Is a vitamin C–based cocktail the cure for severe sepsis and septic shock? If you read headlines and news items that appeared widely in the mainstream media in 2017, you might have concluded that it is. After all, a recent paper in Chest had found that when a single intensive care unit (ICU) rolled out a new protocol in which a “cocktail” of vitamin C, thiamine, and hydrocortisone was given to patients with severe sepsis or septic shock, mortality fell from 40.4 percent to 8.5 percent.¹ This result was both extraordinary and almost implausible, despite some compelling physiological justifications bolstering the theory.

The hype could barely be controlled. Some physicians began using the cocktail right away. A flurry of trials were designed and approved by hospital review boards around the globe. Trialists moved as quickly as they could to begin studying this seriously and employing a variety of rigorous methodologies, assessing various patient populations and a variety of outcome measures. We needed some answers, and we needed them quickly.

Last month, the results from the Vitamin C, Hydrocortisone and Thiamine in Patients With Septic Shock (VITAMINS) trial, the first major international multicenter randomized, controlled effort to be completed, were unveiled in JAMA.2

The findings: negative. Across the board.

The Results

For virtually every outcome that the authors assessed for efficacy in septic shock, the patients who received the vitamin C–based cocktail (often referred to as the Marik protocol, metabolic resuscitation, or HAT for hydrocortisone, ascorbic acid, and thiamine) experienced no added benefit over patients in the control arm who received hydrocortisone only.

The study’s primary outcome was duration of time alive and free of vasopressor administration up to day 7 of treatment. The trial, which enrolled patients from 10 hospitals in Australia, New Zealand, and Brazil, also reported data on 10 prespecified secondary outcomes, including 28- and 90-day mortality, the need for dialysis, and mechanical ventilation, among others. For each of these, the Marik protocol failed to bestow any benefit. Out of 10 secondary outcomes, the only signal of benefit to emerge from the VITAMINS trial was a one-point improvement over controls in the sequential organ failure assessment score. However, as the other outcomes clearly demonstrate, patients who received the Marik protocol fared no better overall in any patient-centered outcome. Numerically, though not statistically, more deaths actually occurred in the vitamin C cocktail group. (In fairness, this was not even a trend; it is only worth mentioning because so very few patients died in the vitamin C group in the 2017 study.)