Intravenous vitamin C given to patients with sepsis was literally a life saver

In 2017 a paper was published asserting that intravenous vitamin C given to patients with sepsis was literally a life saver. Despite the study only looking at 47 subjects, the results garnered international coverage and the treatment was adopted in many ICUs worldwide.

The global burden of sepsis is estimated at up to 19 million cases annually killing 5 million, mainly in low income countries. The infection affects 1.7 million Americans a year and kills more than 250,000, making it one of the top 10 causes of death.

In Australia more than 5,000 die from sepsis each year and it contributes to up to a half of all hospital deaths.

A paper published today in the Journal of the American Medical Association by Monash researchers comprehensively quashes the idea that the vitamin C-based cocktail has any positive impact on patients with sepsis.

Sepsis is the body’s overreaction to a severe infection, leading to multiple organ failure and, frequently, death.

Over the years, there have been indications that vitamin C might be effective against sepsis.

For instance, people with sepsis tend to have surprisingly low levels of vitamin C in their blood. In 2014, Dr. Alpha Fowler published a paper involving just 24 patients, hinting that vitamin C was a benefit.

In particular, Fowler noted that a measure of organ failure improved far more in the patients who had received vitamin C.

Dr. Paul Marik at the Eastern Virginia Medical School in the US, after reading the study, gave a seriously ill patient with sepsis high dose intravenous Vitamin C, together with thiamine and steroids (the traditional treatment for sepsis) and the patient recovered. Dr. Marik started using it regularly in his intensive care unit, reporting that the mortality rate for sepsis in his ICU had plummeted after he switched to this treatment.

What became known as the “Marik protocol” has been adopted by many units worldwide.

In today’s JAMA publication a study led by Professor Rinaldo Bellomo, from Monash University and Co-Director of the Australian and New Zealand Intensive Care Research Centre (ANZIC-RC), refutes the idea that the combination of high dose intravenous vitamin C, thiamine (vitamin B1) and hydrocortisone is beneficial in the treatment of sepsis.

The study (the VITAMINS trial) was set up by the ANZIC-RC across ten intensive care units in Australia, New Zealand and Brazil, looking at 216 patients in septic shock between May, 2018 and July, 2019.

216 patients were randomised to either the intervention group (thus receiving intravenous vitamin C, hydrocortisone and thiamine) or the control group (thus receiving hydrocortisone – a steroid – only).

The study found no improvement in the duration of support with blood pressure drugs for the treatment of shock or survival of those receiving vitamin C + thiamine + steroid therapy compared to steroid therapy alone.

According to Professor Bellomo, the study provides high quality evidence that, in patients with septic shock, the combination of high dose intravenous vitamin C, thiamine and hydrocortisone is not superior to usual care with hydrocortisone alone.

“The findings of the VITAMINS trials are clear: in patients with septic shock from Australia, New Zealand and Brazil there was no signal of benefit with the high dose vitamin C, thiamine and hydrocortisone cocktail.

The search for treatments that might improve the outcome of these very sick patients must now focus on other interventions.”

Journal information: Journal of the American Medical Association

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Vitamin C Alone May Lower Mortality Risk

Most recently, a study led by Dr. Alpha “Berry” Fowler was published in the October 2019 issue of JAMA. The study is not reflective of the Marik protocol per se, as it only used IV vitamin C, but its results are still tantalizing.

Fowler and his team sought to investigate the effectiveness of vitamin C infusion on organ failure scores and biomarkers of inflammation and vascular injury in patients with severe sepsis and acute respiratory failure.

Curiously, while the vitamin C infusion had no detectable influence on these end points, those who received the treatment did have a higher chance of survival, and spent less time in the hospital. As reported by NPR:

“If you read the study summary, vitamin C didn’t help the patients. But if you dig deep into the paper, you will find that the people who got the treatment were much more likely to survive … The rub comes from the way the study … was designed.”

While vitamin C alone had no impact on organ failure scores and biomarkers of inflammation, when the researchers looked at 46 secondary endpoints, they discovered the mortality rate for the treatment group actually dropped from 46% to 30%. As noted by NPR:

“If death had been the primary endpoint of the study, this result would have been highly significant. The conclusion would strongly support the hypothesis that vitamin C is an effective treatment of sepsis.

But there’s a catch. Since Fowler and his colleagues looked at 46 secondary endpoints, it’s likely that something would randomly pop up as statistically significant. It’s as though they had 46 bites at the apple to find something meaningful …

What patients really care about, of course, is … whether they live or die. Fowler tells NPR that he now rues his decision to select an endpoint that seemed more likely to show a benefit …

Though he’s now bound by the rules of experimental design to downplay the mortality results, he personally feels a sense of success. ‘We’re all whooping and hollering because of what we found,’ he says.”

Fowler’s team also found that, on average, those who received vitamin C had by day 28 spent three fewer days in the intensive care unit than the placebo group (seven days compared to 10). By day 60, the treatment group had also spent seven fewer days in the hospital overall —15 days compared to 22.

Vitamin C, Thiamine and Steroids Have Synergistic Effects

When asked for comment on Fowler’s study, Marik pointed out vitamin C and corticosteroids have a synergistic effect. In other words, Fowler’s study cannot really be used to judge the effectiveness of vitamin C, thiamine and steroids in combination, as it only used one of the three ingredients.

Vitamin C is well-known for its ability to prevent and treat infectious diseases on its own. Influenza, encephalitis and measles have all been successfully treated with high-dose vitamin C, and previous research has shown it effectively lowers proinflammatory cytokines and C-reactive protein.

To investigate the mechanism of action for vitamin C in sepsis with and without steroids, Marik, in collaboration with John Catravas, Ph.D., a pharmacology researcher at Old Dominion University, and others performed a study⁴⁷ in which endothelial cells from lung tissue were exposed to lipopolysaccharide — a type of endotoxin found in patients with sepsis — in the absence or presence of ascorbic acid and hydrocortisone.

Interestingly, when either vitamin C or the steroid were administered in isolation, very little improvement in endothelial barrier function occurred. When administered together, however, the infection was successfully eradicated and the cells were restored to normal.

The addition of thiamine is also important. Not only is thiamine required for metabolism of some of the metabolites of vitamin C, thiamine deficiency syndrome (beriberi) has many similarities to sepsis, and thiamine deficiency is relatively common in critically ill patients.

Studies have also shown thiamine can be helpful for a long list of diseases and disorders, including mitochondrial disorders, heart failure, delirium, thyroid fatigue and Hashimoto’s (a thyroid autoimmune disorder). These and other health effects may help explain why thiamine works so well in conjunction with vitamin C and hydrocortisone for sepsis.

Marik told NPR that Fowler’s study does highlight two important things, though. First, that there are no side effects of vitamin C infusion in critically ill patients and, second, a lowered mortality risk. “You can argue about all the statistical nuances, but that’s what the study showed,” Marik told NPR.

Potential Contraindication

While vitamin C and thiamine administration is incredibly safe, it may be contraindicated if you happen to be glucose-6-phosphate dehydrogenase (G6PD) deficient, which is a genetic disorder. G6PD is an enzyme your red blood cells need to maintain membrane integrity.

High-dose IV vitamin C is a strong prooxidant, and giving a prooxidant to a G6PD-deficient individual can cause their red blood cells to rupture, which could have disastrous consequences.

Fortunately, G6PC deficiency is relatively uncommon, and can be tested for. People of Mediterranean and African descent are at greater risk of being G6PC deficient. Worldwide, G6PD deficiency is thought to affect 400 million individuals, and in the U.S. an estimated 1 in 10 African-American males have it.

Know the Signs and Symptoms of Sepsis

One of the most important steps you can take to protect your health is to recognize the symptoms of sepsis and seek immediate medical attention if you suspect it.

It is important not to make a diagnosis at home. Instead communicate your concerns with a medical professional so that proper testing and treatment can be implemented. Common signs and symptoms of sepsis include the following. Many of these symptoms may be confused with a bad cold or the flu. However, they tend to develop much more rapidly than you would normally expect.

A high fever with chills and shivering	Rapid heartbeat (tachycardia)
Rapid breathing (tachypnea)	Unusual level of sweating (diaphoresis)
Dizziness	Confusion or disorientation
Slurred speech	Diarrhea
Difficulty breathing, shortness of breath	Severe muscle pain
Low urine output	Cold and clammy skin
Skin rash	Nausea and/or vomiting

The Sepsis Alliance recommends using the acronym TIME to remember some of the more common symptoms:

• T — Temperature higher or lower than normal?
• I — Have you now or recently had any signs of an infection?
• M — Are there any changes in mental status, such as confusion or excessive sleepiness?
• E — Are you experiencing any extreme pain or illness; do you have a “feeling you may die?”

Post-Sepsis Syndrome

While some will recover fully from sepsis, for many the problems do not end at discharge from the hospital. Survivors may suffer physical, psychological and/or neurological consequences for the rest of their lives. For some survivors, their immune function can remain depressed for as long as a year after their recovery, resulting in frequently recurring infections.

The combination of symptoms is called post-sepsis syndrome and usually last between six and 18 months. Symptoms of post sepsis syndrome may include:

Lethargy (excessive tiredness)	Changes in peripheral sensation	Repeated infections at the original site or a new infection
Poor mobility	Muscle weakness	Shortness of breath
Chest pains	Swollen limbs	Joint and muscle pains
Depression, mood swings, anxiety orsadness	Hair loss	Dry flaking skin and nails
Taste changes	Poor appetite	Changes in vision
Difficulty swallowing	Reduced kidney function	Feeling cold
Excessive sweating	Post-traumatic stress disorder	Flashbacks and nightmares
Poor concentration and clouded thinking	Insomnia	Short-term memory loss

There is no specific treatment for post-sepsis syndrome, but most get better over time. The U.K. Sepsis Trust recommends managing individual symptoms and supporting optimal health as you’re recovering.

Not all medical professionals are aware of post-sepsis syndrome, so it may be helpful to talk about your symptoms and ask for a referral to someone who may help manage your mental, physical and emotional challenges.