By Samuel Nadler, MD, PhD

Critical Care, Pulmonary Medicine, The Polyclinic Madison Center, Seattle; Clinical Instructor, University of Washington, Seattle

Dr. Nadler reports no financial relationships relevant to this field of study.

SYNOPSIS: The combination of vitamin C, thiamine, and hydrocortisone did not improve outcomes compared with hydrocortisone alone in patients with septic shock.

SOURCE: 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;323:423-431.

Since the retrospective before-and-after study by Marik et al, there has been much discussion about the benefits of the combination of hydrocortisone, vitamin C, and thiamine in patients with septic shock.1 That trial demonstrated a remarkable decrease in mortality from 40.4% to 8.5% with these interventions. However, the magnitude of the effect and the retrospective, single-center study design raised concerns. The VITAMINS study was a prospective, randomized, open-label, multicenter trial that evaluated the combination of these three medications for the treatment of septic shock. Patients were included if they were admitted with a primary diagnosis of septic shock with diagnostic criteria of Sepsis-3 fulfilled within 24 hours.2 Exclusion criteria included age younger than 18 years, patients with do-not-resuscitate orders or with imminent death, contraindications to the study medications, or another need for hydrocortisone. The primary outcome was time alive and free of vasopressors up to day 7. Secondary outcomes included mortality, ventilator-free days, need for renal replacement therapy, length of stay (LOS), and change in Sequential Organ Failure Assessment (SOFA) scores. The study was designed to have a 90% power to detect a 25-hour difference of vasopressor-free hours.

The VITAMINS study randomized 216 patients to the combination of vitamin C (1.5 g intravenous [IV] every six hours), hydrocortisone (50 mg IV every six hours), and thiamine (200 mg IV every 12 hours) vs. hydrocortisone alone. Study medications were continued until vasopressor requirements ceased up to 10 days or death occurred. There was no difference in the primary outcome of time alive and free of vasopressors between the intervention and control arms (122.1 vs. 124.6 hours, respectively; P = 0.83). Similarly, there was no difference noted in any mortality metric or the overall incidence of death (hazard ratio [HR], 1.18; 95% confidence interval [CI], 0.69-2.01; P = 0.54). The two groups also had similar ventilator-free days, renal replacement therapy (RRT)-free days, intensive care unit (ICU)-free days, and overall hospital LOS.

COMMENTARY

Why might the VITAMINS study results be so different from the previous study by Marik? The duration of vasopressor need in the control and intervention groups in the VITAMINS study was 43.4 and 45.9 hours, respectively, compared with 54.9 and 18.3 hours in the Marik study. Hospital mortality was 20.4% and 23.4% in the VITAMINS control and intervention groups, compared with 40.4% and 8.5%, respectively, in the Marik study. The medication doses in the two trials were identical, although the VITAMINS protocol ended at 10 days while the Marik study continued until ICU discharge.

The study populations had similar SOFA scores (8.3 and 8.7 in the Marik study, compared with 8.4 and 8.6 in VITAMINS in the control and treatment arms, respectively). The VITAMINS study population had slightly higher rates of mechanical ventilation and vasopressor needs. The need for RRT in the VITAMINS study and the treatment arm of the Marik study were similar, although the control arm of the Marik study had a higher rate of RRT. Thus, neither the population nor the intervention accounts for the difference in outcomes.

The primary differences between these two trials are the strength of the study design and the use of hydrocortisone in the control arm. Specifically, the Marik trial was a before-and-after, single-center study. The interventions occurred during different seasons, with the control group assessed June 2015 through December 2015 and the intervention group assessed January 2016 through June 2016. Although the Marik study used a propensity score adjustment to attempt to control for these factors, this study design is inherently vulnerable to confounding factors.

In contrast, the VITAMINS study was randomized with concurrent control and intervention groups conducted in multiple centers, which is a stronger design. It has been noted before in the Marik study that the mortality rate in the control group was unusually high, while in the intervention group it was surprisingly low. The Marik study also left the use of hydrocortisone in the control group to the discretion of the treatment team, while the VITAMINS study mandated steroids in the control group.

The VITAMINS study failed to demonstrate clinical improvement in patients with septic shock who were treated with vitamin C, thiamine, and hydrocortisone. Although other studies are likely to be performed, this study provides strong evidence against a benefit of these therapies for septic shock. While there is no clear harm to this combination of medications, it seems wiser to focus our efforts on the other, more evidence-based interventions important for sepsis care. 

REFERENCES

  1. Marik PE, Khangoora V, Rivera R, et al. Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: A retrospective before-and-after study. Chest 2017;151:1229-1238.
  2. Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016;315:801-810.