Paul Marik, MD, FCCP, FCCM
Chief, Division of Pulmonary and Critical Care Medicine
Eastern Virgina Medical School
It's hard not to get excited about news of a potentially effective treatment for sepsis, a condition that leads to multiple organ failure and kills more people in the hospital than any other disease.
But there have been so many false promises about this condition over the years, it's also wise to treat announcements — like one published online by the journal, Chest — with caution.
The study, from Eastern Virginia Medical School in Norfolk, Va., reported some remarkable success in treating patients who were at high risk of sudden death.
The story began in January, 2016, when Dr. Paul Marik was running the intensive care unit at Sentara Norfolk General Hospital. A 48-year-old woman came in with a severe case of sepsis — inflammation frequently triggered by an overwhelming infection.
"Her kidneys weren't working. Her lungs weren't working. She was going to die," Marik said. "In a situation like this, you start thinking out of the box."
Marik had recently read a study by researchers at Virginia Commonwealth University in Richmond. Dr. Berry Fowler and his colleagues had shown some moderate success in treating people who had sepsis with intravenous vitamin C.
Marik decided to give it a try. He added in a low dose of corticosteroids, which are sometimes used to treat sepsis, along with a bit of another vitamin, thiamine. His desperately ill patient got an infusion of this mixture.
"I was expecting the next morning when I came to work she would be dead," Marik said."But when I walked in the next morning, I got the shock of my life."
The patient was well on the road to recovery.
Marik tried this treatment with the next two sepsis patients he encountered, and was similarly surprised. So he started treating his sepsis patients regularly with the vitamin and steroid infusion.
After he'd treated 50 patients, he decided to write up his results. As he described it in Chest, only four of those 47 patients died in the hospital — and all the deaths were from their underlying diseases, not from sepsis. For comparison, he looked back at 47 patients the hospital had treated before he tried the vitamin C infusion and found that 19 had died in the hospital.
Chest. 2016 Dec 6. pii: S0012-3692(16)62564-3. doi: 10.1016/j.chest.2016.11.036.
Hydrocortisone, Vitamin C and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study.
Marik PE1, Khangoora V2, Rivera R3, Hooper MH2, Catravas J4.
During the treatment period consecutive patients with a primary admitting diagnosis of severe sepsis or septic shock and a PCT > 2 ng/ml were treated with intravenous vitamin C (1.5 gm q 6 hourly for 4 days or until ICU discharge), hydrocortisone (50 mg q 6 hourly for 7 days or until ICU discharge followed by a taper over 3 days) as well as intravenous thiamine (200 mg q 12 hourly for 4 days or until ICU discharge).
In this observational study the combination of intravenous vitamin C, moderate dose hydrocortisone and thiamine appeared to have a marked effect on the natural history of patients with severe sepsis and septic shock. No patient in the treatment group developed progressive organ failure and the four deaths in this group were related to the patients underlying disease; these patients did not die from sepsis related complications. Our study evaluated the use of intravenous vitamin C, hydrocortisone and thiamine in a real world setting where all eligible patients with sepsis were studied. This is important as less than 20% of eligible patient with severe sepsis and septic shock are commonly included in many of the sepsis trials limiting the applicability and generalizability of the results.61 Furthermore, we did not test an expensive, proprietary designer molecule, but rather the combination of three cheap and readily available agents with a long safety record in clinical use since 1949. 62;63
Experimental studies performed over the last 20 years have demonstrated that both vitamin C and hydrocortisone have multiple and overlapping beneficial pathophysiologic effects in sepsis. Vitamin C is a potent antioxidant which directly scavenges oxygen free radicals, restores other cellular antioxidants including tetrahydrobiopterin and α-tocopherol and is an essential co-factor for iron and copper containing enzymes. 70;71 Both drugs inhibit nuclear factor Ƙ-B (NF-ƘB) activation down regulating the production of proinflammatory mediators, increase tight junctions between endothelial and epithelial cells, preserve endothelial function and microcirculatory flow, and are required for the synthesis of catecholamines and increase vasopressor sensitivity.13-15;26;70-75 Vitamin C plays a major role in preserving endothelial function and microcirculatory flow.70;72 In addition, vitamin C activates the nuclear factor erythroid 2-like 2 (Nrf2)/ heme oxygenase (HO)-1 pathway which plays a critical role in anti-oxidant defences and enhances T cell and macrophage function. 76-78
While the dosing strategy for corticosteroids (hydrocortisone) in patients with severe sepsis and septic shock has been well studied,26;88 that for vitamin C is more uncertain. Critically ill patients have either very low or undetectable vitamin C levels (normal serum levels 40-60 umol/l).18;19 Due to the saturable intestinal transporter (sodium-vitamin C transporter-1), 20;83 oral administration of doses as high as 1500 mg cannot restore normal serum levels. 20 To achieve normal serum vitamin C levels in critically ill patients, a daily dose of more than 3 gm is required. 16;18;21
Due to the lack of clinical equipoise and the ethics of withholding a potentially lifesaving intervention, we were unable to initiate a RCT in our center.