HD, Hunninghake R.E, Riordan NH, et al. Intravenous Ascorbic Acid: Protocol for its 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 in endothelium. 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 the antiviral activity in vitro. Acta Pathologica et Microbiologica Scandinavica. Section B, Microbiology 1976;84(5):280-284.
16. Geber W, Lefkowitz S, Hung C. Effect of ascorbic acid, sodium salicylate, and caffeine on the serum 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 and Immunity 1974;10(2):409-410.
19. Siegel B. Enhancement of interferon production by poly(rI)- poly(rC) in mouse cell cultures by ascorbic acid. Nature 1975;254(5500):531-532.
20. Anderson R, Theron A. Effects of ascorbate on leucocytes. Part III. In vitro and in vivo stimulation of abnormal neutrophil motility by ascorbate. South African Medical Journal 1979;56(11):429-433.
21. Anderson R, Dittrich O. South African Medical Journal. 56 1979 Effects of ascorbate on leucocytes. Part IV. Increased neutrophil function and clinical improvement after oral ascorbate in 2 patients with chronic granulomatous disease;12(476-480).
22. Anderson R, et al. The effects of increasing weekly doses of ascorbate on certain cellular and humoral immune functions in normal volunteers. The American Journal of Clinical Nutrition 1980;33(1):71-76.
23. Anderson R, Hay I, van Wyk H, Oosthuizen R, Theron A. The effect of ascorbate on cellular humoral 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. The New England Journal of Medicine 1976;295(19):1041-1045.
25. Boxer L, et al. Enhancement of chemotactic response and microtubule assembly in human leukocytes 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 C and E in changing the immune response]. Article in Romanian. Revista Medico-Chirurgicala a Societatii de Medici si Naturalisti din Iasi 1998;102(1-2):93-96.
27. Corberand J, Nguyen F, Fraysse B, Enjalbert L. Malignant external otitis and polymorphonuclear leukocyte migration impairment. Improvement with ascorbic acid. Archives of Otolaryngology 1982;108(2):122-124.
28. Cunningham-Rundles S. Effects of nutritional status on immunological function. The American Journal of Clinical Nutrition 35(5 Suppl):1202-1210. 1982.
29. Dallegri F, Lanzi G, Patrone F. Effects of ascorbic acid on neutrophil locomotion. International Archives 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 C and 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 guinea pigs. The American Journal of Clinical Nutrition 1976;29(7):762-765.
32. Goetz! E, Wasserman S, Gigli I, Austen K. Enhancement of random migration and chemotactic response of human leukocytes by ascorbic acid. The Journal of Clinical Investigation 1974;53(3):813-818.
33. Levy R, Schlaeffer F. Successful treatment of a patient with recurrent furunculosis by vitamin C : improvement of clinical course and of impaired neutrophil functions. International Journal of Dermatology 1993;32(11):832-834.
34. Levy R, Shriker O, Porath A, Riesenberg K, SchlaefferF. Vitamin C for the treatment of recurrent furunculosis in patients with impaired neutrophil functions. The Journal of Infectious Diseases 1996;173(6):1502-1505.
35. Nungester W, Ames A. The relationship between ascorbic acid and phagocytic activity. Journal of Infectious Diseases 1948;83:50-54.
36. Oberritter H, Glatthaar B, Moser U, Schmidt K. Effect of functional stimulation on ascorbate content in phagocytes under physiological and pathological conditions. International Archives of Allergy and Applied Immunology 1986;81(1):46-50.
37. Patrone F, Dallegri F, Bonvini E, Minervini F SC. Effects of ascorbic acid on neutrophil function. Studies on normal and chronic granulomatous disease neutrophils. Acta Vitaminologica et Enzymologica 1982;4(1-2):163-168.
38. Sandler J, Gallin J, Vaughan M. Effects of serotonin, carbamylcholine, and ascorbic acid on leukocyte 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 cellular components of blood, in normal individuals, and its relation to the plasma concentration. The British Journal of Nutrition 1982;47(3):473-482.
40. Glick D, Hosoda S. Histochemistry. LXXViii. Ascorbic acid in normal mast cells and macrophages and neoplastic mast cells. Proceedings of the Society for Experimental Biology and Medicine 1965;119:52-56.
41. Goldschmidt M. Reduced bactericidal activity in neutrophils from scorbutic animals and the effect of ascorbic acid on these target bacteria in vivo and in vitro. The American Journal of Clinical Nutrition 1991;54(6):12145-12205.
42. Thomas W, Holt P. Vitamin C and immunity: an assessment of the evidence. Clinical and Experimental Immunology 1978;32(2):370-379.
43. Washko R, Wang Y, Levine M. Ascorbic acid recycling in human neutrophils. The Journal of Biological Chemistry 1993;268(21):15531-15535.
44. Siegel B, Morton J. Vitamin C and immunity: influence of ascorbate on prostaglandin E2 synthesis and implications for natural killer cell activity. International Journal for Vitamin and Nutrition Research 1984;54(4):339-342.
45. Jeng K, Yang C, Siu W, Tsai Y, Liao W, Kuo J. Supplementation with vitamins C and E enhances cytokine production by peripheral blood mononuclear cells in healthy adults. The American 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 various forms of T cell apoptosis. Cellular Immunology 1999;194(1):1-5.
47. Mizutani A, Maki H, Tohi Y, Hitomi K, Tsukagoshi N. Ascorbate-dependent enhancement of nitric oxide formation in activated macrophages. Nitric Oxide: Biology and Chemistry 1998;2(4):235-241.
48. Fraser R, Pavlovic S, Kurahara C, Murata A, Peterson N, Taylor K, et al. The effect of variations in vitamin C intake on the cellular immune response of guinea pigs. The American Journal 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 cellmediated immunity 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 of chickens vaccinated and challenged with infectious bursa) disease virus. Veterinary Immunology and Immunopathology 2000;74(1-2):145-152.
51. Schwager J, Schulze J. Influence of ascorbic acid on the response to mitogens and interleukin production of porcine lymphocytes. International Journal for Vitamin and Nutrition Research 1997;67(1):10-16.
52. Rotman D. Sialoresponsin and an antiviral action of ascorbic acid. Medical Hypotheses 1978;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 for Experimental Biology and Medicine 1940;44:262.
55. Feigen G, et al. Enhancement of antibody production and protection against systemic anaphylaxis by large doses of vitamin C. Research Communications in Chemical Pathology and Pharmacology 1982;38(2):313-333.
56. Haskell B, Johnston C. Complement component Clq activity and ascorbic acid nutriture in guinea 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 component Clq 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 channel catfish. 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 some parameters of the human immunological defence system. International Journal for Vitamin and Nutrition Research 1977;47(3):248-257.
60. Sakamoto M, Kobayashi S, Ishii S, Katoo K, Shimazono N. The effect of vitamin C deficiency on complement systems and complement components. Journal of Nutritional Science and Vitaminology 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 in Ichthyophthirius 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 function by 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 Hypotheses 1979;5(9):969-985. 65. Scott J. On the biochemical similarities of ascorbic acid and interferon. Journal of Theoretical Biology 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 ascorbate on cyclic nucleotide metabolism in human lymphocytes. Journal of Cyclic Nucleotide Reseprch 1979;5(2):107-123.
68. Panush R, Delafuente J, Katz R, J. J. Modulation of certain immunologic responses by vitamin C. III. Potentiation of in vitro and in vivo lymphocyte responses. International Journal for Vitamin and Nutrition Research. 1982;Supplement 23:35-47.
69. Kraut E, Metz E, A. S. In vitro effects of ascorbate on white cell metabolism and the chemiluminescence 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 hydrogen peroxide, ascorbic acid, and lysozyme. Journal of Bacteriology 1969;98(3):949-955.
71. Tappel A. Lipid peroxidation damage to cell components. Federation Proceedings 1973;32(8):1870-1874.
72. Robertson W, Ropes M, W. B. The degradation of mucins and polysaccharides by ascorbic acid and hydrogen peroxide. The Biochemical Journal 1941;35:903.
73. Johnston C, Martin L, X. C. Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis. 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 of histamine 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 Nutrition Research. 1982;Supplement 23:49-52.
77. Versteeg J. Investigations on the effect of ascorbic acid on antibody production in rabbits after injection of bacterial and viral antigens by different routes. Proceedings of the Koninklijke Nederlandse Akademie van Wetenschappen. Series C. Biological and Medical Sciences 1970;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. Total vitamin 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. Plasma concentrations of cytokines, their soluble receptors, and antioxidant vitamins can predict the development 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 of ascorbate 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 despite vitamin 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. Curr Opin Clin Nutr Metab Care 2006;9:697-703.
86. Long CL, Maull KI, Krishnan RS, et al. Ascorbic acid dynamics in the seriously ill and injured. Journal of surgical research 2003;109(2):144-148.
87. Riordan N, Riordan H, Casciari J. Clinical and Experimental Experiences with Intravenous Vitamin C. J Orthomolecular Med 2000;15(4):201-213.
88. Crimi E, et al. The Beneficial Effects of Antioxidant Supplementation in Enteral Feeding in Critically Ill Patients: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial. Anesth Analg 2004;99:857–63.
89. Nathens A, Neff N. Randomized, Prospective Trial of Antioxidant Supplementation in Critically 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 highdose antioxidants on outcomes in acutely injured patients. JPEN J Parenter Enteral Nutr 2008;32(4):384-8.
91. Berger M, et al. Influence of early antioxidant supplements on clinical evolution and organ function in critically ill cardiac surgery, major trauma, and subarachnoid hemorrhage patients. Crit Care 2008;12(4):R101.
92. Giladi AM, Dossett LA, Fleming SB, Abumrad NN, BA. C. High-dose antioxidant administration is associated with a reduction in post-injury complications in critically ill trauma patients. Injury 2010;41(7):857-61.
93. Du WD, Yuan ZR, Sun J, Tang JX, Cheng AQ, Shen DM, et al. Therapeutic efficacy of high-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: Intravenous Use by Complementary and Alternative Medicine Practitioners and Adverse Effects. PLoS ONE 2010;5(7):e11414.
95. Bromley J, Hughes BG, Leong DC, NA. B. Life-threatening interaction between complementary medicines: cyanide toxicity following ingestion of amygdalin and vitamin C. Ann Pharmacother 2005;39:1566–69.
96. Lawton JM, Conway LT, Crosson JT, al. e. Acute oxalate nephropathy after massive ascorbic acid administration. Arch Intern Med 1985;145:950–951.
97. Mashour S, Turner Jr JF, Merrell R. Acute Renal Failure, Oxalosis, and Vitamin C Supplementation - 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 and Kidney Stone Risk. J. Nutr. 2005;135:1673-1677.
99. McAllister CJ, Scowden EB, Dewberry FL, A. R. Renal failure secondary to massive infusion of 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 due to 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 massive intravenous 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 Nutr Metab 1997;41:269-282.
104. Hickey S, Roberts H. Vitamin C Does Not Cause Kidney Stones. Orthomolecular Medicine News Service 2005;July 5.
105. Campbell GD Jr, Steinberg MH, JD. B. Ascorbic acid induced hemolysis in G-6-PD deficiency. 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, et al. Haemolysis induced by ascorbic acid in paroxysmal nocturnal haemoglobinuria. Lancet 1994;343:357.
108. Iwamoto N, Nakakuma H, Ota N, Shimokado H, K. T. Ascorbic acid-induced hemolysis of paroxysmal 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 I clinical 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 treating influenza in healthy adults and children - a review of unpublished data - Cochrane review. Cochrane Database 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: ADHB Media Release, 2010.
114. College of Intensive Care Medicine of Australia and New Zealand. High Dose Intravenous Vitamin C Treatment in Critically Ill Patients in New Zealand: College of Intensive Care Medicine of 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 Medical Association 2010;123(1324).