256px-Sarah-Bernhardt_(Hamlet)

If only Yorik had received IV vitamin C.

Macbeth: How does your patient, doctor?
Doctor: Not so sick, my lord,
As she is troubled with severe sepsis,
That keep her from her rest.
Macbeth: Cure her of that…
Doctor: Therein the patient
Must minister to himself.
Macbeth: Throw ascorbic acid to the dogs; I’ll none of it.

Writing about pseudo-medicine is relatively easy. Most pseudo-medicines are simple and self-contained. Being fundamentally fictional, outside of real complications, you do not have to fret overmuch about physiology and anatomy and plausibility and all the other aspects of medicine that make being a doctor a lot like Barbie in a math class. It’s tough.

After the flood, I’m left high and dry

I have been inundated (two is an inundation for me) with emails about “Hydrocortisone, Vitamin C and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study.” What, they ask, as an ID doctor and skeptic, do you make of it?

I have 34 years plus of taking care of severe sepsis and septic shock and I have seen interventions come and go in the attempt to decrease the mortality from sepsis. Using steroids has waxed and waned, combination antibiotics have had their day in the sun, anti-endotoxin antibodies looked promising, and over a billion dollars was spent on Xigris before studies showed it didn’t work, so never mind.

A career of disappointed hopes has rendered me skeptical. Headlines like:

They fail to impress. Been there, done that. Vitamin C has had such a bad reputation for so long as King of the overhype, having actually efficacy would be like an apology from the current POTUS. Never gonna happen. But let us have a Joan Jett moment and see where the literature leads us.

Before we get to the study, back to basics. Is there any reason to suspect vitamin C would have any effect on sepsis? Maybe.

Some fundamentals

Vitamin C has beneficial effects on the mediators of sepsis in mouse models, although mice are not men:

Highlighting just how poorly the mice reflected the human disease, the correlations of the gene changes in the mouse models with their human disease counterparts came close to those expected by random chance alone.

Vitamin C levels are often very low in septic patients, so repletion and/or super-therapeutic doses may have beneficial effects on variety of septic pathophysiologic processes, especially the low blood pressure that accompanies sepsis.

Patients with severe sepsis present with hypovitaminosis C, and pre-clinical and clinical studies have indicated that administration of high-dose ascorbate decreases the levels of pro-inflammatory biomarkers, attenuates organ dysfunction and improves haemodynamic parameters. It is conceivable that administration of ascorbate to septic patients with hypovitaminosis C could improve endogenous vasopressor synthesis and thus ameliorate the requirement for exogenously administered vasopressors.

I never find these kinds of extrapolations compelling. Sepsis/septic shock is a jaw-droppingly complex reaction to a variety of processes, most often infection, and most of these hoped for effects would appear to be no more than pissing on a forest fire.

But there are a pair of prior studies. One is a prior small, placebo controlled trial that showed benefit from intravenous vitamin C, with septic patients requiring less vasopressors and a decrease in mortality. Another preliminary safety trial also showed benefit. And vitamin C has been used with some benefit in other severely ill patients, including burn unit and surgical patients. The studies had different designs and end points, but pointed the same direction: less organ failure, less mortality, and faster resolution. And with no side effects. A wonder drug working wonders?

A good start, but…

So an encouraging, albeit it small and preliminary, literature. Which brings us to the current paper. It is everything you don’t want a clinical trial to be. It is not blinded, placebo controlled, or randomized, and has small numbers of patients. It is the kind of paper that, when seen through the lens of “Why Most Published Research Findings Are False” leads to a sigh and an eye roll.

After a Hail Mary of giving vitamin C to three septic patients who unexpectedly survived, they started routinely giving vitamin C (plus thiamin and low dose steroids) to all their septic patients.

The paper is a comparison of 47 patients before the intervention with vitamin C and 47 patients after the intervention. In other words 94 anecdotes, an extended riff on the theme of what I call the three most dangerous words in medicine: in my experience.

The patients were similar in both groups, but only a small number had positive blood cultures. But, in line with prior studies, treatment decreased the need for vasopressors and mortality:

The hospital mortality was 8.5% (4 of 47 patients) in the treatment group compared to 40.4% (19 of 47 patients) in the control group (p < 0.001).

The treatment group also improved their SOFA score (a measure of disease severity) more rapidly:

The 72-hour delta SOFA score was 4.8 ± 2.4 in the treatment group compared to 0.9 ± 2.7 in the control group

Impressive results from an unimpressive methodology. Such an impressive effect by vitamin C on such a complex pathophysiology seems just too good to be true. Which means it probably is.

What does the future hold?

What is going to happen now? If history repeats itself, first IV vitamin C will be in short supply followed by a marked increase in acquisition cost. Never saw a pharmaceutical company yet that that didn’t take the opportunity to price gouge. There will be a clinical trial with a good methodology that will show no overall benefit but there will be benefit in post hoc subgroup analysis. And another trial of the subgroup will be done and, a decade from now, after I am retired or dead, vitamin C will be found to be ineffective for sepsis. I sure hope I am wrong.

The pseudo-medical world is already getting their paranoid conspiracy boxers in a twist over suppression of a ‘natural’ way to treat sepsis while demonstrating a lack of understanding of the scientific process.

This story also provides a good case study into how medicine should work: doctors use their knowledge and experience—as well as the work of their colleagues—to test new treatments for intractable diseases, and then determine what works. The government has time and time again proven itself incapable of determining whether the drugs it approves are effective, and the FDA is, of course, susceptible to the self-interested manipulation of scientific research carried out by Big Pharma. The question of efficacy should be left to doctors and patients.

As if massive doses of intravenous vitamin C is natural. I would not be surprised if a naturopath gave patients IV orange juice, you know, to potentiate the effects with a natural source of vitamin C.

I like big buts and I cannot lie

But but but but but. One big but.

What to do now as a clinician? When a patient hits the ICU septic, how to apply this scant, preliminary, unsatisfactory information? Death. That is one hard, impressive, endpoint. Death is not the usual subjective, biased, soft result that is the effect of pseudo-medical interventions. An 8.5% mortality rate for sepsis is damn good. It may be the ICU equivalent of flipping a coin and getting heads 10 times in a row. Or it may be the real deal. It appears they keep coming up heads.

We have now treated over 150 patients with severe sepsis and septic shock. We have had only one patient die from sepsis, this being a complex surgical case who died in the immediate post-operative period. While a few of the treated patients have died, none died from progressive organ failure related to sepsis. All these patients were weaned off pressors/mechanical ventilation and died from their underlying disease

Vitamin C for decreasing mortality from sepsis, no matter how preliminary the data, is so far consistent, and is so tempting, despite my pessimism that it will be yet another overhyped flash in the pan. But we have to fight our wars with the equipment at hand. The future? Hamlet or Macbeth?

Let me see. (Takes the vial) Alas, poor ascorbate! I knew it, Horatio, a vitamin of infinite therapeutic effects, of most excellent fancy. It hath treated a thousand pestilences, and now, how abhorred in my imagination it is!

Or:

I dreamt last night of the three weird trials:
To you they have show’d some truth.

But given the risks, the benefits, and the data until there is a definitive trial I have to side with Vizzini:

Never go in against vitamin C when death is on the line!

Posted by Mark Crislip

Mark Crislip, MD has been a practicing Infectious Disease specialist in Portland, Oregon, since 1990. He is a founder and  the President of the Society for Science-Based Medicine where he blogs under the name sbmsdictator. He has been voted a US News and World Report best US doctor, best ID doctor in Portland Magazine multiple times, has multiple teaching awards and, most importantly,  the ‘Attending Most Likely To Tell It Like It Is’ by the medical residents at his hospital. His growing multi-media empire can be found at edgydoc.com.