Enough with Vitamin C

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Sepsis has been plaguing Resuscitationists and Intensivists for years and we are always looking for “magic bullets” to save lives. We have looked at fluid boluses with starches, drotrecogin alfa for immunomodulation and more recently the use of a cocktail of vitamin C (ascorbic acid), thiamine, and steroids (aka HAT therapy). HAT is not a crazy concept and the use of this cocktail does have some physiologic basis (anti-inflammatory, reduction in free oxygen radicals, reduction in nitric oxide synthase, etc.), evidence in animal studies, and small human trials. The problem is that we don’t have any high-quality evidence to support its use for severely septic patients. 

When I say high-quality evidence, I mean the types of trial with adjectives that make evidence based medicine doctors salivate. Words like randomized, multi-center, placebo-controlled blinded, these are the pillars of the scientific method that we have come to know, love, and demand. These words are absent from the trials that have shown benefit for HAT therapy. On the contrary, the HAT trials that have used those words have not shown any benefit. As a result there are now two camps regarding the use of HAT, you believe that HAT is the magic bullet and no trial will ever be good enough until it demonstrates benefit for HAT or you are just waiting to see the benefit of the therapy before adding in another series of drugs and changing your practice. 

The first big study looking at HAT was Dr. Paul Marik’s 2017 study. This was a before and after trial that showed an amazing mortality benefit when the HAT cocktail was used for patients in septic shock. A little background on Dr. Marik first; Dr. Marik  is an outspoken researcher who has famously picked apart and criticized Rivers’ protocol, debunked the myth of CVP for fluid responsiveness, and consistently demands researchers to provide the highest caliber of evidence when presenting their research. Based on this premise, you would expect Dr. Marik to conduct a high-quality clinical trial that would be large, blinded, and with rigorous methodologies. Well, his trial on HAT was a before and after study of 94 patients that was not blinded or it randomized…and with many methodological flaws. There were not 94 patients in each group, but 94 patients in total. Nevertheless, they proudly reported a “too good to be true” mortality reduction of 40.4% to 8.5% for patients receiving HAT. In fact, the researchers believed that the results were so convincing that they stated “we believe that the results of our study provide sufficient information for the design of an adequately powered, high-quality pragmatic trial to confirm the findings of our study. Because of the lack of clinical equipoise and the ethics of withholding a potentially lifesaving intervention, we were unable to initiate a randomized controlled trial in our center.” In other words, they felt that it would not be unethical to run a sound clinical trial in their hospital after these results because the result speaks for itself. Does this sound like the standards Dr. Marik would accept from any other researcher?  

The next study to look at HAT was the VITAMINS trial . It has all the makings of a great study, randomized, placebo-controlled, and a large number of patients. The results did not show an improvement in mortality but despite checking many of the EBM boxes, the pro-HAT camp wasn’t happy. They argue that there are serious flaws in the study including it taking over 12 hours for some patients to receive HAT in the treatment group, for efficacy it must be started under 12 hours (…not sure where that data came from but that’s the argument). In fact, anyone interested in this topic should watch the presentation where Dr. Marik goes on a tirade regarding all the flaws in the study and berates the first author by asking her “would she withhold the therapy if the patient were her daughter?”. It appears that this study wasn’t good enough for those that are true vitamin C believers because the desired results were not achieved. 

The CITRIS-ALI trial, also a study with all the tasty, delicious EBM buzz words and was demonstrated a reduction in the primary outcome of end-point of inflammatory markers. Good news, there was also a reduction in mortality in the HAT group…but this was a secondary outcome. We shouldn’t make conclusions on a secondary outcome. How do you think the HAT-camp responded…that’s right, these findings weren’t good enough for them. Dr. Marik himself wrote an editorial on this paper (found here) discussing the conspiracy and the statistical acrobatics that were done by the reviewers to discredit HAT therapy. This paper is definitely worth a read, but the bottom line is that the study was still not good enough to appease the pro-HAT people.

Two recent trials, the HYVCTTSSS (aka The Vowel-less trial) and another study here, could not demonstrate a mortality benefit for HAT. In the HYVCTTSSS study there was no reduction in 30-day mortality in patients with sepsis. In the other trial, the number of days on the mechanical ventilator were reduced, but there was no mortality benefit shown…only a trend to lower 30-day mortality. A trend. Ask anyone who believes in EBM what they think of trends. 

So where does this all leave us with regards to using HAT for severe sepsis? As of now, it really depends on which camp you are in. I am in the camp that chooses to wait for more data. For the record, I hope HAT works, I truly do. It makes biochemical sense that it should work and it would provide a new therapy for sepsis which can lead to overwhelming inflammation and multi-organ failure. My hope is that the VICTUS trial (a large, multi-center, double-blind, randomized placebo-control trial that is still enrolling) will put an end to this debate. 

Whatever camp you are in, we should agree that we must hold our scientific standards to the highest level and wait for the best evidence to change practice. If we don’t maintain these standards then we run the risk of becoming early-adopters and jumping at any new therapy that emerges. Early adoption of unproven therapies, no matter how attractive they are from a theoretical standpoint, can put our patients in harm’s way with unknown complications and consequences. 

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