Elsevier

Journal of Critical Care

Volume 57, June 2020, Pages 231-239
Journal of Critical Care

Treating sepsis with vitamin C, thiamine, and hydrocortisone: Exploring the quest for the magic elixir

https://doi.org/10.1016/j.jcrc.2019.12.011Get rights and content

Highlights

  • Recent studies have generated keen interest in the use of vitamin C, thiamine, and corticosteroids (VCTS) to treat sepsis.

  • Many questions surround the effective dosing regimens and laboratory measurements for vitamin C and thiamine.

  • This review explores the current evidence, potential benefits, and adverse effects of the VCTS regimen for treating sepsis.

Abstract

The administration of ascorbic acid (vitamin C) alone or in combination with thiamine (vitamin B1) and corticosteroids (VCTS) has recently been hypothesized to improve hemodynamics, end-organ function, and may even increase survival in critically ill patients. There are several clinical studies that have investigated the use of vitamin C alone or VCTS in patients with sepsis and septic shock or are ongoing. Some of these studies have demonstrated its safety and potential benefit in septic patients. However, many questions remain regarding the optimal dosing regimens and plasma concentrations, timing of administration, and adverse effects of vitamin C and thiamine. These questions exist because the bulk of research regarding the efficacy of vitamin C alone or in combination with thiamine and corticosteroids in sepsis is limited to a few randomized controlled trials, retrospective before-and-after studies, and case reports. Thus, although the underlying rationale and mechanistic pathways of vitamin C and thiamine in sepsis have been well described, the clinical impact of the VCTS regimen is complex and remains to be determined. This review aims to explore the current evidence and potential benefits and adverse effects of the VCTS regimen for the treatment of sepsis.

Introduction

Ascorbic acid (Vitamin C) and thiamine (Vitamin B1) are naturally occurring water-soluble micronutrients that may hold potential as adjuvant therapies in critically ill patients [1]. The early physiology, pathology and laboratory measurements associated with these two vitamins and their deficiencies are described primarily through old diseases such as scurvy, beriberi, Korsakoff syndrome and Wernicke's encephalopathy [[1], [2], [3]]. Nevertheless, there is a large and current body of basic science, preclinical and clinical studies that has evaluated the role of both vitamins in patients with sepsis, acute respiratory distress syndrome (ARDS), and other inflammatory states. Both vitamin C and thiamine have broad physiological and immunological functions. Similarly, deficiencies of both vitamins have been treated empirically, with or without measuring levels, and with variable dosing regimens. Moreover, deficiencies of vitamin C and thiamine may occur rapidly in critical illness, and since these deficiencies are not so prevalent, their diagnosis requires a high level of suspicion.

Recent studies have generated keen interest in the use of vitamin C, thiamine, and corticosteroids (VCTS) to treat sepsis [4,5]. The context of this new approach is the decades of costly failures of new targeted agents to mitigate sepsis. One of the most exciting advantages of the VCTS regimen is the generic availability of these agents, the paucity of reported side-effects and the low cost of both the intravenous (IV) and oral forms of vitamin C and thiamine and the corticosteroids.

In this review, we address vitamin C and thiamine as relates to the knowledge base required of bedside ICU clinicians, and ICU associated pharmacists and laboratorians. We include a brief overview of biochemical properties and then dwell upon the practical aspects of vitamin C and thiamine with a focus on historical perspectives, physiological mechanisms of action, metabolism, route of administration, laboratory testing, and the current evidence supporting these agents alone or in combination, as well as their potential limitations. Considering the abundant literature on the use of corticosteroids during critical illness in general, and sepsis in particular, our focus on corticosteroids will only be addressed within the context of its role within the VCTS regimen for sepsis.

Section snippets

How did vitamin C come about?

The history of vitamin C spans across the centuries beginning with James Lind's discovery of scurvy treatment in the 1700's to the isolation of vitamin C in 1928 by Albert Szent-Gyorgyi [6]. Vitamin C was called by the letter “C” because it was the third “vital mineral” isolated. Vitamin C was also named ascorbic acid because of its antiscorbutic (anti-scurvy) properties.

Why do humans require vitamin C supplementation?

Humans, unlike most animals, are unable to synthesize vitamin C due to the absence of functional L-gulonolactone oxidase, an enzyme required for the final conversion of glucose to ascorbic acid [7]. Hence, humans depend on dietary sources of vitamin C. Failure to generate vitamin C makes humans very susceptible to dysfunction in various vitamin C dependent biochemical pathways necessary for surviving a critical illness [8].

How is vitamin C obtained and stored in the human body?

Ascorbic acid and dehydroascorbic acid (DHAA or oxidized vitamin C), components of fruits and vegetables or marketed as vitamin supplements, are the primary dietary sources of vitamin C for humans. Both ascorbic acid and DHAA are absorbed from the lumen of the intestine and renal tubules by enterocytes and renal epithelial cells, respectively, and then circulate in the blood and enter all body cells (Fig. 1A) [9]. Vitamin C is also secreted into the gastric juice, cerebrospinal fluid, and

What are the physiological functions of vitamin C?

The numerous physiological roles of vitamin C are all dependent on its ability to be an electron donor, or reducing agent. In this capacity, Vitamin C serves as a potent antioxidant directly scavenging oxygen free radicals and also prevents the generation of new free radicals via its suppressive effects on the NADPH oxidase (NOX) pathway (Fig. 1B) [4,13]. Additionally, vitamin C is a co-substrate for the biosynthesis of endogenous vasopressors (e.g., norepinephrine), cortisol, and vasopressin [

What are the clinical manifestations of chronic vitamin C deficiency?

Scurvy, the most well-known disease caused by severe and long-term vitamin C deficiency, is manifested by swollen and bleeding gums, poor wound closure, easy bruising, hair and tooth loss, joint pain and swelling [15]. These symptoms appear to be related to impaired collagen biosynthesis leading to the weakening of blood vessels, connective tissue, and bone.

What happens to vitamin C in critical illness and what acute deficiencies result?

Vitamin C levels become abnormally low within 24 h of acute injury, critical illness, multiple organ failure and sepsis, and is related to the patient's severity of illness [1,4,12,18]. Animal studies have demonstrated that the decrease in plasma vitamin C levels is associated with a fall in intracellular levels. In humans, the rapid decline in vitamin C levels is likely secondary to a combination of decreased vitamin C intake and absorption, increased metabolism and distribution, increased

How did thiamine come about?

Thiamine was first discovered in 1910 by Umetaro Suzuki in Japan when researching how rice bran cured patients afflicted with beriberi [20]. It was first crystallized by Jansen and Donath in 1926 [21]. Thiamine was the first B vitamin discovered hence its name carries the number 1. To date, much of what is known about thiamine originates from studies of alcohol abuse and nutritional deficiency disorders.

How is thiamine obtained and stored in the human body?

Humans cannot synthesize thiamine. Instead, thiamine is obtained through dietary intake of cereal grains, beans, nuts, and meat [22]. Thiamine is also commercially available in combination with other B vitamins (vitamin B complex). Thiamine is largely absorbed in the upper jejunum and to a lesser extent in the duodenum and ileum. Absorption is highly influenced by overall nutritional status and alcohol consumption.

Thiamine exists in four forms due to the addition of one or more phosphate

What are the functions of thiamine?

Thiamine, specifically the TPP form, is an important cofactor for enzymes utilized in multiple biochemical reactions for carbohydrate metabolism and energy production. These include pyruvate dehydrogenase, which catalyzes the conversion of pyruvate to acetyl coenzyme A, α-ketoglutarate dehydrogenase, which converts α-ketoglutarate to succinyl coenzyme A in the Krebs cycle, and transketolase of the pentose phosphate pathway that generates NADPH for reductive biosynthesis (Fig. 2) [24]. Thiamine

What are the clinical manifestations of chronic thiamine deficiency?

Thiamine deficiency occurs through a predominantly carbohydrate-based diet with limited vitamin and mineral intake, as well as in patients with history of alcohol abuse, dialysis, diabetic ketoacidosis, chronic diarrhea, and consumption of high doses of diuretics [26,27]. Prolonged thiamine deficiency results in beriberi with cardiovascular symptoms (wet), or neurologic symptoms (dry), or a combination of the two variants. Neurologic deficiencies may present as Wernicke's encephalopathy with

What happens to thiamine in critical illness and what deficiencies acutely result?

Similar to vitamin C, the hypermetabolic state that occurs during critical illness in the adult patient may be associated with the rapid depletion of thiamine stores [1,3,4,24,26,29]. Thiamine deficiency may also occur due to sudden or aggressive nutrition delivery to malnourished patients (refeeding syndrome) or excessive removal (during prolonged continuous renal replacement therapy [CRRT]) [3]. Inadequate thiamine levels can lead to cellular metabolic and bioenergetic failure with the

Vitamin C

The invigorated interest in vitamin C has highlighted the fact that clear measurement guidelines and cut-offs for vitamin C in critically ill patients are absent. This is partly due to the technical challenges involved with the laboratory measurement of vitamin C [15]. Vitamin C can be measured in plasma (or serum), leukocytes and urine. Plasma or serum vitamin C measurements reflect metabolic turnover and do not correlate well with tissue vitamin C levels [30]. High performance liquid

Vitamin C

In healthy individuals, vitamin C deficiency is readily restored with vitamin C 200 mg/day IV or 500 mg/day orally for seven days. Vitamin C plasma and tissue concentrations are tightly controlled by saturable enteral absorption by SVCT-1 (Fig. 1), tissue transport, and renal reabsorption and excretion. In critically ill patients, variations in timing, dose, and administration route of vitamin C plays a role because direct radical scavenging depends on Vitamin C plasma concentrations >175 mg/l

Vitamin C

Vitamin C alone has been studied in a variety of critical care conditions (sepsis and septic shock, acute respiratory distress syndrome, major burns, trauma, and cardiac surgery) with a variety of dosing regimens (2–10 g/day IV) sometimes described as “low to high” doses by various investigators. Outcome parameters have included vasopressor- and ventilator-free days, organ failure scores, biomarker levels, fluid resuscitation volumes, occurrence of postoperative atrial fibrillation, acute

How did the vitamin C and thiamine cocktail with corticosteroids for sepsis come about?

Experimental studies have shown that both vitamin C and hydrocortisone have multiple and overlapping beneficial pathophysiologic effects in sepsis [5]. Vitamin C helps to reverse the oxidation of the glucocorticoid receptor and restore its function [4,12]. Hydrocortisone increases the expression of the sodium-vitamin C transporter-2 (SVCT2) (Fig. 1), which actively transports vitamin C into the tissue cells, but is downregulated in sepsis [67]. In addition, hydrocortisone works synergistically

Are there safety concerns with using the vitamin C and thiamine cocktail in combination with corticosteroids?

While vitamin C is largely considered a non-toxic vitamin, safety data is limited for the 6 g/day IV vitamin C dosing that is administered as part of the VCTS regimen in the ongoing or completed clinical trials. Known side effects of vitamin C from past studies include gastrointestinal disturbances, hypersensitivity reactions, oxaluria, kidney stones, and glycosuria [71]. There were no unexpected adverse events reported in the most recent trial of vitamin C infusions in patients with sepsis and

What does the future hold for the VCTS cocktail?

The VCTS cocktail appears to be a promising adjuvant therapy for sepsis. Vitamin C and thiamine have favorable side effect and cost profiles. These vitamins are usually readily available; however, recent occasional shortages of the IV formulations have been reported. As of November 2019, there are 14 completed and/or ongoing clinical trials with the VCTS regimen for the treatment of adult patients with sepsis and septic shock listed at clinicaltrials.gov (Table 1) [73]. Five of these RCTs

Author contributions

  • Conception and design: Jennifer Obi, MD, Stephen M Pastores, Neil A Halpern.

  • Collection and assembly of data: All authors.

  • Data analysis and interpretation: All authors.

  • Manuscript writing: All authors.

  • Final approval of manuscript: All authors.

Disclosures

Drs. Pastores and Halpern were clinical investigators in the recently concluded Vitamin C, Thiamine and Steroid (VICTAS) sepsis trial. The remaining authors have no conflicts to disclose.

Financial support

This study was supported, in part, by the Core Grant (P30 CA008748) and the Department of Anesthesiology and Critical Care Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.

Acknowledgments

We acknowledge the assistance of Susan Weil-Kazzaz, CMI, Manager, Design and Creative Services, Department of Communications, Memorial Sloan Kettering Cancer Center, New York, NY for preparation of the figures.

References (75)

  • M Levine et al.

    Vitamin C: a concentration-function approach yields pharmacology and therapeutic discoveries

    Adv Nutr

    (2011)
  • J Rieck et al.

    Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers

    J Lab Clin Med

    (1999)
  • M Zhang et al.

    Vitamin C supplementation in the critically ill: a systematic review and meta-analysis

    SAGE Open Med

    (2018)
  • MW Donnino et al.

    Thiamine deficiency in critically ill patients with sepsis

    J Crit Care

    (2010)
  • WY Kim et al.

    Combined vitamin C, hydrocortisone, and thiamine therapy for patients with severe pneumonia who were admitted to the intensive care unit: propensity score-based analysis of a before-after cohort study

    J Crit Care

    (2018)
  • JB Mehta et al.

    Ascorbic acid-induced haemolysis in G-6-PD deficiency

    Lancet

    (1990)
  • K Amrein et al.

    Vitamin therapy in critically ill patients: focus on thiamine, vitamin C, and vitamin D

    Intensive Care Med

    (2018)
  • J Mallat et al.

    Do not forget to give thiamine to your septic shock patient!

    J Thorac Dis

    (2016)
  • A Moskowitz et al.

    Ascorbic acid, corticosteroids, and thiamine in sepsis: a review of the biologic rationale and the present state of clinical evaluation

    Crit Care

    (2018)
  • KJ Carpenter

    The discovery of vitamin C

    Ann Nutr Metab

    (2012)
  • M Nishikimi et al.

    Molecular basis for the deficiency in humans of gulonolactone oxidase, a key enzyme for ascorbic acid biosynthesis

    Am J Clin Nutr

    (1991)
  • PE Marik et al.

    Doctor-your septic patients have scurvy!

    Crit Care

    (2018)
  • JX Wilson

    Regulation of vitamin C transport

    Annu Rev Nutr

    (2005)
  • KC S, Carcamo JM, Golde DW

    Vitamin C enters mitochondria via facilitative glucose transporter 1 (Glut1) and confers mitochondrial protection against oxidative injury

    FASEB J

    (2005)
  • HM Oudemans-van Straaten et al.

    Vitamin C revisited

    Crit Care

    (2014)
  • F Wu et al.

    iNOS expression requires NADPH oxidase-dependent redox signaling in microvascular endothelial cells

    J Cell Physiol

    (2008)
  • JM May et al.

    Role of vitamin C in the function of the vascular endothelium

    Antioxid Redox Signal

    (2013)
  • SJ Padayatty et al.

    Vitamin C physiology: the known and the unknown and goldilocks

    Oral Dis

    (2016)
  • YL Gao et al.

    The parenteral vitamin C improves sepsis and sepsis-induced multiple organ dysfunction syndrome via preventing cellular immunosuppression

    Mediators Inflamm

    (2017)
  • AC Carr et al.

    Hypovitaminosis C and vitamin C deficiency in critically ill patients despite recommended enteral and parenteral intakes

    Crit Care

    (2017)
  • PE Marik

    Hydrocortisone, ascorbic acid and thiamine (HAT Therapy) for the treatment of sepsis. Focus on ascorbic acid

    Nutrients

    (2018)
  • U Suzuki et al.

    Active constituent of rice grits preventing bird polyneuritis

    Tokyo Kagaku Kaishi

    (1911)
  • BCT Jansen et al.

    On the isolation of the antiberiberi vitamin

  • G Rindi et al.

    Thiamine intestinal transport and related issues: recent aspects

    Proc Soc Exp Biol Med

    (2000)
  • W Manzanares et al.

    Thiamine supplementation in the critically ill

    Curr Opin Clin Nutr Metab Care

    (2011)
  • CA Calderon-Ospina et al.

    B vitamins in the nervous system: current knowledge of the biochemical modes of action and synergies of thiamine, pyridoxine, and cobalamin

    CNS Neurosci Ther

    (2019)
  • JP Counts et al.

    Thiamine use in sepsis: B1 for everyone?

    Crit Care Nurs Q

    (2019)
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