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After hundreds of trials failing to show benefit of drug treatments for sepsis, could a simple, cheap and effective treatment -- high-dose vitamin C -- be hiding in plain sight? A respected leader in critical care medicine thinks so, and his hospital system is all in.
Vitamin C (ascorbic acid) is depleted during sepsis. That might be bad, because ascorbic acid helps maintain the integrity of the endothelium (i.e., the glycocalyx), and is a cofactor required for the production of catecholamines and cortisol: hormones needed for survival from shock.
So why don't we already rush to replace this vital nutrient in septic patients? Lots of endogenous substances are depleted in sepsis, but as most are markers of illness rather than contributors, replacing them may be useless or harmful (and in the case of activated protein C, expensive to boot). See also "The Normalization Fallacy."
The Case for Vitamin C Treatment In Sepsis
Vitamin C is believed generally safe at high doses, but can rarely cause acute renal failure through oxalate crystal deposition. Small studies have found high-dose IV vitamin C during critical illness safe and beneficial:
- In Tanka et al (2000), among 37 patients with major burns, those randomized to receive infusion of vitamin C at high doses (e.g., 4-5 grams an hour) for 24 hours on admission required less fluid resuscitation and had fewer ventilator days than those who got usual care.
- Fowler et al (2014) found less organ dysfunction among the 24 patients with severe sepsis randomized to vitamin C infusion vs placebo, with a significant dose-response (up to a maximum dose of ~3-5 grams IV every 6 hours). No safety issues in this Phase I trial.
- Zabet et al (2016) randomized 24 post-surgical patients with septic shock to vitamin C infusion (~1.5-2.5 grams IV every 6 hours) or placebo; the vitamin-C treated patients had significantly lower mortality and need for vasopressors.
The renowned Dr. Paul Marik et al will soon publish in Chest their own small before-and-after unblinded cohort study, born of an anecdote that should intrigue any intensivist: three patients with "fulminant sepsis ... almost certainly destined to die" from shock and organ failure, infused with vitamin C and moderate dose hydrocortisone out of desperation. All three patients recovered quickly and left the ICU in days, "with no residual organ dysfunction".
Inspired by that experience, they went on to enroll and treat 47 septic patients with a cocktail of 1.5 g vitamin C IV every 6 hours, hydrocortisone 50 mg IV every 6 hours, and thiamine 200 mg IV every 12 hours (thiamine inhibits oxalate production and has potential benefits in septic shock). Controls were 47 patients matched in baseline characteristics.
Hospital mortality was 4 of 47 (8.5%) in those treated with the cocktail, compared to 19 of 47 (40%) in those not. Vasopressors were weaned off all cocktail-treated patients, usually in <24 hours (vs. 4 days for the controls). Renal function reportedly improved in all patients with acute kidney injury.
These are exciting preliminary findings, and a large randomized trial seems warranted, but a look at clinicaltrials.gov shows no studies of any size in progress testing vitamin C in sepsis. (There is one, n=170, testing vitamin C for acute lung injury, which is often due to sepsis.)
Dr. Marik and the hospitals associated with Eastern Virginia Medical School aren't letting that get in the way of following their own data and experience. The vitamin C-steroid-thiamine cocktail is now part of their standard therapy for patients with sepsis, often initiated in the emergency department. They're even doing PR, spreading the word with TV interviews, well-produced video testimonials, and a spot on NPR's Morning Edition:
Vitamin C for Sepsis: A "Cure?" Cue the Controversy
A spirited discussion on this can be found over on Josh Farkas's PulmCrit blog, along with additional commentary from Dr. Marik himself:
We have now treated over 150 patients with severe sepsis and septic shock. We have had only one patient die from sepsis ... [w]hile a few of the treated patients have died, none died from progressive organ failure related to sepsis. Our CEO and CMO has confirmed our results (shorter LOS and fewer deaths) and has requested that the protocol be instituted throughout our hospital system."
Since (if clinicaltrials.gov is accurate) no randomized trials are going to answer this question for years, it will be fascinating to see how this anecdotal therapy is adopted and future results reported and shared. Dr. Marik's stature and the dramatic findings will grant it credibility and a wide audience. The therapy's apparent benignity will lead reasonable physicians to consider it ethical in severe septic shock, or even an ethical imperative under a "compassionate use"-like philosophy.
Meanwhile, skeptics will demand additional efficacy and safety data before changing practice. For example, if acute renal failure develops after off-label vitamin C administration, might a later case review fault the physician, rather than the (more likely) sepsis? (Dr. Marik advised PulmCrit "the cocktail is without side effects; renal function has improved in all treated patients.")
In a sense, these findings pose an exaggerated version of the dilemma all intensivists face every day in treating sick patients with limited evidence and information. How do you plan to respond?
Disclosure: Dr. Paul Marik is an editor of PulmCCM Journal.