REVIEW

CURRENT
OPINION Metabolic support in sepsis: corticosteroids and
vitamins: the why, the when, the how
Tomoko Fujii a,b, Adam M. Deane c, and Priya Nair d

Purpose of review
Sepsis is a global health issue, and there is a need for effective, low-cost adjunct metabolic treatments.
Corticosteroids have been investigated in many trials for decades, and recently the administration of
vitamin C, thiamine (vitamin B1), and vitamin D have been proposed as novel therapies in patients with
sepsis.
Recent findings
APROCCHSS (N ¼ 1241) and ADRENAL (N ¼ 3800) trial reported inconsistent results in mortality outcome;
however, both demonstrated a decreased duration of shock with low-dose corticosteroids. The CITRIS-ALI
trial (N ¼ 170) examined the effects of intravenous vitamin C 200 mg/kg/day and reported no effect on
organ dysfunction or biomarkers. The VITAMINS trial (N ¼ 216) compared combination therapy of vitamin
C 6 g/day, thiamine 200 mg/day, and hydrocortisone 200 mg/day with hydrocortisone alone to find that
the combination did not increase vasopressor free time. A single trial (N ¼ 88) evaluating the effect of
thiamine in patients with sepsis reported a neutral result. Two randomized trials (N ¼ 475 and N ¼ 1360)
on the supplementation of vitamin D in the critically ill patients did not identify statistically significant
reduction in mortality.
Summary
Evidence from high-quality research is still insufficient to support the use of vitamin C, thiamine, and vitamin
D as metabolic support in sepsis treatment.
Keywords
corticosteroid, sepsis, thiamine, vitamin C, vitamin D

INTRODUCTION corticosteroids [3], prompting further trials of cor-

Sepsis is characterized as a dysregulated host
response to infection leading to life-threatening
organ dysfunction [1]. Global sepsis-related deaths
in the year 2017 were estimated to be 11 million
with a disproportionate impact in developing coun-
tries [2]. There is a clear need for effective and
affordable interventions for sepsis, with recent inter-
ests in evaluating adjunctive therapies targeting
metabolic pathways. The objectives of this review
are to summarize the findings of trials on corticoste-
roids and to provide a concise review of vitamin C,
thiamine (vitamin B1), and vitamin D administra-
tion on outcomes in patients with sepsis.
CORTICOSTEROIDS
Corticosteroids inhibit the inflammatory cascades
that contribute to the vasoplegic state characteris-
tic of sepsis. A landmark randomized clinical trial
(RCT) in 1998 reported improved vasopressor
responsiveness with supraphysiological doses of
ticosteroids administration during septic shock.
Subsequent trials have reported conflicting
results [4–6]. This uncertainty generated debate as
to the most appropriate target population, co-admin-
istration of fludrocortisone, adverse effects of corti-
costeroids, and need for exogenous corticosteroids
without co-existing use of etomidate. Recently, two
large RCTs studied patients on mechanical
a
ANZIC-RC, Department of Epidemiology and Preventive Medicine,
Monash University, Melbourne, Victoria, Australia, bHealth Promotion
and Human Behavior, School of Public Health, Kyoto University Graduate
School of Medicine, Kyoto, Japan, cThe University of Melbourne, Depart-
ment of Medicine, Royal Melbourne Hospital, Parkville, Victoria and
d
Intensive Care Services, St Vincents Health Network, Sydney, New
South Wales, Australia
Correspondence to Tomoko Fujii, MD, PhD, ANZIC-RC, Department of
Epidemiology and Preventive Medicine, Monash University, 553 St Kilda
Road, Melbourne, VIC 3004, Australia. Tel: +61 3 9905 6642;
e-mail: Tomoko.fujii@monash.edu
Curr Opin Crit Care 2020, 26:363–368
DOI:10.1097/MCC.0000000000000736

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Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.

Metabolic support
KEY POINTS
 Vitamin C, thiamine, and vitamin D have known to be
depleted in patients with critical illness.
 Two different doses of vitamin C therapy (200 mg/kg/
day, 6 g/day) have been investigated; however,
considering the lack of consistent beneficial effects in
studies at low risk of bias, we do not recommend the
routine administration of intravenous vitamin C to
patients with septic shock at the moment.
 Given the cost and a lack of randomized clinical trial
data alongside conflicting observational data with high
risk of bias, to support pharmacological administration
of thiamine to patients with septic shock without risk
factors for preexisting deficiency, we do not
recommend empiric wide-spread use of
pharmacological thiamine to patients with septic shock.
 Whilst vitamin D supplementation does not appear to
cause harm to critically ill patients with sepsis, there is
insufficient data to recommend supplementation.
ventilation with vasopressor-dependent septic shock
(APROCCHSS, N ¼ 1241, and ADRENAL, N ¼ 3800)
&& &&
[7 ,8 ]. The APROCCHSS trial compared the combi-
nation of intravenous hydrocortisone 200 mg/day
and enteral fludrocortisone 50 mg/day to placebo.
The ADRENAL trial compared intravenous hydrocor-
tisone 200 mg/day to placebo. In APROCCHSS trial,
90-day mortality was lower in the steroid group (43
vs. 49%, P ¼ 0.03), whereas, hydrocortisone did not
affect mortality in ADRENAL (27.9 vs. 28.8%,
P ¼ 0.50). However, both trials demonstrated a signif-
icant decrease in duration of vasopressor dependency
&& &&
[7 ,8 ]. A recent meta-analysis of current evidence
concluded that corticosteroids administration had
no significant effect on mortality but was associated
with shorter duration of septic shock, mechanical
ventilation, and ICU length of stay [9].
VITAMIN C
Vitamin C, or ascorbic acid, is a water-soluble vitamin
that affects the synthesis and function of endothe-
lium [10] and serves as a cellular antioxidant by
detoxifying reactive oxygen species (ROS) in cells
[11]. It also works as a co-factor for many enzymes,
including dopamine b-hydroxylase, which catalyzes
the conversion of dopamine to noradrenaline [12]
and reportedly suppresses inflammatory cascade [13].
Why vitamin C?
As humans cannot synthesize vitamin C endoge-
nously, it has to be sourced exogenously. In patients
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with sepsis or critical illness, studies have described
oxidative stress arising because of the imbalance of
the ROS production and the protection by antiox-
idants [14,15]. Furthermore, plasma vitamin C con-
centrations are frequently low in patients with
sepsis or septic shock [16–18]. In animal models
of sepsis, exogenous vitamin C improves capillary
blood flow and/or microvascular barrier function,
and arteriolar vasoconstrictor responsiveness
[19,20].
How should vitamin C be administered?
Plasma concentrations of vitamin C less than
23 mmol/l are considered diagnostic of hypovitami-
nosis [21]. In health, dietary intake of vitamin C up
to 200 mg per day is recommended [22]. When high-
dose vitamin C is ingested; plasma concentrations
are tightly controlled within normal ranges by the
efficiency of transportation at intestinal epithelium
[23]. Intravenous administration bypasses the chan-
nel in the intestine, causing supraphysiological
plasma concentrations.
Initial dosing studies suggested 3 g/day of intra-
venous vitamin C was required to achieve normal
plasma concentrations in patients with trauma or
infection [18]. More recently, a pharmacokinetic
study in critically ill patients with multiple organ
dysfunction reported that with 1 g of intravenous
vitamin C every 12 h restored plasma vitamin C
concentrations to ‘normal’ concentrations and that
10 g/day achieved supra-physiologic concentrations
[24]. In a nested cohort within a RCT, 1.5 g of
intravenous vitamin C every 6 h to patients with
septic shock was sufficient to achieve and sustain
supraphysiological plasma concentrations [25].
When or whether to treat with vitamin C?
Several recent studies have evaluated the effect of
intravenous vitamin C in patients with sepsis.
Twenty-four patients with severe sepsis were allo-
cated to receive either an intravenous infusion of
vitamin C 50 mg/kg/24 h, 200 mg/kg/24 h or pla-
cebo in a parallel-group-blinded RCT [17]. Patients
receiving either dose exhibited a greater decrease in
sequential organ failure assessment (SOFA) scores
over 96 h than those receiving placebo, and the
reduction was the greatest in patients who received
the 200 mg/kg/24 h dose [17].
Many of the same investigators recently pub-
lished a placebo-controlled, multicentre RCT of 170
patients who presented with sepsis and developed
acute respiratory distress syndrome (CITRIS-ALI)
&&
[26 ]. The investigators reported that intravenous
infusion of vitamin C (50 mg/kg every 6 h) had no
Volume 26  Number 4  August 2020

effect on modified SOFA scores at 96 h (difference,
0.10; 95% CI 1.23 to 1.03; P ¼ 0.86) or concen-
trations of C-reactive protein (difference, 7.94 mg/
mL; 95% CI 8.2 to 24.11; P ¼ 0.33) and thrombo-
modulin (difference, 0.69 ng/ml; 95% CI 2.8 to
4.2; P ¼ 0.70) at 168 h [26 ]. The authors also con-
&&
ducted analyses on 46 prespecified secondary out-
comes and identified that 28-day all-cause
mortality, ICU-free days, and hospital-free days were
reduced, at the 0.05 significance level, in patients
&&
allocated to vitamin C [26 ]. However, the thresh-
old for statistical significance when analysing 46
secondary outcomes was not adjusted for multiple
comparisons. The interpretation of multiple com-
parisons is not straightforward [27,28], and these
observations warrant further evaluation.
In 2017, a thought-provoking single-centre
before–after study assessing the combination of
high-dose intravenous vitamin C (1.5 g every 6 h),
hydrocortisone (50 mg every 6 h) and thiamine
(200 mg every 12 h) in 94 patients with severe sepsis
or septic shock. The authors reported shorter dura-
tion of vasopressor administration and markedly
reduced hospital mortality [29]. The combination
therapy warranted further evaluation, given the
dramatic effect observed in the study [30].
The rationale for this combination includes syn-
ergistic effects of vitamin C and glucocorticoids in
sepsis. Vitamin C is taken up into cells through a
transporter, SVCT2 (sodium-vitamin C cotrans-
porter 2). An in-vitro experiment reported dexa-
methasone increased the expression of SVCT2
[31], and another experiment reported the combi-
nation of hydrocortisone and vitamin C reversed
lipopolysaccharide-induced endothelial cell barrier
dysfunction, mimicking septic milieu [32]. In turn,
vitamin C reportedly reversed oxidation of the glu-
cocorticoid receptor, hence increasing the activities
of glucocorticoids [33]. Given the findings are only
from in-vitro experiments, the mechanism needs to
be further examined [34].
Thiamine was added to the combination ther-
apy based on an observation that oxalate accumu-
lated in thiamine-deficient rats because of an
increased pool of glyoxylate [35]. A part of the
accumulated glyoxylate could be oxidized to oxalate
in kidneys.
A number of RCTs were undertaken to investi-
gate the effect of the combination therapy. Given
hydrocortisone shortens the duration of vasopressor
&&
dependency in septic shock [8 ,9], a RCT was con-
ducted with hydrocortisone included in the control
&
group (VITAMINS) [36 ,37]. The VITAMINS trial
enrolled 216 patients with septic shock with the
primary outcome of time alive and vasopressor-free
up to 7 days. When compared with hydrocortisone
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Metabolic support in sepsis Fujii et al.
monotherapy, the combination of vitamin C, thia-
mine, and hydrocortisone did not affect the primary
outcome (difference, 0.6 h; 95% CI 8.3 to 7.2;
P ¼ 0.83) [38 ]. Several ongoing RCTs compare com-
&&
bination therapy to placebo or ‘usual care’. Some
beneficial effects from corticosteroids on shock res-
olution are, therefore, anticipated in the absence of
corticosteroids from the control group. Results from
those trials should be cautiously interpreted as they
may significantly overestimate the effect of vitamin
&
C [36 ].
No serious adverse events occurred in any of the
&& &&
trials [17,26 ,38 ]. Intravenous vitamin C appears
well tolerated; however, it should be noted that
those trials excluded patients who might be at risk
of oxalate nephropathy or hemolysis [39].
THIAMINE
Thiamine (vitamin B1) is a water-soluble vitamin
that must be obtained from exogenous sources [40].
Once absorbed from the small intestine, thiamine is
stored in various forms with thiamine pyrophos-
phate the active compound [41]. Well nourished
adults will store approximately 30 g of thiamine in
muscle, liver, and kidneys but, even in health, these
stores can be depleted in as little as 18 days of a
thiamine-deficient diet [42].
Why thiamine?
The predisposing factors for thiamine deficiency in
patients with septic shock are usually multifactorial
and include both preexisting risk factors, such as
alcohol use disorders, hyperemesis in pregnant
women, and risk factors during critical illness, such
as reduced nutritional intake before establishment
of enteral nutrition, impaired absorption during
enteral nutrition, and loss during renal replacement
therapy [40,43–45]. Accordingly, thiamine stores
are quickly depleted in states of severe illness
or injury.
Thiamine pyrophosphate is an essential coen-
zyme in carbohydrate metabolism, via oxidation of
pyruvate to acetyl-CoA for entry into the Krebs cycle
[41]. Inadequate thiamine pyrophosphate cofactor
reduces pyruvate dehydrogenase activity causing
pyruvate accumulation, which is converted to lac-
tate [46]. Improving metabolic pathways is the pro-
posed mechanistic benefit of thiamine treatment.
When to consider treatment with thiamine?
If pharmacological thiamine administration is to be
an effective treatment for patients with sepsis, it is
likely that benefit will be most apparent in patients
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Metabolic support
with thiamine deficiency. However, thiamine defi-
ciency during critical illness is currently a presump-
tive clinical diagnosis, as there is no point of care or
rapid laboratory-based methodology [43].
A prospective, single-centre observational study
of 58 critically ill patients reported that 23 (40%)
were thiamine deficient on admission [47]. The
investigators did not identify how many patients
had sepsis. Of interest, the investigators repeated
measuring the concentrations at 24-h intervals for
48 h and reported that thiamine concentrations did
not reduce over time [47]. A prospective cohort
study of 202 consecutively admitted children to
an ICU in Brazil reported that thiamine deficiency
was present in 61 (30%) children with septic shock
[48]. The proportion of children who were malnour-
ished at presentation was 46%, and it is uncertain
how these data relate to adult critically ill patients
from developed countries.
In an important, albeit older, prospective obser-
vational study, investigators assessed 30 patients
with septic shock and 30 control patients with
minor emergencies [49]. Six (30%) patients with
septic shock and none of those with minor emer-
gencies had thiamine deficiency [49]. Only one of
the six patients with thiamine deficiency received
thiamine during ICU admission. This observation
encouraged others to evaluate thiamine concentra-
tions in this cohort. In a single-centre cohort study
in Brazil of 108 consecutively admitted patients
with septic shock, 77 (71%) were thiamine-deficient
[50]. Sixty-eight (63%) patients died in hospital but
there was no association between thiamine concen-
trations and mortality in unadjusted or adjusted for
age and severity of illness models (hazard ratio
0.995; 95% CI 0.987–1.004) [50].
A well conducted matched cohort study of 369
patients with septic shock was recently reported [51].
In this study, 123 patients received thiamine, and 246
did not [52]. Administration of thiamine was associ-
ated with improved likelihood of lactate clearance
(hazard ratio, 1.30; 95% CI 1.00–1.70) and reduction
in 28-day mortality (hazard ratio, 0.67; 95% CI 0.49–
0.91) [51]. However, there was variability in the
amount of thiamine administered to patients such
that the authors were unable to recommend a specific
thiamine regimen. A retrospective single-center
cohort study of 53 patients with an alcohol use
disorder who presented with septic shock reported
that only 34 (64%) patients received intravenous
thiamine during hospitalization [52]. The authors
reported an extremely high mortality rate (15/19,
79%) in those who did not receive thiamine.
However, randomized clinical trial data evaluat-
ing thiamine administration during sepsis is sparse.
Donnino et al. conducted a two-centre RCT of 88
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patients with septic shock, evaluating the effect of
administration of 200 mg thiamine twice daily com-
pared with placebo for 7 days [46]. The investigators
also measured baseline thiamine concentrations via
liquid chromatography and subsequently identified
28 patients as being thiamine-deficient. Upon fur-
ther analysis, patients with thiamine deficiency who
received thiamine had markedly reduced lactate
concentrations and mortality. In a post hoc evalua-
tion, thiamine administration was associated with
improved renal function [53]. This signal supports
the hypothesis that treatment with thiamine may be
particularly efficacious if patients with thiamine
deficiency can be identified in real-time.
How to treat with thiamine?
Recent retrospective studies of patients with septic
shock suggest that thiamine administration is
uncommon, even in those with risk factors for
pre-existing thiamine deficiency [52]. The ‘average’
patient receiving liquid enteral nutrition receives
approximately 2.5 mg of thiamine per day. Pharma-
cological doses of thiamine can be administered in
the form of thiamine hydrochloride orally or intra-
venously. In most regions, oral is substantially
cheaper than intravenous preparations. However,
thiamine is absorbed from the small intestine by a
rate-limited process. The maximum amount of thi-
amine that can be absorbed from a single oral dose is
estimated to be 4.5 mg [54]. During critical illness,
the absorption of macronutrients from the small
intestine is attenuated because of down-regulation
in intestinal receptors [55]. If pharmacological thia-
mine is deemed necessary, it should be administered
intravenously at doses between 100 and 600 mg/
day.
VITAMIN D
The understanding and interest of the role of vita-
min D have now extended beyond its effects on the
musculoskeletal system and calcium metabolism
[56].
Why vitamin D?
We now know that most tissues and cells in the
body, not only bone, have a vitamin D receptor. A
number of these have the enzymatic ability to con-
vert the major circulating form 25-hydroxyvitamin
D, to the active form, 1,25-dihydroxyvitamin D
locally at tissue level. This has provided new insights
into the pleiotropic function of this vitamin.
Indeed, this has led to its characterization as a
hormone, rather than a vitamin [57].
Volume 26  Number 4  August 2020

When to consider vitamin D administration?
More recently, however, its association with and
potential contributory role during critical illness
and multiorgan failure, particularly sepsis, has been
of interest. There are suggestions that deficiency in
this vulnerable population could be relevant and
that measuring and supplementing low vitamin D
levels in critical illness may be considered, some-
thing that has not been incorporated into current
clinical practice [58]. This is because of justified
scepticism about whether deficiency is merely a
marker, rather than a contributor to ill health.
The higher prevalence in critically ill patients
may, therefore, be a result of illness severity and
consequently, of limited clinical significance.
How to treat with vitamin D?
Assays for the measurement of vitamin D levels are
more reliable than those for vitamin C and thia-
mine. However, there remains uncertainty around
how levels may vary in acute illness [59,60]. A phase
2 RCT evaluated the effects of enteral supplementa-
tion in 475 vitamin D-deficient medical and surgical
critically ill patients [61]. The primary outcome was
duration of hospital stay, and there was no signifi-
cant effect of the intervention. Whilst there was an
8% absolute difference in 6-month mortality, this
did not reach the 0.05 threshold for statistical sig-
nificance. However, there was a statistically signifi-
cant difference in mortality in severely deficient
patients. This observation prompted the ongoing
European multicentre RCT of 2400 critically ill
patients with vitamin D levels of less than 12 ng/l
looking at the effect of supplementation using a
loading dose followed by daily dosing on 28-day
all-cause mortality [62]. There is a strong inverse
association between vitamin D levels and mortality.
Therefore, the expected effects would be stronger,
and the expected power would be higher for studies
that target only patients who are vitamin D-defi-
cient [63].
A large RCT was recently published that evalu-
ated early supplementation with a single enteral
dose in 1078 vitamin D-deficient ICU patients at
high risk of death. Patients who were considered ‘at
risk’ for ARDS, who were not necessarily critically ill
were enrolled. There was no difference in 90-day
mortality or clinically important differences in any
of the secondary endpoints. The severity of defi-
ciency at baseline did not affect the association
between treatment assignment and mortality. This
study was terminated prematurely prior to the
enrolment target of 3000 patients. Also, a single
loading dose of vitamin D can achieve therapeutic
levels in critical illness; however, it has a half-life of
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Metabolic support in sepsis Fujii et al.
approximately 2 weeks. Therefore, repeat dosing
may be required to realize the benefits of supple-
&
mentation [64 ].
CONCLUSION
This review focused on corticosteroids, vitamin C,
thiamine, and vitamin D, as novel therapies targeting
different pathways in sepsis pathophysiology. The
vitamins are reportedly depleted in patients with
sepsis or critical illness, and their supplementations
are expected to help resuscitation of sepsis. However,
there is insufficient evidence from high-quality
research to support the use of vitamins currently.
We believe data from well designed RCTs of the
administration of these vitamins to determine the
benefits, cost-effectiveness and safety are required.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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Volume 26  Number 4  August 2020