Episode 44- “Moonshot”: Vitamin C, thiamine, and hydrocortisone in septic shock

Hello and welcome to Episode 44 of ER-Rx. In this week’s Fresh Fruit series, we discuss an article published in January 2021 in the Journal of Intensive Care Medicine. This article is entitled “Vitamin C, thiamine, and hydrocortisone in the treatment of sepsis: a meta-analysis and trial sequential analysis of randomized controlled trials.” For the sake of time, I won’t go over the exact dosing schemes or the hypotheses of why it’s thought that Vitamin C and thiamine are useful in sepsis and septic shock- instead, I’ll direct the listeners to my references in the Show Notes.

Back in 2017, Dr. Marik and his team published a retrospective study that took the medical world by storm. In this study of 94 patients with severe sepsis and septic shock (47 in each group), they found that using a concoction of Vitamin C, thiamine, and hydrocortisone led to an 8.5% hospital mortality rate compared to the control group’s 40.4% mortality rate (P< 0.001). SOFA scores decreased in all patients given the vitamin concoction, with none of them developing organ failure. All of these patients were weaned off vasopressors about 24 hours after starting the protocol. The results were incredible, and they led to a media frenzy in the healthcare world and beyond. I also got the chance to see Dr. Marik himself present these results at SCCM to a packed conference room. It seemed like we were finally discovering the cure for septic shock– an entity that causes an enormous burden on the healthcare system and leads to death in about half of affected patients.

Since then, there have been dozens of studies published in an attempt to replicate Dr. Marik’s astounding results; studies with clever names like “VITAMINS ”and “ORANGES,” for example. To try to synthesize all of this data, the authors of this particular meta-analysis looked only at randomized controlled trials in adult patients with sepsis or septic shock that were treated with the vitamin concoction. They excluded retrospective studies and those that used Vitamin C only.

In the end, their review included six studies in a total of 839 patients (mean age 64.2 +/- 18 years, SOFA scores 8.7 +/- 3.3, and ~ 50% males). Of course, this meta-analysis isn’t perfect. Three studies had a high risk of bias due to a lack of blinding, baseline Vitamin C levels were measured only in one study (it was similar between groups), and three studies included only septic shock patients while the rest included patients with septic shock or sepsis.

Let’s talk results. Overall, there was no significant differences between the group receiving the vitamin concoction and the control group in long term mortality (29.5% vs 28%, P=0.64), ICU mortality (17.7% vs 17.2%, P=0.87), or incidence of AKI (24.9% vs 23.3%, P=0.75). There was also no difference in hospital or ICU lengths of stay. Multiple sensitivity analyses including removal of certain studies or including only patients with septic shock showed similar results. There was, however, a significant reduction in SOFA scores on day 3 in the vitamin concoction group (MD -0.92, P <0.05). To be fair, in their trial sequential analysis they found that a lack of long term and ICU mortality benefit could be due to a false negative (type II) error as the meta-analysis was not powered enough to detect these differences.

In conclusion, the results of the overall meta-analysis are consistent with the individual randomized controlled studies, which included several recent, hotly discussed studies like “VITAMINS,” “ORANGES,” “ATESS,” “ACTS,” and the Chang and Wani studies from 2020. Some trials have shown a significant reduction in SOFA scores (of about – 1), but this reduction is likely clinically insignificant. Although there are some retrospective studies that did show reductions in mortality, we have to take these studies with a grain of salt given their retrospective nature. To be clear, the authors admit that they can’t be absolutely sure based on this meta-analysis alone that the vitamin concoction had no benefit- due to the insufficient sample size and a lack of power. They call on additional studies in larger numbers of patients and also suggest looking at subgroups of patients, particularly those that have shown benefit in certain studies (such as the exploratory analysis from the CITRIS-ALI study, which showed a benefit in patients with septic shock and ARDS). Others have called for giving the vitamin concoction much earlier in the patient’s course, and working to find the optimal dose and duration of the concoction.

My personal take on all of this Vitamin C/ thiamine data is that I appreciate the moonshot, I really do- finding something that is effective in septic shock would have a drastic impact on the care of these patients globally. With a plausible mechanism and little in the way of side effects, a concoction like this seems intuitive, affordable, and safe. But as we learned in the last few weeks in the stock market, just because you desperately want your moonshot to work doesn’t mean that it will. And sometimes your rocket will fizzle out before it reaches the moon.

As always, thank you so much for your time. For a list of our references and a full transcript of this episode and past episodes, please check out our website, errxpodcast.com. Also, please remember to leave a review on Apple Podcasts for a chance to win some medically-related prizes and a chance to be featured on the website.