Hydrocortisone, Vitamin C, and Thiamine for Treating Sepsis
Alan Gaby, MD
Author: Marik PE, et al
Reference: Hydrocortisone, vitamin C, and thiamine for the treatment of severe sepsis and septic shock: a retrospective before-after study. Chest 2017;151:1229-1238.
Design: Retrospective review of medical records.
Participants: Forty-seven consecutive patients with severe sepsis or septic shock who were treated at Sentara Norfolk General Hospital beginning in January, 2016 (treatment group). Their outcomes were compared with those of a control group of 47 similar patients treated at the same hospital between June and December, 2015.
Study Medication and Dosage: The treatment group received the combination of vitamin C, hydrocortisone, and thiamine, all intravenously. The dosages were as follows:
- Vitamin C: 1.5 g every 6 hours for 4 days or until discharge from the intensive care unit (ICU).
- Hydrocortisone: 50 mg every 6 hours for 7 days or until ICU discharge, followed by a tapering dose over 3 days.
- Thiamine: 200 mg every 12 hours for 4 days or until ICU discharge.
The control group did not receive vitamin C or thiamine, but 60% of the control patients received hydrocortisone at the discretion of the treating physician.
Primary Outcome Measures: Hospital mortality rate and progression or regression of organ damage.
Key Findings: The hospital mortality rate was 78.9% lower in the treatment group than in the control group (8.5% vs. 40.4%; p < 0.01). None of the patients in the treatment group died of complications related to sepsis; rather, the 4 patients who died succumbed to complications of their underlying disease.
The Sequential Organ Failure Assessment score decreased (improved) in all patients in the treatment group, with none developing progressive organ failure. Approximately two-thirds of the patients in each group had acute kidney injury at presentation. However, significantly fewer patients in the treatment group than in the control group ended up requiring dialysis or other renal replacement therapy (10% vs. 37%; p = 0.02).
All patients in the treatment group were weaned off vasopressors at a mean of 18.3 hours after starting vitamin C, and the dose of vasopressors was typically reduced at 2-4 hours after the first vitamin C infusion. In contrast, 9 patients in the control group required increasing doses of vasopressors and died of refractory septic shock. In the treatment group, renal function improved in all patients with acute kidney injury.
Practice Implications: Sepsis is a life-threatening condition that occurs when the body mounts an intense immune/inflammatory response to an infection, resulting in tissue and organ damage.
Severe sepsis is defined as sepsis associated with organ dysfunction or impaired blood flow to one or more parts of the body. Septic shock is defined as severe sepsis accompanied by hypotension that does not respond adequately to fluid replacement.
In developed countries, the 28-day mortality rates from sepsis and septic shock are around 25% and 50%, respectively. These rates are even higher in developing countries.
Conventional treatment consists mainly of intravenous antibiotics, supportive care, and vasopressors to treat hypotension. Despite decades of research and numerous clinical trials, no other drugs have been clearly shown to improve outcomes in patients with sepsis.
Vitamin C has multiple effects that might be expected to be beneficial for patients with severe sepsis or septic shock. These include free radical-scavenging and antioxidant activity; enhancing tissue integrity, endothelial function, and blood flow; functioning as a cofactor in the synthesis of catecholamines; and increasing the body’s sensitivity to vasopressors.
Serum levels of vitamin C are typically very low in patients with sepsis, and as much as 3 g per day of intravenous vitamin C is needed to bring those levels up to normal. In animal studies, administration of large doses of vitamin C was effective for preventing and treating hemorrhagic shock.   Frederick Klenner, a pioneer in the use of large doses of vitamin C, stated that shock can be reversed in minutes by giving 12 g of vitamin C intravenously in a 50-ml syringe.
Hydrocortisone (without vitamin C) is frequently given to patients with severe sepsis, although a randomized controlled trial found that it does not improve outcomes. Marik and associates included hydrocortisone in their protocol because of evidence that it may act synergistically with vitamin C in patients with severe sepsis.
Thiamine was also given, because thiamine deficiency is common in septic patients and is associated with an increased risk of death.
The results of the new study suggest that intravenous administration of vitamin C in combination with hydrocortisone and thiamine can markedly decrease the mortality rate and preserve organ function in patients with severe sepsis and septic shock. If confirmed by randomized controlled trials, this treatment will revolutionize the care of septic patients.
Already, more than 50 medical centers are using Marik’s protocol, and they are reportedly seeing the same dramatic benefits. Others remain skeptical and would like to see the results of controlled trials before changing the standard of care in their intensive care units.
One concern is that high-dose vitamin C can cause the deposition of oxalate in soft tissues of patients with compromised renal function, potentially resulting in worsening renal function and damage to other tissues and organs. That concern is why Marik limited the dose of intravenous vitamin C to 6 g per day, even though some practitioners have used much higher doses to treat burns, viral illnesses, and other conditions.
As noted above, renal function improved in all patients with acute kidney injury who received vitamin C. It is possible that the inclusion of thiamine in the treatment protocol minimized the increase in oxalate levels, since thiamine deficiency is thought to increase the conversion of glyoxylate (a byproduct of amino acid metabolism) to oxalate.
Randomized controlled trials should also investigate whether the addition of hydrocortisone increases, decreases, or has no effect on the efficacy of vitamin C and thiamine.
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 Mays BW, et al. Ascorbic acid improves survival and decreases pulmonary neutrophil sequestration in hemorrhagic shock. J Trauma Injury Infect Crit Care 1997;42:156.
 Klenner FR. Significance of high daily intake of ascorbic acid in preventive medicine. J Int Acad Prev Med 1974;1(1):45-69.
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