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

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.

intravenous vitamin C uses in medical practices

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.

IV vitamin C side effects from one study

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.


Intravenous vitamin C as cancer therapy

Vit C in food and oral supplements


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ACNEM Journal Vol 30 No 1 – April 2011

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