Journal of Critical Care 43 (2018) 230–234

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Journal of Critical Care

journal homepage: www.jccjournal.org

Vitamin C: The next step in sepsis management?

J. Teng a, A. Pourmand a,⁎, M. Mazer-Amirshahi b,c
a
Emergency Medicine Department, George Washington University School of Medicine and Health Sciences, Washington, DC, United States
b
Department of Emergency Medicine, MedStar Washington Hospital Center, Washington, DC, United States
c
Georgetown University School of Medicine, Washington, DC, United States

a r t i c l e i n f o a b s t r a c t

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
Sepsis is a severe life threatening condition that arises from a system-
ic inflammatory response by the body to infection. It represents a spec-
trum 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
⁎ Corresponding author at: Department of Emergency Medicine, George Washington
University, Medical Center, 2120 L St., Washington, DC 20037, United States.
E-mail address: pourmand@gwu.edu (A. Pourmand).
and bundled therapy [1]. Over the years, there have been over 100
phases II and phase III clinical trials investigating novel drugs and inter-
ventions to more effectively treat severe sepsis and septic shock; howev-
er, 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 re-
sponse has not been fully elucidated, it is known that the widespread dis-
tribution 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 en-
dothelial layers, which act locally by mitigating hemorrhage from
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
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 treat-
ment 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 perfu-
sion 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 fur-
ther damage through the bactericidal effects of antibiotic administration
[1]. Clearly, there is a need for new, targeted adjuvant therapies that re-
verse 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. Immunomodula-
tors 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 necro-
sis antibodies, and anti-TNF receptor antibodies were examined; howev-
er, these immunomodulators did not improve 28-day outcomes in
patients with sepsis [9]. Inhibitors to signaling receptors were also exam-
ined in their effectiveness. Additional studies have examined blockade of
other important mediators in the immune cascade such as toll-like re-
ceptor proteins, interleukin 1, and granulocyte colony stimulating factors
and found no improvement in outcomes [10]. Recombinant human acti-
vated protein C (Xigris) was hypothesized to benefit patients in sepsis
due to its fibrinolytic effects and inhibition of thrombosis, which was be-
lieved to improve sepsis survival by preventing microvascular dysfunc-
tion 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 hy-
pothesized 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 adju-
vant therapy in sepsis to reduce mortality. (Table 1).
Table 1
List of ineffective targeted adjuvant therapies.
List of ineffective targeted therapies
- Activated protein C
- Anti-LPS HA-1A antibody
- Toll-like receptor 4 antagonist
- Tumor necrosis factor receptor antagonist
- Anti-tumor necrosis factor monoclonal antibody
- Granulocyte colony-stimulating factor
- Interleukin-1 receptor antagonist
231
2. 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 through the PubMed search. One hundred seventy-six ar-
ticles were discovered through our search methods. Forty articles were
identified meeting criteria for use in this review. Preference for selection
was given to clinical trials and review articles that assessed the utility of
Vitamin C administration to septic patients.
3. 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 functions. It
can scavenge ROS directly, such as superoxide and peroxynitrite, thus
preventing damage to cellular proteins [4]. This is achieved through do-
nation of an electron-generating ascorbic radical from ascorbic acid. The
ascorbic radical is relatively stable and does not react with other mole-
cules due to the position of its free electron, which is rapidly reduced
[14].
Vitamin C can also reactivate other ROS scavengers, such as glutathi-
one and alpha-tocopherol, by donating an electron to these compounds
and allowing for their function [5]. Importantly, Vitamin C has been
shown to act on the enzyme nicotinamide adenine dinucleotide oxidase
(NOX). NOX is activated in the setting of endothelial dysfunction during
sepsis and other ischemic conditions. NOX is a key enzyme in the activa-
tion and production of many other reactive oxygen species such as su-
peroxide and peroxynitrite, which are both potent and damaging
reactive oxidants [4]. Production of these ROS by NOX damages the en-
dothelial barrier and disrupts tight junctions leading to extravasation
and vascular compromise. Furthermore, superoxide oxidizes
tetrahydrobiopterin, a cofactor of nitric oxide synthetase leading to de-
creased nitric oxide production and reduced microvascular perfusion.
Vitamin C has been shown to inhibit NOX activation and scavenge su-
peroxide and peroxynitrite, thus protecting endothelial integrity and
maintenance of endothelial tight junctions. Vitamin C also recovers
tetrahydrobiopterin from its oxidized form and allows for nitric oxide
production leading to increased microvascular perfusion. Vitamin C
also inhibits nuclear factor kappa-B, reducing levels of inflammatory
modulators, to further increase endothelial junctions, and preserve ad-
equate perfusion [2].
4. 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 perfu-
sion throughout the body. One such hormone is vasopressin or
antidiuretic hormone. Vasopressin is a peptide neurohypophysial hor-
mone synthesized in the hypothalamus and stored in the posterior pitu-
itary [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 the collecting duct of the kidneys to induce vasocon-
striction and increase water retention. Vasopressin also works on the
anterior pituitary by inducing the release of adrenocorticotrophic hor-
mone (ACTH) allowing for the synthesis of corticosteroids, which
serve to activate the stress response [16]. Vitamin C acts a co-factor for
232 J. Teng et al. / Journal of Critical Care 43 (2018) 230–234
the enzyme peptidylgylcine alpha-amidating monooxygenase (PAM),
which is required for the synthesis of vasopressin [17]. In sepsis, vaso-
pressin levels increase dramatically in the initial phases of septic
shock, however, levels of vasopressin and vitamin C deplete as patient
progress into hypotension and shock [18].
Vitamin C also is required for the catecholamine biosynthetic path-
way. Catecholamines, such as epinephrine and dopamine, play a key
role in increasing arterial pressure by causing the contraction of vascular
smooth muscle cells through binding of alpha-adrenergic receptors. Cat-
echolamines are also involved in increasing cardiac output by increasing
contractility and heart rate by activation of beta-adrenergic receptors on
cardiac myocytes [19]. Decreased catecholamine synthesis has been ob-
served in critically-ill patients, including patients with severe sepsis, pos-
sibly to adrenal ascorbic acid depletion [20]. Vitamin C is required in two
key steps in the synthesis of catecholamines. In the first step, vitamin C is
used as a cofactor for the enzyme dopamine beta-hydroxylase [17]. This
enzyme converts dopamine into epinephrine, a critical vasopressor for
septic patients that acts on both alpha and beta-adrenergic receptors to
maintain vascular tone and increase cardiac output. New research has
also implicated vitamin C in the rate-limiting step of synthesizing L-
DOPA, the precursor of dopamine [21]. Research also suggest that vita-
min C may increase the synthesis of tyrosine hydroxylase, further in-
creasing dopamine production [17]. Additionally, vitamin C has been
shown to modulate both alpha-adrenergic and beta-adrenergic receptor
activity through binding of these receptors and enhancing their activa-
tion by epinephrine [22].
5. 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 exam-
ple, vitamin C has been shown to improve chemotaxis, support lympho-
cytic proliferation, and assist in oxidative neutrophilic killing of bacteria
by leukocytes [1]. Vitamin C deficiency was associated with delayed kill-
ing of bacteria by natural killer (NK) cells and suppressed cytotoxic T cell
activity [4]. In an observational animal study, Gaut et al. reported mice
with vitamin C deficiency had an increased rate of death from Klebsiella
pneumoniae infection versus those supplemented with ascorbate after
24 days [23]. Vitamin C has also been shown to have profound bacterio-
static activity. In vitro studies have shown significantly inhibited bacteri-
al replication in the presence of vitamin C, although it is unknown
whether this confers any protection to human patients [24]. In mouse
models, vitamin C was shown to attenuate lipopolysaccharide mediated
lung injury during sepsis [25]. Vitamin C has also been shown to inhibit
tumor necrosis factor (TNF)-induced production of intercellular adhe-
sion molecules (ICAMs), which decreases leukocyte stickiness and slug-
ging, improving microcirculatory flow [26]. Additionally, vitamin C has
been shown to support immune function by inhibiting apoptosis and
protecting endothelial progenitor cells [27,28]. Other studies have
found that high dose vitamin C decreases nuclear factor-ϰB leading to a
reduction of immune response [29]. (Table 2).
6. 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 re-
ducing ROS and regenerating other ROS scavengers, mitigating damage
Table 2
Summary of key roles of vitamin C in sepsis.
Key role Mechanism
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
ROS = reactive oxygen species, RNS = reactive nitrogen species.
to endothelial cells under the hypoxic conditions found in sepsis. It also
aids in production of catecholamines and vasopressin - important hor-
monal controls in maintaining vasculature tone and perfusion. These
two biologic systems are disrupted in sepsis. Systemic inflammation
causes endothelial compromise through ROS and extravasation of intra-
vascular fluid leading to collapse of the vascular tone and ultimately
septic shock. Importantly, several studies have suggested that critical-
ly-ill patients have marked deficiency in available vitamin C, and inflam-
matory mediators may inhibit uptake of vitamin C into endothelial cells
[30,31]. Furthermore, decreased concentrations of vitamin C in patients
are associated with increased inflammation, organ failure, and mortality
[5]. These findings suggest that deficiency of vitamin C is correlated with
increased oxidative and inflammatory stress as well as vascular collapse.
Several studies have been undertaken to see the effects, if any, of vita-
min C repletion in patients with sepsis in outcomes, including mortality.
Recently, in a phase I randomized, double blind, placebo controlled
study of 24 patients, by Fowler et al. intravenous vitamin C administra-
tion in patients with severe sepsis was undertaken to determine the safe-
ty of vitamin C infusion [32]. In this study, patients diagnosed with severe
sepsis were given high dose intravenous infusion of vitamin C at either
50 mg/kg/24 h or 200 mg/kg/24 within 48 h of admission to the ICU. Vi-
tamin C was administered for a total of 96 h. This dosing is much higher
than the recommended dietary allowance of 60 mg/day of vitamin C in
normal adults. The study found that patients who received vitamin C
had rapid reduction in Sequential Organ Failure Assessment (SOFA)
scores, a measure of organ dysfunction due to sepsis, while controls
group did not have such reductions. Vitamin C was also associated
with reduced levels of C-reactive protein and procalcitonin, biological
markers used to measure levels of inflammation [32]. The study demon-
strated no adverse events in patients who received vitamin C during se-
vere sepsis [32].
Other studies have examined vitamin C′s effect on other inflammato-
ry markers in sepsis. Cell-free DNA and mitochondrial DNA are promis-
ing new biomarkers that have been associated with sepsis-related
mortality [33]. Increasing levels of mitochondrial DNA are associated
with intensive care unit (ICU) mortality and rising levels of cell-free
DNA have been shown to be specific and sensitive for poor outcomes
[34,35]. Using the patient data from the Fowler et al. study, Natarajan
et al. in a recent retrospective phase I, randomized, double-blinded, pla-
cebo controlled safety study evaluating vitamin C′s effect on circulating
levels of cell-free DNA and mitochondrial DNA demonstrated a reduction
of circulating levels of cell-free DNA and mitochondrial DNA in patients
infused with vitamin C, either at 50 mg or 200 mg/kg/24 h, in a dose de-
pendent manner [36]. Furthermore, the study found infusions of vitamin
C during sepsis lead to reduced red cell distribution width (RDW) and in-
creased levels of host defensins [36]. These findings may be significant
for patients with sepsis, as increased RDW has been shown to be related
to severity of sepsis, and associated with higher rates of adverse clinical
outcomes [37,38]. These findings suggest that use of vitamin C in critical-
ly ill patients with sepsis may be effective in lowering biomarkers associ-
ated with increased sepsis mortality.
Vitamin C administration was also shown to positively impact hemo-
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
vasopressor requirements for patients in septic shock. Patients who re-
ceived intravenous vitamin C at a dose of 25 mg/kg every 6 h showed a
significant reduction in vasopressor requirements with reductions in
 J. Teng et al. / Journal of Critical Care 43 (2018) 230–234 233

both duration and dose of vasopressor. With statistically significant find-

Treatment:14.28%mortality

Treatment: 47.3% mortality

Treatment: 8.5% mortality

Control: 64.28% mortality

ings, the vitamin C group required around half the dose of vasopressors

Control: 40.4% mortality

Control: 38.9% mortality

Study not powered to

Study not powered to

compared to those in the treatment group (7.44 μg of epinephrine com-
pared to 13.79 μg/min), and had a significant decrease in 28-day mortal-

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].

requirements, body weight gain, wound edema,

sepsis is safe and may lead to reduction of SOFA
A new and controversial study published in 2017, Marik et al. retro-

hydrocortisone saw a reduction of mortality in

Early treatment with vitamin C, thiamine, and

Decrease in biomarkers of sepsis (cf-DNA and

spectively examined the role of vitamin C use synergistically with hydro-

patients with severe sepsis and septic shock

Vitamin C treatment in patients with severe

Reduction of vasopressor requirement and

cortisone and thiamine in patients with sepsis. In the study, 47

Reduction of resuscitation fluid volume

decreased mortality in treatment with
observational treatment cases were retrospectively matched to 47 con-
trol cases. The treatment group was treated within 24 h of ICU admission

mtDNA) and decrease in RDW

with 1.5 g of intravenous vitamin C every six hours, 50 mg of hydrocor-

and respiratory dysfunction

tisone every six hours, and 200 mg of intravenous thiamine every 12 h.
Hydrocortisone and thiamine were administered for its hypothetical
synergistic effect with vitamin C [2]. The study found that patients in
the treatment group had a marked reduction in mortality compared to
matched controls. In hospital mortality of those receiving vitamin C, hy-

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-

Dose of Vitamin C (RDA 60 mg per day)

drocortisone and thiamine, and did not examine vitamin C monotherapy.

66 mg/kg IV based off body surface

50 mg/kg or 200 mg/kg IV infusion

50 mg/kg or 200 mg/kg IV infusion

The study is limited by its single centered design, with small sample size,

25 mg/kg intravenous every 6 h

but had statistically significant results with well-matched controls.

area burned and urine output

(Table 3).

7. Limitations
1.5 g IV every 6 h

This review was limited by the small number of studies evaluating

every 24 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

gistically with hydrocortisone and thiamine. The studies presented are

hypothesis generating and represent areas for further research in clinical
medicine.
Single center retrospective randomized
Single center retrospective before-after

Single center randomized double-blind

Single center prospective randomized

8. Conclusion

Sepsis remains a serious and life-threatening condition with high

Single center double-blinded
Comparison of recent vitamin C studies in patients with sepsis.

randomized controlled trial

morbidity and mortality. It is marked by dysregulated inflammation

placebo controlled trial

and hemodynamic instability. The current bundle care treatment proto-

cols 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. Re-
cent clinical findings give evidence supporting vitamin C as a possible ef-
Design

study

fective adjunct treatment agent in targeting the deleterious effects of

systemic inflammation and vascular compromise caused by sepsis. The
preliminary data provide support that vitamin C can be safely adminis-
tered to critically ill patients. Additionally, recent results from single cen-
ter trials provide encouraging data in vitamin C's effectiveness to treat
Natarajan et al. [36]

sepsis, especially when given synergistically with hydrocortisone and

Tanaka et al. [40]
Fowler et al. [32]

Zabet et al. [39]

Marik et al. [2]

thiamine. However, lack of large multi-center randomized controlled tri-

als investigating the utility of vitamin C in treating sepsis leave doubt as
to the strength of the currently available data and in its actual efficacy
Study
Table 3

and effectiveness in treating patients. Further research is required to

prove its value in treatment; though tentative preliminary evidence
234 J. Teng et al. / Journal of Critical Care 43 (2018) 230–234
suggest vitamin C may be safely administered in septic patients, further
evidence is required before it can be reasonably used as an adjuvant
treatment in sepsis.
Author disclosure statement
No competing financial interests exist.
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