After a couple years wandering in the wilderness after the Marik report, and a few small or unrevealing trials, we finally have our first RCT evidence regarding the use of thiamine, vitamin C, and steroids in sepsis: the VITAMINS trial.
In this trial, 216 patients with septic shock received hydrocortisone 50mg every six hours, and were then randomized to usual care or open-label vitamin C 1.5g every six hours plus thiamine 200mg every twelve hours. The primary outcome was time alive and free of vasopressor administration up to day 7, along with pre-specified secondary mortality outcomes. Important exclusions in the eligibility screening process included onset of septic shock >24 hours, imminent death, and use of study drugs for other reasons. Few differences between the two groups were observed at baseline, although the control arm had median lactate level of 3.3 at enrollment compared with 4.2 in the intervention arm.
The primary outcome was: no different, 122.1 hours with the intervention and 124.6 hours in the control arm. The secondary mortality outcomes: at 28 days, no different, 22.6% vs. 20.4%; at 90 days, no different, 28.6% vs 24.5%. The remaining secondary outcomes, including ventilation-free days, renal replacement, and acute kidney injury were no different, but there was a small different in SOFA scores at day 3 favoring the intervention. The authors appropriately caution this observed improvement in SOFA score should be interpreted at your peril, as its significance is not adjusted for multiple comparisons and subject to both competing risks from early death and early discharge from the ICU.
So, the pure frequentist conclusion: this trial, repeated, would provide an estimate containing the true effect size with bounds crossing unity most of the time. The Bayesian conclusion, accounting for the weak, positive, prior evidence: there is a low probability of the true effect being positive. If you were holding off adopting the addition of thiamine and vitamin C, this trial reinforces your skepticism. If you’ve already adopted thiamine and vitamin C, it is unlikely harms were caused, but it is now more likely than not these treatments are not resulting in benefit. Additional trials will report results capable of further clarifying these observations.
The accompanying editorial by Andre Kalil sums up the interpretation of these results in context beautifully:
“Given that other studies are forthcoming, there appears to be no immediate justification for adoption of high-dose vitamin C, alone or in combination, as a component of treatment for sepsis. Moreover, use of high-dose vitamin C in combination or alone “just in case” or as a “measure of last resort,” aside from providing no survival benefits, could have several other potential consequences, including diverting funding from needed research to examine sepsis mechanisms and diagnostics; stifling the development of other sepsis therapies; perpetuating false hopes for patients, families, and clinicians; and delaying proven lifesaving therapies such as prompt initiation of antibiotic therapy.”
“Effect of Vitamin C, Hydrocortisone, and Thiamine vs Hydrocortisone Alone on Time Alive and Free of Vasopressor Support Among Patients With Septic Shock”
https://jamanetwork.com/journals/jama/fullarticle/2759414