In 2017, an article in the journal Chest reported a 5-fold reduction in the mortality of septic shock by a simple treatment with steroids, vitamin C, and thiamine. A study published last month refuted those results and showed that vitamin C has no benefit in sepsis. It is time for physicians to accept that vitamin C is not the cure for sepsis.
When the 2017 article was published, many critical care physicians wanted to believe it. Sepsis is an enormous public health problem affecting 1.7 million Americans every year and resulting in death in 250,000 of these. Worldwide, sepsis affects 50 million people and causes one-fifth of all deaths. For decades, the treatment of sepsis has focused on antibiotics and restoration of blood pressure. However, much of the damage from sepsis is not from the bacteria and other pathogens that initially cause sepsis, but instead is from the body’s immunologic reaction to those pathogens. For that reason, by the time antibiotics and intravenous fluids are started on a patient with sepsis, the cascade of inflammatory mediators and other substances produced by the body’s immune system has already started. In severe sepsis, this cascade of mediators turns into an avalanche of mediators resulting in refractory hypotension, organ failure, and death, despite antibiotics. Medical science has been searching for the magic bullet that would cure sepsis for years and thus the appeal of vitamin C.
Why vitamin C?
Vitamins are chemicals that our bodies need to function properly. We are unable to produce sufficient quantities of these ourselves so they must come from our diets. When we don’t have enough of one of these vitamins, a vitamin deficiency disorder develops. Some vitamins are fat-soluble and can be stored in our body’s fat tissues for slow release over a long period of time. Other vitamins are water-soluble and cannot be easily stored in the body. Vitamin C is one of those water-soluble vitamins our bodies cannot produce and without dietary vitamin C, scurvy can develop. Scurvy was once a common condition in people who lacked fruits and vegetables in their diets, most famously in 16th century sailors. Scurvy can result in gingivitis, bruising, shock, and death. I remember diagnosing scurvy a few years ago in a patient with alcoholism who was admitted to our ICU with his teeth falling out, dermatitis, and bruising. He had undetectable plasma vitamin C levels and improved with intravenous vitamin C.
Vitamin supplements are $30 billion a year business the United States. The theory is that if too little of them makes you sick and the recommended daily dose prevents you from getting a deficiency disease, then maybe a lot more might prevent you from getting even more diseases. One of the most famous advocates of vitamin C supplementation was Linus Pauling. He is one of only 4 people to win 2 Nobel Prizes: in his case, the 1954 Nobel Price in Chemistry and the 1962 Nobel Peace Prize. In the 1970’s, he became enamored with vitamin C and claimed that it could treat cancer, brain-injured children, and the common cold. Although subsequent clinical trials showed no benefit compared to placebo and re-examination of Pauling’s research in vitamin C was shown to be flawed, he continued to promote vitamin C as a cure for the common cold and as a treatment for cancer. Because of his stature as a scientist, he influenced many people to take large doses of vitamin C to treat or prevent various diseases. The result was a legacy of a belief that vitamin C was a miracle cure in search for a disease to treat.
The arguments for vitamin C’s benefits had some basis in science. Sepsis is accompanied by oxidative stress and the resultant oxidants cause damage to various tissues. In the lab, antioxidants can reduce the amount of injury to cells by oxidants. Vitamin C is a naturally-occurring antioxidant and so it seemed logical that vitamin C could reduce oxidant injury from sepsis.
When physicians at Eastern Virginia Medical School were faced with three patients with sepsis and in whom death appeared inevitable, they gave the patients intravenous vitamin C as a last-ditch effort. The patients recovered, leading the physicians to believe that vitamin C could be the cure for sepsis that medical science had been looking for. So, they treated 47 septic patients with a combination of intravenous vitamin C, hydrocortisone, and thiamine and compared those patients to 47 other patients who that had sepsis in the past, before they had the idea of IV vitamin C. The results were astounding with a mortality rate of 40.5% in the untreated patients and 8.5% in the vitamin C treated patients. Their findings were published in the June 2017 edition of the journal Chest.
Vitamin C enters the mainstream
Physicians throughout the United States saw the publication and jumped on the vitamin C bandwagon. The lay press was all over it. NPR reported: “Doctor turns up possible treatment for deadly sepsis”. NBC reported: “Virginia doctor’s possible cure could save millions from deadly sepsis”. A Smithsonian Magazine headline was: “Could vitamin C be the cure for deadly infections?”. In our hospital, some of the critical care physicians were convinced and started using the cocktail of vitamin C, hydrocortisone, and thiamine in patients with sepsis but other critical care physicians remained skeptical. Soon, family members of patients in our ICU were asking that their loved ones be treated with vitamin C and became angry if they were not treated with it.
I was in a unique position, I was both a critical care physician and the medical director of the hospital. Should I mandate the use of vitamin C in sepsis? Should I forbid the use of vitamin C in sepsis? Physicians are notoriously independent and critical care physicians even more so. We are often in the position of providing the treatment of last resort to dying patients. We have to make treatment decisions quickly, often without time to get consultation from other specialists or get second opinions. And since so many of our patients die, there is often a sense of “what could trying something new hurt?” It is rarely a good idea for a medical director to make a unilateral decision for the entire hospital about a controversial treatment in these situations.
Practice guidelines are a help, whether from national medical societies or from internal hospital experts. As the medical director, I could use these guidelines to base decisions about what treatments the hospital should adopt. But it takes months or years to bring together a guideline committee and have that committee deliver a final guideline document. In the short term, we could have convened a workgroup of physicians at the hospital to develop recommendations and we used these workgroups quite regularly during the first year of the COVID-19 pandemic. Instead, we influenced physician behavior by example.
One of the benefits and curses of being a senior physician is that everyone thinks you have a lot more wisdom than you actually do have. For the past 30 years, I had seen promising treatments for sepsis come and go. When I was young, I was often an early-adopter of proposed new treatments in the ICU but by 2017, I had become considerably more cautious and skeptical of treatments that seemed on the surface to be too good to be true. And so I and other senior critical care physicians did not order the vitamin C cocktail on patients during our shifts in our ICU. Soon, the other physicians started saying “Well, if the old guys aren’t prescribing it, maybe I shouldn’t either.” After an initial flurry of vitamin C orders, the doctors in our ICU stopped prescribing it.
The final nail in the vitamin C coffin
The strongest medical evidence comes from clinical trials that (1) are randomized, (2) are double-blinded, (3) involve multiple hospitals, and (4) are placebo-controlled. The 2017 vitamin C study was open-label, had no placebo group, was only performed at one hospital, and was not randomized. In other words, it used a very weak study design. But it was convincing enough to prompt the creation of other, more rigorous clinical trials. In 2019, a multicenter, randomized, double-blind, placebo-controlled study published in JAMA found no improvement in outcomes of patients with sepsis who were treated with vitamin C. In 2020, a second multicenter, randomized, double-blind, placebo-controlled study published in JAMA also found that the vitamin C cocktail did not improve any of the outcomes in sepsis. Earlier this year, two meta-analyses were published that contested the value of vitamin C in sepsis.
The most recent study in the New England Journal of Medicine showed that not only did patients with sepsis treated with vitamin C fail to improve, the vitamin C patients actually had a higher death rate than those treated with placebo. This was a massive study involving 872 patients from 35 hospitals in 3 countries. The study was randomized, double-blinded, and placebo-controlled. 31.6% of patients receiving placebo died whereas 35.4% of those receiving vitamin C died.
It would appear that this study will be the final word on vitamin C and sepsis – it doesn’t make patients better and may actually make them worse.
Lessons learned (again)
Medicine has seen remarkable breakthrough treatments over the past 50 years. And we as physicians are constantly looking for the next remarkable treatment to improve the lives of patients who have the diseases that we treat. History has shown us over and over again that the future always brings more effective treatments for almost every health condition. It is that inherent optimism for the future of medicine and our drive to find something to make our own patients better that causes us to latch our hopes onto promising preliminary studies.
In my own outpatient interstitial lung disease practice, I have treated idiopathic pulmonary fibrosis patients with medications from promising preliminary studies, only to have the medications be proven ineffective in randomized, placebo-controlled, double-blinded, multi-center trials. In the 1980’s, it was Cytoxan, In the 1990’s, it was prednisone and Imuran, In the 2000’s, it was gamma interferon and later, N-acetyl cysteine. Each drug offered hope to patients with a terminal disease… and each one was later found to not work.
Studies that suggest that a treatment is effective get a lot more attention and press coverage than studies that show a treatment doesn’t work. All too often, these negative studies are the more rigorously designed randomized, placebo-controlled, double-blinded, multi-center trials that should be the final word. Last month’s study in the New England Journal of Medicine may not get as much coverage in the lay news but it underscores the importance that as physicians, it is essential that we base our own medical practice on well-designed studies published in peer-review journals.
July 15, 2022