“Doctor – Your Sepsis Patients Have Scurvy,” asserted Paul Marik MD in a Critical Care Editorial. Marik, who at the time was a respected critical care physician at Eastern Virginia Medical School in Norfolk, Virginia, supported his scurvy claim by noting that patients with sepsis suffer a “severe total body depletion” of vitamin C. He argued that antioxidant vitamin C counteracts the “excessive production of reactive oxygen species” (ROS) caused in sepsis by nitric oxide synthase among other enzymes. He further observed that humans are unable to synthesize vitamin C, and that vitamin C is an essential cofactor in the synthesis of catecholamines and vasopressin. These increase blood pressure (which is low in patients with septic shock).

The idea that vitamin C should be used in sepsis gained traction after Marik published a report in the journal Chest. In that small, uncontrolled study, sepsis patients received a combination therapy of hydrocortisone, vitamin C, and thiamine. He reported an unbelievable decrease in mortality – from 40.4% prior to using the protocol to 8.5% after starting the protocol. (In fact, it really was unbelievable; read-on)

Marik’s now infamous study received a lot of press, including a favorable write-up on NPR.org, it also drew critics who noted the lack of an adequate control group. This prompted calls for a large well-designed multi-centered trial. Researchers heeded the call. The most recent of these, the #LOVIT trial by Lamontagne and colleagues, was published today in the New England Journal of Medicine. Did treating the supposed deficiency of vitamin C save these patients? Did patients improve because of extra anti-oxidants that mopped up excessive free radicals? Were sepsis patients discharged more often because cathecholamine receptor function was improved by vitamin C?

No they did not. The primary outcome – death or persistent organ dysfunction – was made worse by vitamin C in this trial. From the abstract: Death or organ dysfunction (defined as needing persistent mechanical ventilation or renal replacement or still on vasopressors) was significantly higher in patients getting vitamin C. (risk ratio, 1.21; 95% confidence interval [CI], 1.04 to 1.40; P=0.01).

This result is only the most recent nail in the vitamin C coffin. Two years ago, the VITAMINS trial showed no benefit to adding vitamin C to standard treatment that included hydrocortisone. The investigators concluded that the combination therapy that included vitamin C did not lead to a more rapid resolution of septic shock versus hydrocortisone alone. Also, the ACTS trial compared the same combination versus placebo, and found no effect on illness severity or mortality. The VICTAS trial compared vitamin C + thiamine + hydrocortisone to placebo – this trial was terminated early for administrative reasons, and found no effect on its primary outcome. The LOVIT trial published today was the largest and the most recent trial of vitamin C in sepsis, and it’s definitive result may signal the end for vitamin C advocates.

As for Paul Marik, he became notorious for hawking ivermectin for COVID-19 as one of the FLCCC “front line doctors.” He became embroiled in a legal battle with the Eastern Virginia Medical School and ultimately separated from that place of employment. His departure apparently involved a dispute over his use of ivermectin and other unproved treatments on ICU patients.

This is not a morality story about a flawed researcher. This is a lesson about our assumptions about sepsis. Marik was right about vitamin C levels that plummet during sepsis, and right about high NOS synthase levels, and right about increased levels of oxygen radicals in sepsis; he was wrong about what this means for patients.

Low vitamin C might be more helpful than harmful during sepsis. Higher mortality in vitamin C treated patients in today’s NEJM report is consistent with this view. Similarly, it might be adaptive for sepsis patients to have high levels of inducible nitric oxide synthase activity. A previous trial of an experimental nitric oxide synthase inhibitor resulted in increased mortality in sepsis: 28 day mortality was 59% in the inhibitor group (259/439) and 49% (174/358) in the placebo group (p <.001). These results suggest that we are wrong when we assume that high NOS activity is pathological in sepsis. Vitamin C is probably not deficient in sepsis either. A closer look into the mechanisms of vitamin C transport will probably reveal pathways that evolved because they benefit hosts during a life threatening infection.

Post-script: Even though I disagree with Paul Marik’s current preoccupation with ivermectin and Vitamin C, I thought it necessary to point out I appreciate his earlier work. In the recent past, Dr. Marik’s perspective on Surviving Sepsis was quite well aligned with mine. I strongly recommend this article and the especially the attached podcast: Point: should the Surviving Sepsis Guidelines be retired? Yes.

Copyright © Joe Alcock MD

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Joe Alcock

Emergency Physician, Educator, Researcher, interested in the microbiome, evolution, and medicine