As you all know, I am a skeptic of almost all supplements, and I never thought that using vitamin C for sepsis was supported by robust and repeated data. Well, an analysis by an Australian physician, statistician, and Ph.D. student may have found fraudulent data, and it’s becoming a topic of conversation among physicians who have used the protocol to treat sepsis.
Let’s take a peek at this story since it is so amazing because this shows how science really works.
Contents
Vitamin C for sepsis — how this started
A paper, published on 6 December 2016, by Paul Marik, MD and colleagues, in CHEST, described a protocol that could prevent death from sepsis. It included a simple regimen of hydrocortisone, ascorbic acid (vitamin C), and thiamine (the procedure was dubbed the HAT protocol), that could save many lives. The paper has been the subject of significant debate in the intensive medicine community since it was first published.
Other studies contradicted Marik’s study adding to the debate about the validity of the HAT protocol. Several larger and more methodologically robust studies followed, and to date, none of at least nine randomized trials — including the VITAMINS and VICTAS clinical trials — has shown a similar reduction in mortality. Even if the original study was not fraudulent, it was becoming clear that other independent data did not support the effectiveness of the HAT protocol.
Dr. Kyle Sheldrick, MD, who is completing his Ph.D. at the University of New South Wales, alleges that the pre- and post- comparison groups involved in the small 94-patient study were too good to be realistic. Dr. Sheldrick wrote to the editors of CHEST outlining several factors that lead him to the conclusion of fraud. He concluded:
There is simply no apparent explanation for this other than fraud. The methods are described clearly and these are explicitly two cohorts of consecutive patients, so the only real innocent explanation here (undisclosed matching by baseline characteristics) did not occur (and it clearly didn’t anyway as matching patients this exactly would not be possible even with thousands of such patients).
OUCH! I’m so used to very careful language in science (well, I’m not one of those), it was remarkable to see such blunt commentary on Marik’s paper.
In an interview with MedPage Today, Dr. Sheldrick described how he figured out that the vitamin C protocol for treating sepsis was probably bogus:
…the key problem with the Marik paper is “probably the most common sign of fraud that we see, which is overly similar groups at baseline.”
Generally, when people are asked to fake a random distribution, they will consistently fake an even distribution, he explained: “You will fake data that’s far too close to the averages with not enough variation.”
Sheldrick said he first looked at the study methods, which noted a pre- and post- comparison design, rather than a randomized or matched case-control design. With such a design, one would expect a more random distribution of baseline characteristics, but that wasn’t the case for the Marik paper, he said.
He calculated P-values for the comparisons of the baseline characteristics using the Fisher Exact test, which he would expect to range fully from 0 to 1 given the study design. But he found the majority of P-values were 1 — meaning they were distributed perfectly evenly across two time periods — and only one fell below 0.5.
“We would expect to see these evenly spread between 0 and 1,” he told MedPage Today, with an overall average of around 0.5.
I can’t believe that Dr. Sheldrick was the first person to notice that the p-values were 1.0. I hate statistics, and if I saw perfect p-values I would have wondered what was going on. There should be a simple rule of science — if the data is too good to be true, be skeptical. Very skeptical.
Dr. Sheldrick said:
This is extreme. This is probably the most obviously fake data I have seen. … These groups are more similar than would be probable.
Dr. Sheldrick sent a letter to CHEST and Dr. Marik’s former employer, Sentara Norfolk General Hospital, but neither responded to him. However, MedPage Today was told by a spokesperson for CHEST that it couldn’t confirm whether they had begun an investigation of Marik’s paper based on Sheldrick’s letter to them. Apparently, the journal does have a procedure for investigating claims about published articles, but they won’t comment on the process.
Of course, Dr. Marik responded that these were false allegations with no merit. He cites two studies that support his claims while ignoring the seven other, much better, studies that show no difference in sepsis outcomes with vitamin C therapy. This is a perfect example of cherry-picking, but Marik is trying to defend his work by deflecting to other studies. He makes no mention of his perfect p-values, which was the basis of Dr. Sheldrick’s claims.
More about Paul Marik
But the story gets better. Dr. Marik co-authored a paper, that was published in November 2021 in the Journal of Intensive Care Medicine that described the MATH+ protocol for COVID-19. The MATH+ protocol, which includes methylprednisolone, ascorbic acid, thiamine, and low molecular weight, supposedly improved COVID-19 outcomes. He even created one of those quack groups that push COVID-19 treatments like ivermectin.
In case you were wondering, Marik’s COVID-19 paper was retracted.
In other words, Marik has discovered two “miracle” cures, one for sepsis and another for COVID-19, within a few years of each other. It makes my skeptical radar blare all kinds of warnings.
Vitamin C is useful for treating scurvy and probably not for sepsis (and certainly not for COVID-19), that’s it. I wish people would quit giving it more magical powers than that, but that’s what people do to push vitamin C.
Citations
- Fujii T, Luethi N, Young PJ, Frei DR, Eastwood GM, French CJ, Deane AM, Shehabi Y, Hajjar LA, Oliveira G, Udy AA, Orford N, Edney SJ, Hunt AL, Judd HL, Bitker L, Cioccari L, Naorungroj T, Yanase F, Bates S, McGain F, Hudson EP, Al-Bassam W, Dwivedi DB, Peppin C, McCracken P, Orosz J, Bailey M, Bellomo R; VITAMINS Trial Investigators. 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. JAMA. 2020 Feb 4;323(5):423-431. doi: 10.1001/jama.2019.22176. PMID: 31950979; PMCID: PMC7029761.
- Fujii T, Salanti G, Belletti A, Bellomo R, Carr A, Furukawa TA, Luethi N, Luo Y, Putzu A, Sartini C, Tsujimoto Y, Udy AA, Yanase F, Young PJ. Effect of adjunctive vitamin C, glucocorticoids, and vitamin B1 on longer-term mortality in adults with sepsis or septic shock: a systematic review and a component network meta-analysis. Intensive Care Med. 2022 Jan;48(1):16-24. doi: 10.1007/s00134-021-06558-0. Epub 2021 Nov 9. PMID: 34750650; PMCID: PMC8724116.
- Jung SY, Lee MT, Baek MS, Kim WY. Vitamin C for ≥ 5 days is associated with decreased hospital mortality in sepsis subgroups: a nationwide cohort study. Crit Care. 2022 Jan 5;26(1):3. doi: 10.1186/s13054-021-03872-3. PMID: 34983595; PMCID: PMC8728994.
- Kory P, Meduri GU, Iglesias J, Varon J, Marik PE. Clinical and Scientific Rationale for the “MATH+” Hospital Treatment Protocol for COVID-19. J Intensive Care Med. 2021 Feb;36(2):135-156. doi: 10.1177/0885066620973585. Epub 2020 Dec 15. Retraction in: J Intensive Care Med. 2021 Nov 9;:8850666211049062. PMID: 33317385.
- Litwak JJ, Cho N, Nguyen HB, Moussavi K, Bushell T. Vitamin C, Hydrocortisone, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Analysis of Real-World Application. J Clin Med. 2019 Apr 9;8(4):478. doi: 10.3390/jcm8040478. PMID: 30970560; PMCID: PMC6518003.
- 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 Jun;151(6):1229-1238. doi: 10.1016/j.chest.2016.11.036. Epub 2016 Dec 6. PMID: 27940189.
- Patel JJ, Ortiz-Reyes A, Dhaliwal R, Clarke J, Hill A, Stoppe C, Lee ZY, Heyland DK. IV Vitamin C in Critically Ill Patients: A Systematic Review and Meta-Analysis. Crit Care Med. 2022 Mar 1;50(3):e304-e312. doi: 10.1097/CCM.0000000000005320. PMID: 34637420.
- Sevransky JE, Rothman RE, Hager DN, Bernard GR, Brown SM, Buchman TG, Busse LW, Coopersmith CM, DeWilde C, Ely EW, Eyzaguirre LM, Fowler AA, Gaieski DF, Gong MN, Hall A, Hinson JS, Hooper MH, Kelen GD, Khan A, Levine MA, Lewis RJ, Lindsell CJ, Marlin JS, McGlothlin A, Moore BL, Nugent KL, Nwosu S, Polito CC, Rice TW, Ricketts EP, Rudolph CC, Sanfilippo F, Viele K, Martin GS, Wright DW; VICTAS Investigators. Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial. JAMA. 2021 Feb 23;325(8):742-750. doi: 10.1001/jama.2020.24505. Erratum in: JAMA. 2021 Sep 21;326(11):1072. PMID: 33620405; PMCID: PMC7903252.
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