For patients with septic shock, treatment with intravenous vitamin C, hydrocortisone, and thiamine did not significantly improve the duration of survival and time free of vasopressor treatment over 7 days compared with intravenous hydrocortisone treatment alone. These data, published in JAMA, were based on a multicenter, open-label, randomized clinical trial conducted in 10 intensive care units in Australia, New Zealand, and Brazil (ClinicalTrials.gov Identifier: NCT03333278).
A total of 216 patients who fulfilled the Sepsis-3 definition of septic shock were recruited, 109 of whom were randomly assigned to the intervention group and received intravenous vitamin C (1.5 g every 6 hours), hydrocortisone (50 mg every 6 hours), and thiamine (200 mg every 12 hours). The remaining 107 patients were randomly assigned to the control group and received intravenous hydrocortisone (50 mg every 6 hours) alone until shock resolution or up to 10 days. The final cohort comprised 211 patients who provided consent and completed the primary outcome measurement; their mean age was 61.7 years (standard deviation [SD], 15.0 years), and 63% were male.
In the intervention group, time alive and vasopressor free up to day 7 was 122.1 hours (interquartile range [IQR]. 76.3-145.4 hours) compared with 124.6 hours (IQR, 82.1-147.0 hours) in the control group. The median of all paired differences was found to be –0.6 hours (95% CI, –8.3 to 7.2 hours; P =.83). For 10 prespecified secondary outcomes, no statistical difference was found between groups except for 90-day mortality. In the intervention and control groups, this was 28.6% and 24.5%, respectively (hazard ratio, 1.18; 95% CI, 0.69-2.00). There were no reports of severe adverse events.
There was the possibility of performance and ascertainment bias in this trial because of the open-label design and a lack of blinding of outcome assessment; the complexity of double-blinding 2 interventions at multiple sites in 3 countries led researchers to consider this design to be the practical approach. Trial patients were also cared for by more than 100 specialists and intensive care fellows, making systematic bias unlikely. The study design also prevented the assessment of the individual effects of vitamin C and thiamine. Furthermore, thiamine levels were not measured, meaning it was unknown whether patients had thiamine hypovitaminosis at randomization or not, and whether such hypovitaminosis was corrected.
Other forms of data that were not collected included the target mean arterial pressure, set for each patient by treating clinicians, and time to the administration of antibiotics. The trial was also underpowered to detect differences in mortality, other patient-centered outcomes, and differences in outcomes among specific subgroups. Finally, adverse events were only reported after individual judgment from treating clinicians; patients were not systematically examined for possible events that might develop with high doses of intravenous vitamin C.
Investigators concluded that treatment with intravenous vitamin C, hydrocortisone, and thiamine did not significantly improve the measured outcomes compared with intravenous hydrocortisone alone. Therefore, the data suggest that this treatment does not lead to a more rapid resolution of septic shock.
Fujii T, Luethi N, Young PJ, et al. Effect of vitamin C, hydrocortisone, and thiamine vs hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: The VITAMINS randomized clinical trial. JAMA. 2020;323(5):423-431.