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Sepsis is implicated in 20 per cent of deaths worldwide and is twice as prevalent as previously believed. In 2017, 11 million people worldwide died in connection with sepsis.
Sepsis is life-threatening organ dysfunction due to a dysregulated host response to infection. It is considered a major cause of health loss, but data for the global burden of sepsis are limited. As a syndrome caused by underlying infection, sepsis is not part of standard Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimates. Accurate estimates are important to inform and monitor health policy interventions, allocation of resources, and clinical treatment initiatives. We estimated the global, regional, and national incidence of sepsis and mortality from this disorder using data from GBD 2017.
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Vitamin C & Thiamine in Sepsis
Investigators propose to investigate the use of IV vitamins B1 and C in a randomized, double-blinded, prospective trial to determine if these medications decrease mortality rates in patients with severe sepsis or septic shock.
Drug: Vitamin C
Drug: Vitamin B1
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Vitamin C: The next step in sepsis management?
Journal of Critical Care
Volume 43, February 2018, Pages 230-234
Sepsis is a life threatening condition marked by dysregulated inflammation and hemodynamic instability leading to shock, multiple organ dysfunction, and death.
•Currently, the mainstay of sepsis treatment is directed at early identification and treatment of infection, source control when applicable, as well as reversing hemodynamic instability.
•There have been several investigations into potential therapies for sepsis using targeted adjuvant therapies, however many of have failed to improve clinical outcomes in the treatment of sepsis.
•Vitamin C has been hypothesized to be a cost-effective and novel adjuvant therapy that can be used to ameliorate the effects of inflammation and oxidative stress in sepsis.
•We discuss the role of Vitamin C as an antioxidant, in vasopressor synthesis, in immune function, and review detail recent studies in sepsis.
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Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation
Ari Moskowitz, Lars W. Andersen, David T. Huang, Katherine M. Berg, Anne V. Grossestreuer, Paul E. Marik, Robert L. Sherwin, Peter C. Hou, Lance B. Becker, Michael N. Cocchi, Pratik Doshi, Jonathan Gong, Ayan Sen and Michael W. Donnino
Critical Care 201822:283
https://doi.org/10.1186/s13054-018-2217-4
Received: 9 August 2018 Accepted: 3 October 2018 Published: 29 October 2018
The combination of thiamine, ascorbic acid, and hydrocortisone has recently emerged as a potential adjunctive therapy to antibiotics, infectious source control, and supportive care for patients with sepsis and septic shock. In the present manuscript, we provide a comprehensive review of the pathophysiologic basis and supporting research for each element of the thiamine, ascorbic acid, and hydrocortisone drug combination in sepsis. In addition, we describe potential areas of synergy between these therapies and discuss the strengths/weaknesses of the two studies to date which have evaluated the drug combination in patients with severe infection. Finally, we describe the current state of current clinical practice as it relates to the thiamine, ascorbic acid, and hydrocortisone combination and present an overview of the randomized, placebo-controlled, multi-center Ascorbic acid, Corticosteroids, and Thiamine in Sepsis (ACTS) trial and other planned/ongoing randomized clinical trials.
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Evidence is stronger than you think: a meta-analysis of vitamin C use in patients with sepsis
Two recent publications by Sheikh and Horner and Teng et al. reviewed studies on incorporating vitamin C to treat septic patients; however, a meta-analysis was not offered in either report. This commentary extends both reviews by integrating a meta-analysis and sharing aggregated results. Pooled analyses demonstrated a marked reduction in mortality and duration of vasopressor administration in the group with the use of vitamin C.
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Vitamin C, Thiamine, and Hydrocortisone for Sepsis Patients
During 6 months, all patients admitted to the medical intensive care unit (MICU) in a Norfolk, VA, hospital with severe sepsis or septic shock and elevated procalcitonin levels (≥2 ng/mL), received intravenous high-dose vitamin C (6 g daily), hydrocortisone (50 mg every 6 hours), and thiamine. In a before–after study design, 47 intervention patients were compared with 47 patients who had been admitted to the MICU in the 6 months prior to implementation. Patients in the two groups had remarkably similar baseline characteristics.
Mortality was markedly lower in the patients treated with vitamin C, hydrocortisone, and thiamine (9% vs. 41% in the earlier group). Intervention patients also had faster resolution of shock with shorter mean duration of vasopressor use and less need for renal replacement therapy.
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Vitamin C for the treatment of sepsis: The scientific rationale
Pharmacology & Therapeutics
Volume 189, September 2018, Pages 63-70
Most vertebrates can synthesize vitamin C with synthesis increasing during stress. Humans, however, have lost the ability to synthesize vitamin C. Vitamin C is an important anti-oxidant and an enzyme cofactor for many important biological reactions. Sepsis results in the overwhelming production of reactive oxygen species with widespread endothelial, cellular and mitochondrial injury leading to progressive organ failure. Sepsis is associated with an acute deficiency of vitamin C. In experimental sepsis models, intravenous vitamin C reduces organ injury and improves survival. In addition, emerging evidence suggests that the combination of vitamin C, corticosteroids and thiamine may act synergistically to reverse sepsis induced organ dysfunction. These findings are supported by a recent observational study. Randomized controlled trials are underway to investigate this novel approach to the treatment of sepsis.
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Vitamin C cocktail for sepsis: randomized trials to test efficacy
Since Marik et al announced exceptional survival rates among patients with septic shock given a cocktail of vitamin C, thiamine, and hydrocortisone, physicians taking care of septic patients have expressed both enthusiasm and skepticism about the cocktail’s reported lifesaving effects.
Soon, more rigorous testing from randomized, double-blind placebo-controlled trials should provide harder data about the sepsis cocktail's efficacy.
Jonathan Sevransky, MD of Emory University announced plans for a clinical trial enrolling between 500 and 2,000 patients at multiple centers over about 18 months, completing by the end of 2019. Patients with septic shock would get either the cocktail, or placebo. Mortality will be tested, as well as days free of vasopressors or a ventilator. The study will be funded by a private foundation.
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Could vitamin C save lives in sepsis? These hospitals aren’t waiting for proof.
Small studies have found high-dose IV vitamin C during critical illness safe and beneficial:
In Tanka et al (2000), among 37 patients with major burns, those randomized to receive infusion of vitamin C at high doses (e.g., 4-5 grams an hour) for 24 hours on admission required less fluid resuscitation and had fewer ventilator days than those who got usual care.
Fowler et al (2014) found less organ dysfunction among the 24 patients with severe sepsis randomized to vitamin C infusion vs placebo, with a significant dose-response (up to a maximum dose of ~3-5 grams IV every 6 hours). No safety issues in this Phase I trial.
Zabet et al (2016) randomized 24 post-surgical patients with septic shock to vitamin C infusion (~1.5-2.5 grams IV every 6 hours) or placebo; the vitamin-C treated patients had significantly lower mortality and need for vasopressors.
The renowned Dr. Paul Marik et al will soon publish in Chest their own small before-and-after unblinded cohort study, born of an anecdote that should intrigue any intensivist: three patients with "fulminant sepsis ... almost certainly destined to die" from shock and organ failure, infused with vitamin C and moderate dose hydrocortisone out of desperation. All three patients recovered quickly and left the ICU in days, "with no residual organ dysfunction".
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Metabolic sepsis resuscitation: the evidence behind Vitamin C
The primary outcome was mortality, which was substantially reduced in patients receiving vitamin C (p<0.001, figure below). Similar results were obtained when the data was analyzed via two alternative methods, using either a propensity-adjusted outcome or logistic multivariate analysis. The robustness of these analyses suggest that mortality differences reflect a true treatment effect, rather than statistical confounding.
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