Elsevier

Journal of Critical Care

Volume 43, February 2018, Pages 230-234
Journal of Critical Care

Sepsis / Infection
Vitamin C: The next step in sepsis management?

https://doi.org/10.1016/j.jcrc.2017.09.031Get rights and content

Highlights

  • 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.

Abstract

Sepsis is a life-threatening medical condition, affecting approximately 26 million people worldwide every year. The disease is a continuum, marked by dysregulated inflammation and hemodynamic instability leading to shock, multi-system organ dysfunction, and death. Over the past decades, there has been a focus on the early identification and treatment of sepsis primarily with bundled and goal directed therapy. Despite these advances, morbidity and mortality has remained high, prompting investigation into novel therapies. Vitamin C is a water-soluble vitamin that plays a role in mediating inflammation through antioxidant activities and is also important in the synthesis of cortisol, catecholamines, and vasopressin, which are key mediators in the disease process. Emerging evidence provides cursory data in support of the administration of vitamin C in addition to standard therapy to ameliorate the effects of inflammation and improve hemodynamic stability in patients with sepsis and septic shock; however, further evidence is needed to support this practice. This review discusses the physiologic role of vitamin C as well as the recent literature and evidence for the use of vitamin C in patients presenting with sepsis.

Introduction

Sepsis is a severe life threatening condition that arises from a systemic inflammatory response by the body to infection. It represents a spectrum of disease that encompasses a state of systemic inflammation to multi-organ dysfunction and shock. The mortality of sepsis ranges from 20 to 35% in those with signs of severe sepsis to nearly 50% in patients that present with septic shock despite advances in early goal directed and bundled therapy [1]. Over the years, there have been over 100 phases II and phase III clinical trials investigating novel drugs and interventions to more effectively treat severe sepsis and septic shock; however, no new agents have been successful in directly targeting the pathophysiologic effects of sepsis [2]. While the complete mechanism of the evolution of sepsis and septic shock from a local inflammatory response has not been fully elucidated, it is known that the widespread distribution of pro-inflammatory mediators play an important role in the pathogenesis and high morbidity and mortality associated with sepsis. These pro-inflammatory mediators cause increased permeability in endothelial layers, which act locally by mitigating hemorrhage from disrupted blood vessels and increase the delivery of immune cells and antimicrobial mediators. However, when this process is distributed throughout the body, it leads to hypotension, hemodynamic instability, and marked impairment of tissue perfusion. Hypoxia within tissues causes production of large quantities of reactive oxygen species (ROS) and reactive nitrogen species (RNS), leading to oxidative stress within cells and ultimately, tissue and organ damage. These ROS and RNS cause post-translational modifications to cellular proteins impairing the function of cells causing endothelial dysfunction, increased endothelial permeability, and impairment of microcirculatory flow. These effects eventually lead to cell death, shock, organ failure, and if not reversed, death [3], [4], [5].

Currently, the mainstay of sepsis treatment, as recommended by the Surviving Sepsis Campaign, is directed at early identification and treatment of infection through antibiotic administration and source control when applicable, as well as reversing hemodynamic instability through fluid resuscitation and use of vasopressors if necessary [6]. Even when shock is prevented by these supportive therapies, patients with severe sepsis can still die of multi-system organ failure despite adequate perfusion and cardiac output [7]. Some research suggests that deaths in septic patients are often attributable to the microvascular dysfunction due to inflammation [8]. However, current sepsis care bundles do not target the inflammatory and oxidative stress caused by sepsis; and current standard therapies can potentially increase inflammation and cause further damage through the bactericidal effects of antibiotic administration [1]. Clearly, there is a need for new, targeted adjuvant therapies that reverse the inflammatory and oxidative stress present in septic patients, however search for an effective targeted therapy has proven difficult.

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. Immunomodulators were initially studied in hopes that downregulating and controlling the body's inflammatory response would lead to improvement in sepsis outcomes. In the 1990s, antibodies against pro-inflammatory molecules, such as the anti-LPS HA-1A antibodies (or centotoxin), anti-tumor necrosis antibodies, and anti-TNF receptor antibodies were examined; however, these immunomodulators did not improve 28-day outcomes in patients with sepsis [9]. Inhibitors to signaling receptors were also examined in their effectiveness. Additional studies have examined blockade of other important mediators in the immune cascade such as toll-like receptor proteins, interleukin 1, and granulocyte colony stimulating factors and found no improvement in outcomes [10]. Recombinant human activated protein C (Xigris) was hypothesized to benefit patients in sepsis due to its fibrinolytic effects and inhibition of thrombosis, which was believed to improve sepsis survival by preventing microvascular dysfunction that contributes to multisystem organ failure in sepsis [11]. Initially promising, activated protein C was later found to be ineffective for treatment of sepsis and was withdrawn from the market [12].

Despite these many early failures, the search continues for effective targeted therapies in improving sepsis outcomes. 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. Recent, emerging clinical and experimental data are giving new evidence for the utility of administration of Vitamin C as a possible adjuvant therapy in sepsis to reduce mortality. (Table 1).

Section snippets

Methods

To complete a review of the literature, the PubMed database was queried with the following search terms: “vitamin C,” “ascorbic acid,” “sepsis,” “severe sepsis,” “treatment,” and “septic shock.” Search results were further limited to English language studies. Boolean operators and medical subject headings (MeSH) terms were used to combine search terms. Further literature was discovered using the Google Scholar database with the same search terms and using the reference section of articles found

Vitamin C as an antioxidant

Vitamin C, or ascorbic acid, is a water-soluble vitamin that acts in the body as an antioxidant and a cofactor for several enzymes [13]. It plays an important role in collagen and carnitine synthesis, and in the context of sepsis, facilitates the production of catecholamines, vasopressin, and cortisol. Vitamin C is also necessary for the metabolism of folate and iron and has been shown to have a modulating effect on the immune system [3]. As an anti-oxidant, vitamin C performs several

Vitamin C in vasopressor synthesis

Vitamin C also plays an important in the synthesis of catecholamines and other hormones important for the maintenance of adequate perfusion throughout the body. One such hormone is vasopressin or antidiuretic hormone. Vasopressin is a peptide neurohypophysial hormone synthesized in the hypothalamus and stored in the posterior pituitary [15]. It is released in response to decreased intravascular volume or pressure, or increased plasma osmolality. It acts on vascular smooth muscle cells and in

Vitamin C in immune function

Vitamin C is also found in high concentrations in leukocytes [5]. It has been implicated in several immune responses and functions. For example, vitamin C has been shown to improve chemotaxis, support lymphocytic proliferation, and assist in oxidative neutrophilic killing of bacteria by leukocytes [1]. Vitamin C deficiency was associated with delayed killing of bacteria by natural killer (NK) cells and suppressed cytotoxic T cell activity [4]. In an observational animal study, Gaut et al.

Recent studies of vitamin C in sepsis

Clearly, vitamin C serves several important physiologic functions in the body. As previously discussed, it acts as an oxidant protectant by reducing ROS and regenerating other ROS scavengers, mitigating damage to endothelial cells under the hypoxic conditions found in sepsis. It also aids in production of catecholamines and vasopressin - important hormonal controls in maintaining vasculature tone and perfusion. These two biologic systems are disrupted in sepsis. Systemic inflammation causes

Limitations

This review was limited by the small number of studies evaluating the utility of vitamin C use in sepsis. The review was further limited by the lack of large, multi-center, randomized, blinded studies. Of the studies selected, all were single center studies with small sample sizes, with the largest study including only 97 patients. Additionally, studies reviewed used different treatment protocols of vitamin C with differing doses and frequencies, including one study, which used vitamin C

Conclusion

Sepsis remains a serious and life-threatening condition with high morbidity and mortality. It is marked by dysregulated inflammation and hemodynamic instability. The current bundle care treatment protocols do not treat the underlying mechanism behind the development and progression of sepsis to septic shock. Vitamin C has been associated with reducing inflammation and supporting hemodynamic stability. Recent clinical findings give evidence supporting vitamin C as a possible effective adjunct

Author disclosure statement

No competing financial interests exist.

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