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Available online xxxx 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,
Keywords: multi-system organ dysfunction, and death. Over the past decades, there has been a focus on the early identifica-
Sepsis tion and treatment of sepsis primarily with bundled and goal directed therapy. Despite these advances, morbidity
Septic shock and mortality has remained high, prompting investigation into novel therapies. Vitamin C is a water-soluble vita-
Vitamin C
min that plays a role in mediating inflammation through antioxidant activities and is also important in the synthe-
Ascorbic acid
Ascorbate
sis 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.
© 2017 Elsevier Inc. All rights reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
3. Vitamin C as an antioxidant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
4. Vitamin C in vasopressor synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231
5. Vitamin C in immune function . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
6. Recent studies of vitamin C in sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232
7. Limitations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233
Author disclosure statement. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234
1. Introduction and bundled therapy [1]. Over the years, there have been over 100
phases II and phase III clinical trials investigating novel drugs and inter-
Sepsis is a severe life threatening condition that arises from a system- ventions to more effectively treat severe sepsis and septic shock; howev-
ic inflammatory response by the body to infection. It represents a spec- er, no new agents have been successful in directly targeting the
trum of disease that encompasses a state of systemic inflammation to pathophysiologic effects of sepsis [2]. While the complete mechanism
multi-organ dysfunction and shock. The mortality of sepsis ranges from of the evolution of sepsis and septic shock from a local inflammatory re-
20 to 35% in those with signs of severe sepsis to nearly 50% in patients sponse has not been fully elucidated, it is known that the widespread dis-
that present with septic shock despite advances in early goal directed tribution of pro-inflammatory mediators play an important role in the
pathogenesis and high morbidity and mortality associated with sepsis.
⁎ Corresponding author at: Department of Emergency Medicine, George Washington
These pro-inflammatory mediators cause increased permeability in en-
University, Medical Center, 2120 L St., Washington, DC 20037, United States. dothelial layers, which act locally by mitigating hemorrhage from
E-mail address: pourmand@gwu.edu (A. Pourmand). disrupted blood vessels and increase the delivery of immune cells and
http://dx.doi.org/10.1016/j.jcrc.2017.09.031
0883-9441/© 2017 Elsevier Inc. All rights reserved.
J. Teng et al. / Journal of Critical Care 43 (2018) 230–234 231
the enzyme peptidylgylcine alpha-amidating monooxygenase (PAM), to endothelial cells under the hypoxic conditions found in sepsis. It also
which is required for the synthesis of vasopressin [17]. In sepsis, vaso- aids in production of catecholamines and vasopressin - important hor-
pressin levels increase dramatically in the initial phases of septic monal controls in maintaining vasculature tone and perfusion. These
shock, however, levels of vasopressin and vitamin C deplete as patient two biologic systems are disrupted in sepsis. Systemic inflammation
progress into hypotension and shock [18]. causes endothelial compromise through ROS and extravasation of intra-
Vitamin C also is required for the catecholamine biosynthetic path- vascular fluid leading to collapse of the vascular tone and ultimately
way. Catecholamines, such as epinephrine and dopamine, play a key septic shock. Importantly, several studies have suggested that critical-
role in increasing arterial pressure by causing the contraction of vascular ly-ill patients have marked deficiency in available vitamin C, and inflam-
smooth muscle cells through binding of alpha-adrenergic receptors. Cat- matory mediators may inhibit uptake of vitamin C into endothelial cells
echolamines are also involved in increasing cardiac output by increasing [30,31]. Furthermore, decreased concentrations of vitamin C in patients
contractility and heart rate by activation of beta-adrenergic receptors on are associated with increased inflammation, organ failure, and mortality
cardiac myocytes [19]. Decreased catecholamine synthesis has been ob- [5]. These findings suggest that deficiency of vitamin C is correlated with
served in critically-ill patients, including patients with severe sepsis, pos- increased oxidative and inflammatory stress as well as vascular collapse.
sibly to adrenal ascorbic acid depletion [20]. Vitamin C is required in two Several studies have been undertaken to see the effects, if any, of vita-
key steps in the synthesis of catecholamines. In the first step, vitamin C is min C repletion in patients with sepsis in outcomes, including mortality.
used as a cofactor for the enzyme dopamine beta-hydroxylase [17]. This Recently, in a phase I randomized, double blind, placebo controlled
enzyme converts dopamine into epinephrine, a critical vasopressor for study of 24 patients, by Fowler et al. intravenous vitamin C administra-
septic patients that acts on both alpha and beta-adrenergic receptors to tion in patients with severe sepsis was undertaken to determine the safe-
maintain vascular tone and increase cardiac output. New research has ty of vitamin C infusion [32]. In this study, patients diagnosed with severe
also implicated vitamin C in the rate-limiting step of synthesizing L- sepsis were given high dose intravenous infusion of vitamin C at either
DOPA, the precursor of dopamine [21]. Research also suggest that vita- 50 mg/kg/24 h or 200 mg/kg/24 within 48 h of admission to the ICU. Vi-
min C may increase the synthesis of tyrosine hydroxylase, further in- tamin C was administered for a total of 96 h. This dosing is much higher
creasing dopamine production [17]. Additionally, vitamin C has been than the recommended dietary allowance of 60 mg/day of vitamin C in
shown to modulate both alpha-adrenergic and beta-adrenergic receptor normal adults. The study found that patients who received vitamin C
activity through binding of these receptors and enhancing their activa- had rapid reduction in Sequential Organ Failure Assessment (SOFA)
tion by epinephrine [22]. scores, a measure of organ dysfunction due to sepsis, while controls
group did not have such reductions. Vitamin C was also associated
5. Vitamin C in immune function with reduced levels of C-reactive protein and procalcitonin, biological
markers used to measure levels of inflammation [32]. The study demon-
Vitamin C is also found in high concentrations in leukocytes [5]. It has strated no adverse events in patients who received vitamin C during se-
been implicated in several immune responses and functions. For exam- vere sepsis [32].
ple, vitamin C has been shown to improve chemotaxis, support lympho- Other studies have examined vitamin C′s effect on other inflammato-
cytic proliferation, and assist in oxidative neutrophilic killing of bacteria ry markers in sepsis. Cell-free DNA and mitochondrial DNA are promis-
by leukocytes [1]. Vitamin C deficiency was associated with delayed kill- ing new biomarkers that have been associated with sepsis-related
ing of bacteria by natural killer (NK) cells and suppressed cytotoxic T cell mortality [33]. Increasing levels of mitochondrial DNA are associated
activity [4]. In an observational animal study, Gaut et al. reported mice with intensive care unit (ICU) mortality and rising levels of cell-free
with vitamin C deficiency had an increased rate of death from Klebsiella DNA have been shown to be specific and sensitive for poor outcomes
pneumoniae infection versus those supplemented with ascorbate after [34,35]. Using the patient data from the Fowler et al. study, Natarajan
24 days [23]. Vitamin C has also been shown to have profound bacterio- et al. in a recent retrospective phase I, randomized, double-blinded, pla-
static activity. In vitro studies have shown significantly inhibited bacteri- cebo controlled safety study evaluating vitamin C′s effect on circulating
al replication in the presence of vitamin C, although it is unknown levels of cell-free DNA and mitochondrial DNA demonstrated a reduction
whether this confers any protection to human patients [24]. In mouse of circulating levels of cell-free DNA and mitochondrial DNA in patients
models, vitamin C was shown to attenuate lipopolysaccharide mediated infused with vitamin C, either at 50 mg or 200 mg/kg/24 h, in a dose de-
lung injury during sepsis [25]. Vitamin C has also been shown to inhibit pendent manner [36]. Furthermore, the study found infusions of vitamin
tumor necrosis factor (TNF)-induced production of intercellular adhe- C during sepsis lead to reduced red cell distribution width (RDW) and in-
sion molecules (ICAMs), which decreases leukocyte stickiness and slug- creased levels of host defensins [36]. These findings may be significant
ging, improving microcirculatory flow [26]. Additionally, vitamin C has for patients with sepsis, as increased RDW has been shown to be related
been shown to support immune function by inhibiting apoptosis and to severity of sepsis, and associated with higher rates of adverse clinical
protecting endothelial progenitor cells [27,28]. Other studies have outcomes [37,38]. These findings suggest that use of vitamin C in critical-
found that high dose vitamin C decreases nuclear factor-ϰB leading to a ly ill patients with sepsis may be effective in lowering biomarkers associ-
reduction of immune response [29]. (Table 2). ated with increased sepsis mortality.
Vitamin C administration was also shown to positively impact hemo-
6. Recent studies of vitamin C in sepsis dynamic stability in several studies. In a double-blinded randomized
clinical trial of 28 patients Zabet et al. looked at ascorbic acid's effect on
Clearly, vitamin C serves several important physiologic functions in vasopressor requirements for patients in septic shock. Patients who re-
the body. As previously discussed, it acts as an oxidant protectant by re- ceived intravenous vitamin C at a dose of 25 mg/kg every 6 h showed a
ducing ROS and regenerating other ROS scavengers, mitigating damage significant reduction in vasopressor requirements with reductions in
Table 2
Summary of key roles of vitamin C in sepsis.
Antioxidant Scavenges ROS and RNS, prevents endothelial damage maintaining microvascular integrity
Synthesis of catecholamines Acts as cofactor in synthesis of epinephrine, dopamine, and vasopressin allowing for maintenance of vascular tone and cardiac output
Immune function Supports lymphocytic proliferation, assists in neutrophilic killing of bacteria, improves chemotaxis
Treatment:14.28%mortality
Mortality benefit
assess mortality
assess mortality
ity (14.28% versus 64.28%) in comparison to the control. However, length
P = 0.009
of ICU stay did not differ between the two groups [39]. Tanaka et al. in a
P b 0.001
P = 0.97
prospective randomized study of 37 patients, reported that patients in
critical condition due to burns, high dose vitamin C administration was
shown to reduce the amount of resuscitation volume, improve gas ex-
change, and reduce the numbers of day required on mechanical ventila-
tion [40].
vitamin C
Findings
drocortisone, and thiamine was 8.5% compared to 40.4% in the control
scores
group, a significant result. Patients in the treatment group also required
a shorter duration of vasopressor therapy - 18.3 h versus. 54.9 h in the
control [2]. Patients receiving vitamin C developed lower rates of acute
kidney injury and a more rapid reduction in SOFA scores. Importantly,
this study evaluated the synergistic administration of vitamin C with hy-
7. Limitations
1.5 g IV every 6 h
every 24 h
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 stud-
ies 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 syner-
47
24
24
28
37
N
8. Conclusion
study
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[21] May JM, Qu ZC, Meredith ME. Mechanisms of ascorbic acid stimulation of norepineph-
rine synthesis in neuronal cells. Biochem Biophys Res Commun 2012;426(1):148–52.
Author disclosure statement [22] Dillon PF, Root-Bernstein RS, Lieder CM. Antioxidant-independent ascorbate en-
hancement of catecholamine-induced contractions of vascular smooth muscle. Am
No competing financial interests exist. J Physiol Heart Circ Physiol 2004;286(6) (H2353-60).
[23] Gaut JP, Belaaouaj A, Byun J, et al. Vitamin C fails to protect amino acids and lipids
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