This will be seen as a major disappointment for observers desperately looking for therapies to offer patients with life-threatening sepsis syndromes. However, this was always the most likely outcome, given the improbable magnitude of reported benefit found in the original Marik study, upon which the entire vitamin C frenzy has been based. Alas, desperation, hope, and hype were never going to be enough. What we always needed was a well-executed trial to either confirm or refute Marik’s hypothesis and potentially game-changing findings. We now have the first credible report. From the looks of it, it’s back to the drawing board.

Breaking Down What Happened

How did we get here? When the vitamin C protocol first made news in 2017, there were two polar responses to this. The believers celebrated the treatment as a brilliant innovation, based on a genuine understanding of complex physiology, that could save hundreds of thousands of lives. The skeptics pointed out that the study upon which the excitement was based was a before-after retrospective chart study design performed in a single ICU. Many noted that the study, designed and led by the outspoken intensive care physician Paul Marik, MD, FCCP, was not a genuine trial. Rather, it amounted to a quality improvement project. In the Marik study, all patients with severe sepsis or septic shock received the vitamin C–based cocktail over a six-month period in early 2016. Those outcomes were then compared to those of a similar number of patients treated in that ICU before the protocol was rolled out in 2016 and who met similar inclusion criteria.

It bears mentioning that quality improvement studies almost always yield favorable results for the problem being addressed. When resources—institutional, financial, and cognitive—are being applied to a challenging task, the short-term results are frequently good, yet difficult to maintain. The hidden costs of quality improvement efforts, however, are difficult to assess and not usually reported. For example, if a project to expedite CT for every patient with a neurological complaint is undertaken, a few patients may have their cerebrovascular accidents diagnosed sooner. But how many patients with acute aortic syndromes had diagnoses delayed because of that? Similarly, when we concentrate substantial human and financial resources onto one problem, do other problems suffer in silence?

This is why randomized, controlled trials are required to make statements about the effectiveness of experimental therapies. Double-blinding is preferred as well because patients in the control arm are assured to receive as much attention as those in the intervention arm. The VITAMINS trial was unblinded (open label). This occurred because the study was initially an unfunded “passion” project by the team of investigators. Blinding is expensive and requires administrative muscle (which is not free). Treatments need to be concealed from both the providers and the subjects. While this study would be stronger if it had been blinded, you could argue that the lack of blinding favored the intervention. While we can’t know whether the authors were skeptical or optimistic about the cocktail’s chances, it is difficult to imagine that providers in 10 ICUs across three countries were all biased against an inexpensive therapy that had the potential to save lives.