The American Association of Naturopathic Physicians issued a press release calling for intravenous vitamin C to be used in the treatment of COVID-19. Does the evidence support this call?
By Sarah Hourston, ND, MS and Les Witherspoon, ND
Currently, there are no clear best treatment options for COVID-19. There are no clear preventative measures beyond hygiene practices and social distancing. The exact pathogenesis of the virus remains unclear. Most people only have a mild illness, but some will require intensive care. In such a pandemic, what role can naturopathy play?
Licensed naturopathic doctors (NDs) are trained for outpatient care. There are a few exceptions of NDs who obtain additional specialized training in hospital settings, typically in the setting of adjunctive cancer therapy; however, most licensed NDs are prepared to work in outpatient medicine only. In this setting, NDs can choose to provide integrative or complementary care for their patients. Some NDs focus on specific therapeutic methods, some on specific conditions, and some practice a full range of primary care. However, NDs are not trained as hospitalists or intensivists.
During the current COVID-19 pandemic, the AANP has mainly focused upon advice that is useful to NDs in outpatient practices. As well, the AANP’s other press releases and resources for naturopathic doctors have strongly emphasized supporting public-health recommendations. With this background in mind, we were shocked to see the American Association of Naturopathic Physicians (AANP) release a PR statement calling for hospitals to use intravenous Vitamin C therapy in treating moderately and severely ill COVID-19 patients1. This statement was included in multiple posts on Facebook, including a post with an infographic2 describing several ways to share the document, including sharing it directly to hospitals.
The focus of the PR statement was not on mild cases of COVID-19, which may be encountered in the outpatient practices where most NDs practice. Instead, the AANP’s announcement was directed towards treating moderate to severe cases of COVID-19. These cases usually refer to patients who have pneumonia; with SpO2 (oxygen) saturation levels <94%; who are in the ICU, or are on mechanical ventilation. These cases are not treated by NDs. Yet the AANP sent out a statement with cherry-picked data urging “physicians and hospitals” to use IV vitamin C in “high risk and hospitalized patients”. The AANP even went so far as to urge people to contact their hospitals and ask them to support this controversial therapy.
We are unclear why the AANP is taking this action. While well-intentioned, this press release is an inappropriate and unprofessional move by the national organization representing NDs in the United States. Additionally, the AANP’s press release does not provide sufficient evidence to support these recommendations.
The goal of this article is not to resolve the question of IV vitamin C use in the ICU by intensivists and hospitalists. That is properly left to those specialists trained to make those recommendations. Instead, our response focuses on whether the AANP should be making recommendations on hospital-based care during a pandemic and whether the evidence cited in their press release is sufficient to make their case.
Advising or Kibitzing?
Before advising someone else on how to practice within their field, one should have knowledge and experience within that field. This is especially true when advising on procedures that have substantial risks for all parties involved. Otherwise one is kibitzing, offering untimely and uninformed advice.
As specialists in natural medicine, NDs complete a four-year naturopathic medical school training; some have the option to complete a one to three-year naturopathic residency after graduation. The emphasis is on management of outpatient conditions. It is possible for an ND student or resident to find an opportunity to shadow in a hospital, but this would be the exception, not the norm.
By contrast, a hospitalist first completes four years of medical school, followed by a three-year residency in internal medicine. An intensivist will usually further train for an additional two or more years, focusing on critical care of the most severely ill patients. Both hospitalists and intensivists have their own board certifications. Other MD specialists would not typically try to advise intensivists on critical care. For example, an ophthalmologist would not advise an intensivist on ventilator settings for acute respiratory distress syndrome (ARDS) and presumably an intensivist would avoid advising the ophthalmologist on treating glaucoma.
NDs, who are trained extensively on botanical remedies, no doubt would not appreciate an intensivist telling them how to administer herbal preparations outside the intensivist’s scope of training. It is likewise inappropriate, we believe, for NDs to attempt to tell hospital-based specialists how to practice. This is especially inappropriate when advising the use of therapies that are still controversial.
We understand that the AANP is attempting to advocate for patients whom they believe would benefit from a relatively safe intervention. Perhaps they feel that hospitalists and intensivists are unaware of these therapies. Based on the evidence the AANP cites for advocating for these therapies, they additionally believe that there is strong evidence for these recommendations. Neither of these last two points are correct.
MDs know about vitamin C
Discussion on vitamin C use in intensive care is not uncommon. As will be noted below, several recent studies have been published on the topic. Intensive care specialists have considered how the evidence fits into their treatment protocols and whether it is appropriate therapy. They do this with advanced, detailed knowledge about the nuances of managing patients in sepsis, severe pneumonia, ARDs, multiorgan failure, and the other complications of COVID-19.
Based on the evidence, which is already being discussed by hospitalists and intensivists (see commentary on these articles in JAMA3 and Chest4), ICU physicians may or may not use vitamin C based on their clinical judgement. Indeed, IV vitamin C is being studied precisely because some medical doctors are already using it. However, it appears that the majority of critical care specialists do not feel the evidence is strong enough yet to support the widespread use of this therapy.
Any potential benefits of vitamin C therapy in COVID-19 must also be weighed against the potential risks of increased exposure to the staff, and through them other patients in the hospital. Placing IV lines, adding and removing the infusion bags – all bring additional exposure and require scarce PPE (personal protection equipment). With each additional patient contact, providers face additional exposure to the virus – and increased risk of carrying it to others in the hospital, and those outside. Already, well-substantiated standard-of-care management has been altered to decrease potential viral exposure to providers and other patients in the hospital5.
Review of the Evidence Cited
The AANP press release cites a selection of six studies to support the use of vitamin C, plus a set of guidelines issued in Shanghai, China in February 2020. However, a quick PubMed search for “vitamin C sepsis” shows that in the last five years alone, 158 papers have been published6. Sixty papers were published in the last year alone,showing varying results for the use of IV Vitamin C in sepsis. The AANP press release does not provide a thorough, holistic survey of the evidence regarding IV vitamin C use. Notably the AANP does not cite studies that did not show a benefit for vitamin C in sepsis.
To support the AANP’s call for vitamin C usage in COVID-19, the press release primarily relies on a document auto-translated from Mandarin. This document, the “Shanghai 2019 Expert Coronary Disease Comprehensive Treatment Consensus”7, is inaccurately depicted as a research study with data on outcomes. However, the document is actually a practice guideline put forward by the Shanghai New Coronavirus Disease Clinical Treatment Expert Group. While the Shanghai guidelines discuss the group’s recent experiences with COVID-19 diagnosis and a wide range of treatments, they do not provide outcome data. Plus these guidelines only briefly mention the use of intravenous vitamin C, which the Shanghai clinicians used in conjunction with heparin, apparently to improve oxygenation. The Shanghai practice guidelines do not cite any evidence to support the use of this therapy in SARS-related ARDS. Only one reference is included that mentions vitamin C or ascorbic acid, and that reference is for a study done in rats, focusing on the prevention of renal injury in hemorrhagic shock8.
Next, the press release cites a small (n=47) retrospective study looking at a combination therapy of vitamin C, corticosteroids, and thiamine for patients with sepsis or septic shock9. This study showed some benefit with regard to progressive organ failure and mortality. However, a follow-up randomized control trial (n=211) controlled for the use of steroids and did not find benefit for the use of vitamin C and thiamin10. The conflicting results of this RCT were not addressed by the authors of the AANP press release. Bolstering the negative results of this treatment, another study published after the press release also found that a combination of hydrocortisone, thiamine, and vitamin C did not reduce mortality among patients with sepsis/septic shock11.
The second study cited – the CITRIS-ALI randomized controlled trial12 – studied intravenous vitamin C therapy in ARDS secondary to sepsis. The CITRIS-ALI study focused primarily on intravenous vitamin C effects on biomarkers typically found in sepsis and ARDS, rather than its effects on mortality. Interestingly, CITRIS-ALI showed no benefit for IV Vitamin C on any of its primary endpoints, which were the biomarkers used to evaluate the severity of illness in the patients. However, the CITRIS-ALI study did show some benefit in a few secondary endpoints, including mortality. While this seems promising, these secondary results can only be considered exploratory. Why? First, the study looked at forty-six outcomes in all. When a study looks at numerous outcomes, it is not surprising that a few would be positive based on statistical chance. Studies with numerous outcomes are not quite like “throwing mud at the wall to see what sticks,” but they come close. When a treatment is checked to see if it affects forty-six different outcomes, it has a 90% chance that something will turn up positive, just by the luck of the draw13 14 . To determine if secondary results are real or just due to chance, researchers usually make corrections, or follow-up with a study designed to test for those outcomes. However, in the CITRIS-ALI study, Fowler explained that they did not correct for multiple comparisons in their analyses. Therefore, these secondary results are considered exploratory and thus we cannot yet draw a conclusion about IV Vitamin C in sepsis and ARDs without further study.
The third study cited in the AANP press release is a commentary that includes a meta-analysis of three RCTs15, each with less than one hundred participants. The criteria for inclusion were a diagnosis of sepsis or septic shock. One of these studies, a 2014 study16 to establish the safety of IV vitamin C in septic shock, was performed by the same researchers that later performed the CITRIS-ALI11 study discussed above. While this 2014 study showed promising results with regards to scores tied to organ failure, that result was not replicated in the later, and larger, CITRIS-ALI trial – performed by the same investigative team. In short, the AANP press release cites studies that were later disproved.
Two other meta-analyses are included in the press release17 18 . The studies in these meta-analyses do not focus on patients with sepsis and ARDS, but instead included several patient populations with a variety of conditions. Only two of the studies, which are on sepsis, are related to conditions that patients with COVID-19 face. The rest of the studies were about CABG (coronary artery bypass grafting), and patients with burns. The cited meta-analyses ultimately have significant critical flaws in mixing varying study populations and outcomes which makes it difficult to draw meaningful conclusions. Under the principle of “treat the cause,” it should be clear that just because Vitamin C may be potentially useful post-CABG, it does not follow that it would automatically be beneficial for sepsis, ARDS, or COVID-19.
Summary
The evidence cited in the American Association of Naturopathic Physician’s late March 2020 press release does not support the AANP’s claim that IV Vitamin C should be used in COVID-19. While there is some evidence that vitamin C may be useful for certain situations in the hospital setting, the evidence is fairly weak. Additionally, in drawing their conclusion, the AANP did not consider the nuances of care required for severely ill covid patients nor the nuances of the literature.
In its other pandemic-related communications, the AANP has appropriately focused on guiding NDs on how to safely practice during the pandemic as well as reinforcing CDC and public health messaging around COVID-19 (i.e., hand washing, social distancing, etc.). This is within the AANP’s scope and how they should be helping NDs. Providing guidance to NDs about whether to use vitamin C in naturopathic practices in the pandemic would also be appropriate. Any guidance should evaluate the whole of the literature. We hope that future announcements will contain more carefully vetted references and that the AANP continues to offer guidance that is directed to procedures and concerns within the scope of naturopathic practice.
Sarah Hourston earned her doctorate of naturopathic medicine and master’s in integrative medicine research from the National University of Natural Medicine. After completing an NIH post-doctoral fellowship at the Oregon Health and Science University, Hourston then worked for a couple years in research compliance. Wishing to combine the best of integrative and conventional medicine, she is now a medical student at the University of Utah.
Les Witherspoon, ND is the formerly practicing ND behind EBM-ND.org.
The views expressed in this article are the authors’ own and do not represent the views of any other individuals or organizations. This article does not constitute medical advice; please consult your licensed healthcare provider for advice regarding COVID-19, and follow national and state public health guidelines.
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Fowler AA, Truwit JD, Hite RD, et al. Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial. JAMA. 2019;322(13):1261–1270. doi:10.1001/jama.2019.11825 https://jamanetwork.com/journals/jama/fullarticle/2752063
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Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229‐1238. doi:10.1016/j.chest.2016.11.036 https://pubmed.ncbi.nlm.nih.gov/27940189/ accessed 5/6/2020
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See https://annals.org/aim/fullarticle/2763037/how-should-u-s-hospitals-prepare-coronavirus-disease-2019-covid , https://acgme.org/Newsroom/Newsroom-Details/ArticleID/10085/ACGME-Resident-Fellow-Education-and-Training-Considerations-related-to-Coronavirus-COVID-19 and https://www.aamc.org/system/files/2020-04/meded-April-14-Guidance-on-Medical-Students-Participation-in-Direct-Patient-Contact-Activities.pdf
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For example, see https://pubmed.ncbi.nlm.nih.gov/?term=vitamin+c+sepsis&filter=ds1.y_5 and https://pubmed.ncbi.nlm.nih.gov/?term=vitamin+c+sepsis&filter=ds1.y_1
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Shanghai Clinical Treatment Expert Group for corona virus disease. “Comprehensive treatment and management of corona virus disease 2019: expert consensus statement from Shanghai.” Zhonghua chuan ran bing za zhi = Zhonghua chuanranbing zazhi = Chinese journal of infectious diseases, vol. 38, no. 00, Chinese Medical Journals Publishing House Co., Ltd., Mar. 2020, pp. E016–E016, doi:10.3760/cma.j.issn.1000-6680.2020.0016. http://rs.yiigle.com/yufabiao/1183266.htm accessed 5/6/2020. Google translate used to access Chinese text.
8/7/2022: access the original archive at https://web.archive.org/web/20200504125021/http://rs.yiigle.com/yufabiao/1183266.htm -
Qi, Meng-Zhi & Yao, Yi & Xie, Rong-Li & Sun, Si-Lei & Sun, Wen-Wu & Wang, Jin-Long & Chen, Ying & Zhao, Bing & Chen, Er-Zhen & Mao, En-qiang. (2018). Intravenous Vitamin C attenuates hemorrhagic shock-related renal injury through the induction of SIRT1 in rats. Biochemical and biophysical research communications. 501. 10.1016/j.bbrc.2018.04.111. https://www.researchgate.net/publication/324679553_Intravenous_Vitamin_C_attenuates_hemorrhagic_shock-related_renal_injury_through_the_induction_of_SIRT1_in_rats/citation/download accessed 5/6/2020
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Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017;151(6):1229‐1238. doi:10.1016/j.chest.2016.11.036
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Fujii T, Luethi N, Young PJ, et al. Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock: The VITAMINS Randomized Clinical Trial [published online ahead of print, 2020 Jan 17]. JAMA. 2020;323(5):423‐431. doi:10.1001/jama.2019.22176 accessed 5/6/2020
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Chang, Ping, et al. “Combined Treatment with Hydrocortisone, Vitamin C, and Thiamine for Sepsis and Septic Shock (HYVCTTSSS): A Randomized Controlled Clinical Trial.” Chest, Mar. 2020, doi:10.1016/j.chest.2020.02.065. accessed 5/6/2020
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Fowler, Alpha A., 3rd, et al. “Effect of Vitamin C Infusion on Organ Failure and Biomarkers of Inflammation and Vascular Injury in Patients With Sepsis and Severe Acute Respiratory Failure: The CITRIS-ALI Randomized Clinical Trial.” JAMA: The Journal of the American Medical Association, vol. 322, no. 13, Oct. 2019, pp. 1261–70, doi:10.1001/jama.2019.11825. https://jamanetwork.com/journals/jama/fullarticle/2752063 accessed 5/6/2020
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Goldman, Megan. Spring 2008 – Stat C141/ Bioeng C141 – Statistics for Bioinformatics. 2008, https://www.stat.berkeley.edu/~mgoldman/Section0402.pdf. Accessed 5/6/2020
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Also see https://www.statisticsdonewrong.com/p-value.html “As you can see, making multiple comparisons means multiple chances for a false positive. For example, if I test 20 jelly bean flavors which do not cause acne at all, and look for a correlation at p<0.05 significance, I have a 64% chance of a false positive result.54 If I test 45 materials, the chance of false positive is as high as 90%.” Reinhart, Alex, Statistics Done Wrong: The Woefully Complete Guide, accessed 4/19/2020
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Li J. Evidence is stronger than you think: a meta-analysis of vitamin C use in patients with sepsis. Crit Care. 2018;22(1):258. Published 2018 Oct 11. doi:10.1186/s13054-018-2191-x https://ccforum.biomedcentral.com/articles/10.1186/s13054-018-2191-x accessed 5/6/2020. A letter in response to this commentary is at https://ccforum.biomedcentral.com/articles/10.1186/s13054-019-2538-y
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Fowler, Alpha A., 3rd, et al. “Phase I Safety Trial of Intravenous Ascorbic Acid in Patients with Severe Sepsis.” Journal of Translational Medicine, vol. 12, Jan. 2014, p. 32, doi:10.1186/1479-5876-12-32. Accessed 5/6/2020
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Hemilä H, Chalker E. Vitamin C Can Shorten the Length of Stay in the ICU: A Meta-Analysis. Nutrients. 2019; 11(4):708. https://www.mdpi.com/2072-6643/11/4/708#cite accessed 5/6/2020
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Hemilä H, Chalker E. Vitamin C may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis. J Intensive Care. 2020;8:15. Published 2020 Feb 7. doi:10.1186/s40560-020-0432-y https://pubmed.ncbi.nlm.nih.gov/32047636/ accessed 5/6/2020