Does Vitamin C in Sepsis Live Up to the Hype?
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Does Vitamin C in Sepsis Live Up to the Hype?

October 11, 2019

Welcome to Impact Factor, you’re weekly
dose of commentary on a new medical study. I’m Dr. F. Perry Wilson. When it comes to sepsis and septic shock,
docs are used to disappointment. When I was training, the new hotness was stress-dose
steroids and dual coverage for Gram negatives. Then Rivers’ early goal-directed therapy,
then activated protein C. Time and again, early dramatic successes gave
way to less impressive or negative studies and the hope that there was a silver bullet
for sepsis diminished. But one therapy has proven tantalizingly resilient,
not only for reports of dramatic successes but also because of its low cost and virtual
absence of side effects. That therapy? Vitamin C.
Dateline June, 2017. Dr. Paul Marik publishes an observational
before / after study in Chest that many in the community called simply too good to be
true. 47 patients with sepsis before institution
of a vitamin C based protocol – mortality rate 40%. 47 patients after institution of a vitamin
C protocol – mortality rate 8.5%. Not a randomized trial, but crazy good results. I spoke with Dr. Marik – asking how things
have gone since he published the Chest paper: “Patients in our ICU do not die of sepsis. It just does not happen.” But the lack of a randomized trial was a real
blemish in this area research. Skeptics noted that before/after studies are
uniquely susceptible to selection bias, even cherry picking. Show us the evidence. Well, the evidence may be here. Though it’s not all we would have hoped
for. The CITRIS-ALI trial appears in JAMA this
week. It enrolled 167 patients with sepsis and ARDS
and randomized them to high dose IV vitamin C 50mg/kg every 6 hours for 96 hours – versus
placebo in a double-blind fashion. The primary outcome was NOT mortality, but
rather changes in inflammatory biomarkers and SOFA score. I asked lead author Dr. Berry Fowler why the
surrogate outcomes: “We were afraid to put mortality as a primary
outcome, when we designed it. And we were thinking you know, holy cow, if
we put this as a primary outcome, and it fails, you can kiss vitamin C goodbye.” In other words, this was going to be a small
study. You’d therefore need a big difference in
a hard outcome like mortality to achieve statistical significance – they played it safe, and
looked at changes in continuous metrics like SOFA score for their primary outcome. The team may be regretting that decision. At 96 HOURS there was no difference in SOFA
score, c-reactive protein, or thrombomodulin levels in the two groups. Primary outcome – negative – no effect
of vitamin C. Except that, oh yeah, there were fewer deaths
in the Vitamin C arm: 30% mortality versus 46% in the placebo arm. To quote Dawn from the hit Broadway musical
“Waitress”, “What do I do with that?”. I asked Dr. Fowler – did he consider this
study a success? “I’m pretty excited about it. It’s a small trial. I realize you can’t say much about 167 patients,
but it’s at least a start.” Why can’t we just say – “look, significantly
lower mortality in the Vitamin C arm! Who cares about the semantics of primary and
secondary outcomes”. The reason this is an issue becomes clear
if you imagine the opposite outcome occurred – no difference in mortality between Vitamin
C and placebo. Since mortality was a secondary outcome, the
authors could legitimately say “we didn’t power the study for mortality – this was
a small study looking at intermediate outcomes” and we’d all be happy with that. In other words, if we embrace the mortality
outcome here we’re basically saying there’s no way to lose with this study design. Significant difference in mortality? Sing it from the rooftops. No difference in mortality? Oh well, it was a secondary outcome anyway. So… back to my question. What do we do? The pat answer is call for more research. If nothing else, the Vitamin C researchers
have earned themselves the right (and hopefully the funding) for a truly large scale study. But what do we do in the meantime? If this were a drug with big risks, or if
it were particularly expensive, I’d do the slow medicine thing – wait for more info. But… it’s not expensive. And it’s not that risky. The nephrologist in me was worried about oxalate
nephropathy, but apparently that hasn’t emerged. Dr. Fowler pointed out to me that IV vitamin
C causes the point-of-care glucose checks to read too high – helpful FYI there. But basically – this is a pretty low risk
intervention. It’s easy for me to sit here and say “unless
the patient has scurvy, wait for more data”. But if a loved one was in the ICU with sepsis,
would you ask for Vitamin C? After reviewing the literature to prepare
for this commentary, I’d be hard pressed to dismiss it out of hand.

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