In this episode, I’ll discuss a long-awaited randomized, controlled trial of vitamin C, thiamine, and hydrocortisone in sepsis.
Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock
Lead author: Tomoko Fujii
Published in JAMA January 2020
In December of 2016 a retrospective study was published ahead of print in the journal Chest about the dramatic impact that a combination of vitamin C, thiamine, and hydrocortisone had on mortality in a group of patients with sepsis. A few months later a major push in the lay press publicizing these findings led to articles in NPR and articles and news releases proclaiming a cure for sepsis, complete with B-roll footage to make lay press media reports even easier to put together.
This flurry of activity prompted many research studies to be initiated to replicate the impressive results from this first study. This article from JAMA is the first of these trials to be reported.
The study was a multicenter, open-label, randomized clinical trial with patients from 10 intensive care units in Australia, New Zealand, and Brazil. 216 patients that met Sepsis-3 definitions for septic shock were included. The intervention group used the exact protocol from the original CHEST trial of IV vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours).
The control group only received hydrocortisone IV 50 mg q6 hours. Therapy was continued until shock resolved or 10 days. The primary trial outcome was the duration of time alive and free of vasopressor administration up to day 7. Ten secondary outcomes were prespecified, including 90-day mortality.
There was no difference between groups for the primary outcome and 9 out of 10 secondary outcomes, including those which focused on mortality. Only the day 3 change in SOFA score favored the vitamin C group, and this is not a patient-focused outcome.
No serious adverse events were reported among the participants.
The authors concluded:
In patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine, compared with intravenous hydrocortisone alone, did not significantly improve the duration of time alive and free of vasopressor administration over 7 days. The finding suggests that treatment with intravenous vitamin C, hydrocortisone, and thiamine does not lead to a more rapid resolution of septic shock compared with intravenous hydrocortisone alone.
This is certainly a disappointment in that vitamin C, thiamine, and hydrocortisone do not appear to be the cure for sepsis that was first hoped. An editorial accompanied this study in JAMA and was quite harsh in its critique of how this treatment was originally published and encouraged, and the fact that it consumed research time, dollars, and provided false hope to patient families via the stories in the lay press. I tend to agree with this assessment.
One criticism of this study has been the ~12 hour delay in starting therapy. The suggestion is that because therapy was “delayed” that a trial of “early” vitamin C and thiamine might still prove beneficial. I do not see the logic in this argument as the original trial counted patients that had vitamin C and thiamine started within 24 hours of ICU admission, and the index case that led to publication of the original trial was a patient who received therapy very late in their course of therapy. If there was any benefit to this intervention, I would expect it to show within the timeframe study subjects received treatment.
There are other randomized trials of vitamin C and thiamine in sepsis that are in various stages of completion. However unless or until one or more of these trials produces positive results, I do not consider this treatment a worthwhile intervention. As there is no risk of harm identified I would still faciliate an individual physician who wished to use the therapy, but I would provide retrospective feedback that included the outcomes from this first randomized trial.
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