SURGICAL INFECTIONS

Volume 19, Number X, 2018 Review Article

ª Mary Ann Liebert, Inc.
DOI: 10.1089/sur.2018.111

Patterns of Death in Patients with Sepsis

and the Use of Hydrocortisone, Ascorbic Acid,
and Thiamine to Prevent these Deaths

Paul E. Marik
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Abstract

Background: In general, patients with sepsis die from the host response to the infecting pathogen rather than
from the infecting pathogen itself. Four patterns of death have been identified in sepsis, namely vasoplegic
shock, single-organ respiratory failure (acute respiratory distress syndrome [ARDS]), multi-system organ
failure (MSOF), and persistent MSOF with ongoing inflammation and immunosuppression with recurrent
infections (persistent inflammation-immunosuppression and catabolism syndrome [PICS]). To improve the
outcome of sepsis adjunctive therapies that modulate the immune system have been tested; these therapies that
have targeted specific molecules or pathways have universally failed.
Conclusion: We propose that the combination of hydrocortisone, intravenous ascorbic acid, and thiamine (HAT
therapy), which synergistically targets multiple pathways, restores the dysregulated immune system and organ
injury, and reduces the risk of death and organ failure following sepsis.

Keywords: hydrocortisone; multi-system organ failure; sepsis; thiamine; vitamin C

T he global burden of sepsis is substantial with an es-

timated 32 million cases and 5.3 million deaths per year
with most of these cases occurring in low income countries
[1]. Data from the United States and Australia demonstrate
that over the last two ecades the annual incidence of sepsis
has increased by approximately 13% with a decrease in in-
hospital mortality from approximately 35% to 20% [2–4]. In
2013 more than 1.3 million patients were hospitalized in the
United States with a diagnosis of sepsis, of whom more than
300,000 died [5]. Despite the vast number of patients who die
from sepsis and our increasing understanding of the patho-
physiology of this syndrome the patterns of death in patients
with sepsis have not been well defined [6]. To improve the
outcome of this deadly disease it is important to understand
why patients with sepsis die. In this article, we propose four
patterns of death related to different but inter-related patho-
physiologic mechanisms and suggest that all four patho-
physiologic processes are influenced positively by treatment
with intravenous vitamin C (ascorbic acid), corticosteroids,
and thiamine (HAT therapy; Figs. 1 and 2). These four
phenotypic patterns are supported by clinical, immunologic,
and metabolomic data [7–9].
The first pattern is that of refractory vasoplegic septic
shock caused by a cytokine storm, leading to death within
96 hours [10,11]. The second pattern is that of death caused
by single-organ respiratory failure (acute respiratory distress
syndrome [ARDS]) resulting from the combined effects of an
exuberant proinflammatory response combined with volume
overload; death usually occurs between three and seven days
of onset [9,12,13]. The third pattern of death is from multi-
system organ failure (MSOF) caused by cellular bioenergetic
failure with cell hibernation, with death typically occurring
between four days and two weeks [9,14]. The final pattern is
one of prolonged and persistent MSOF with ongoing inflam-
mation and immunosuppression with recurrent and unresolved
infection (persistent inflammation-immunosuppression and
catabolism syndrome [PICS]) [15,16]. It is likely that the
characteristics of the pathogen (type of pathogen and mi-
crobial load) together with host factors (site of infection, age,
immune status, comorbidities, and genetic makeup) as well
as treatment factors (delay in initiating treatment, inappro-
priate antibiotic agents, fluid overload, adjunctive treatment
modalities) interact to determine the outcome and pattern of
death.

Division of Pulmonary and Critical Care Medicine, Eastern Virginia Medical School, Norfolk, Virginia.

1
 2 MARIK
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FIG. 1. The four patterns of sepsis related deaths. SIRS =
systemic inflammatory response syndrome; CARS = com-
pensatory anti-inflammatory response syndrome; MSOF =
multi-system organ failure; PICS = persistent inflammation-
immunosuppression and catabolism syndrome.
A limited number of studies have evaluated the causes of
death in patients with sepsis. Vincent et al. [7] analyzed the
cause of death in 4,459 patients with severe sepsis. In this
study, 27% of patients died during the 28-day study period.
Twenty-two percent of patients died of refractory septic
shock, 13% from respiratory failure, and 43% died from
MSOF. Frencken et al. [17] studied the patterns of death
among 708 patients with severe sepsis and septic shock ad-
mitted to two Dutch intensive care units (ICUs). The one-year
mortality was 53.8% with 12% of patients dying within four
days of admission, 20% between days four and 28, and 22%
between day 29 and one year. Weiss et al. [18] evaluated the
patterns of death in pediatric sepsis. The median time to death
was eight days. The most common cause of death was re-
fractory shock (34%), followed by MSOF (27%) and single-
organ respiratory failure (9%). Early deaths (£3 d) were
mostly caused by refractory septic shock whereas MSOF
predominated after three days.
FIG. 2. Treatment with hydrocortisone, ascorbic acid, and
thiamine (HAT therapy) attenuates both the pro- and anti-
inflammatory response in patients with sepsis.
Synergistic Anti-Inflammatory Properties
of HAT Therapy
Sepsis is fundamentally an inflammatory disease medi-
ated by the activation of the innate immune system by
both pathogen-associated molecular patterns (PAMPs) and
damage-associated molecular patterns (DAMPs). Calvano
et al. [19] demonstrated that exposure of blood leukocytes to
endotoxin altered the expression of 3,714 genes. These in-
clude genes for pro- and anti-inflammatory cytokines, che-
mokines, adhesion molecules, transcription factors, enzymes,
clotting factors, stress proteins, and anti-apoptotic molecules
[20]. The excess production of proinflammatory mediators
plays an important role in four pathogenetic mechanism
leading to death in patients with sepsis. We believe that HAT
therapy has potent anti-inflammatory properties that under-
lies the benefit of this treatment in patients with sepsis.
Vitamin C suppresses activation of nuclear factor kappa-B
(NF-kB) by inhibiting tumor necrosis factor-a (TNF-a)–
induced phosphorylation of inhibitory kappa-B kinase (IkB
kinase) [21]. The primary anti-inflammatory action of gluco-
corticoids is to repress the transcriptional activity of NF-kB and
activator protein-1 (AP-1). Nuclear factor kappa-B and AP-1
increase the transcription of multiple proinflammatory media-
tors that contribute to the generation of reactive oxygen species
(ROS), cellular injury, coagulation activation, and the endo-
thelial and microvascular dysfunction characteristic of sepsis.
Ascorbic acid decreases high mobility group box 1 (HMGB1)
secretion [22]; HMGB1 is an important late proinflammatory
cytokine. Histamine has been shown to play an important role
in sepsis [23]. Vitamin C has been demonstrated to decrease the
synthesis and to inactivate histamine [24].
Sepsis is characterized by the excessive production of ROS
by the induction of enzymes such as nicotinamide adenine
dinucleotide phosphate-oxidase (NOX) and the uncoupling
of mitochondrial oxidative phosphorylation and iNOS [25].
In addition, ROS are produced by xanthine oxidase, lipox-
ygenase, and cyclo-oxygenase. When the antioxidant de-
fenses are overwhelmed, ROS can induce injury to lipids,
proteins, and nucleic acids thereby resulting in widespread
endothelial dysfunction, mitochondrial dysfunction, cellular
injury, and multiple organ dysfunction. Unopposed ROS
oxidizes tetrahydrobiopterin (BH4), the cofactor of endo-
thelial nitric oxide synthase (eNOS), and thereby reduces
eNOS activity, the enzyme producing endothelial nitric oxide
[25]. Endothelial nitric oxide (eNO) maintains microcircu-
latory flow and inhibits platelet aggregation and adhesion of
activated platelets and leukocytes. In the absence of BH4,
eNOS becomes uncoupled, producing superoxide (O2-) ra-
ther than nitric oxide (NO). Superoxide (O2-) and NO yield
peroxynitrite, a more damaging ROS. Vitamin C is a key
cellular antioxidant, detoxifying exogenous oxidant radical
species that have entered cells or that have arisen within cells
because of excess O2-generation by mitochondrial metabolism,
by NOX, xanthine oxidase, or by uncoupled nitric oxide syn-
thase (NOS) [25,26]. In addition, vitamin C recycles other an-
tioxidants including a-tocopherol (vitamin E) and BH4.
Tetrahydrobiopterin plays a critical role in the function of eNOS.
Vitamin C deficiency results in the incomplete regeneration of
BH4 resulting in the uncoupling of eNOS and the generation of
superoxide and peroxynitrite.[25] Thiamine may act together
with vitamin C to decrease oxidative injury [27,28].
 HAT THERAPY AND SEPSIS
We propose that HAT therapy may have synergistic anti-
inflammatory and anti-oxidative properties thereby modu-
lating the proinflammatory response of sepsis. This postulate
is supported by experimental studies. Barabutis et al. [29].
have demonstrated that hydrocortisone together with vitamin C
protects the vascular endothelium from damage by endotoxin
while neither agent alone had this effect. Azari et al. [30]
compared the protective effects of vitamin C, vitamin E, and
hydrocortisone alone and in combination, in a renal and in-
testinal ischemia-reperfusion model [31]. In these studies
both vitamin C and hydrocortisone reduced the ischemia-
reperfusion injury with the combination having synergistic
protective effects. Many interventions in critically ill patients
are time sensitive; the use of antibiotic agents and source
control in patients with sepsis are examples in which a delay
in the initiation of therapy may adversely affect outcomes
[32,33]. Similarly, it is likely the benefits of HAT therapy
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may diminish with delays in administration. It is important to
emphasize that early initiation of HAT therapy is critical to a
good outcome as the pathologic processes leading to organ
failure become less reversible with time. Furthermore, it is
likely that fluid overload with an aggressive approach to fluid
resuscitation attenuates the benefit of HAT treatment [34–36].
Refractory Vasoplegic Shock and the Cytokine Storm
The early phase of sepsis is generally believed to result
from the uncontrolled production of proinflammatory medi-
ators, the so-called cytokine storm, which may lead to re-
fractory vasoplegic shock [37,38]. The early proinflammatory
response to bacteremic shock can be reproduced by admin-
istration of proinflammatory cytokines [39–41]. Using ad-
vanced informatics techniques from sepsis transcriptomic
datasets, Sweeney et al. [8] identified three functional tran-
scriptomic subtypes that they termed ‘‘inflammopathic,
adaptive, and coagulopathic.’’ The inflammopathic subtype
was characterized by overactivation of the innate immune
system with increased expression of proinflammatory sig-
naling pathways, pattern recognition receptor activity, and
complement activation. Clinical features of this subtype in-
cluded a high disease severity with shock, high bandemia, and
high mortality. Although the early systemic inflammatory
response has been considered the hallmark of sepsis, immu-
nosuppression occurs both early and late in the host sepsis
response.
Refractory vasodilatory shock develops from uncontrolled
vasodilation and vascular hyporesponsiveness to endogenous
vasoconstrictors, causing failure of physiologic vasor-
egulatory mechanisms [11]. Vasoplegic shock results from
failure of the vascular smooth muscle to constrict with pro-
found arterial and venodilatation [10]. Vasoplegic shock is
believed to be caused by the massive production of proin-
flammatory cytokines with increased expression of inducible
nitric oxide synthetase with increased production of nitric
oxide (NO), activation of KATP channels resulting in hyper-
polarization of the muscle cell membrane, increased pro-
duction of natriuretic peptides (which act synergistically with
NO), and a relative vasopressin deficiency [10]. These factors
lead to profound vasodilation with hypotension and vaso-
pressor resistance. This hemodynamic pattern is complicated
by decreased contractility with decreased myocardial per-
formance and diastolic dysfunction [42].
3
Prevention of vasoplegic shock with HAT therapy
Vitamin C and hydrocortisone act via multiple mechanism
to reverse vasoplegic shock and restore organ perfusion. Both
molecules suppress activation of NF-kB; NF-kB increase
the transcription of multiple proinflammatory mediators
responsible for the cytokine storm [21]. Vitamin C is an
essential cofactor for the synthesis of norepinephrine,
epinephrine, and vasopressin; in addition, vitamin C in-
creases adrenergic transmission [43]. In a murine cecal li-
gation and puncture (CLP) model, prophylactic bolus
injection of vitamin C attenuated the loss of arteriolar and
blood pressure responsiveness to the vasoconstrictors nor-
epinephrine and angiotensin [44–46]. Glucocorticoids are
potent anti-inflammatory agents that suppress inflammation
by multiple mechanisms that involve both the innate and
adaptive immune responses. In addition to attenuating the
cytokine storm, low-dose glucocorticoids have immune-
stimulating effects that may limit the anti-inflammatory im-
munosuppressive state. In addition, glucocorticoids have
additional beneficial effects including increasing adrenergic
responsiveness [47] and preserving the endothelial glycoca-
lyx [48]. Based on the overlapping beneficial effects of
vitamin C and glucocorticoids in experimental models of
sepsis [49,50], we have postulated that these two agents may
act synergistically to reverse vasoplegic shock [51,52]. In a
retrospective before and after study we have demonstrated
that HAT therapy rapidly reserves vasoplegic shock with a
reduction in the dose of vasopressors within two hours of the
initiation of treatment with vasopressor independence within
24 hours [52].
Acute Respiratory Distress Syndrome
According to the Berlin Definition, ARDS is defined as an
‘‘acute diffuse, inflammatory lung injury, leading to in-
creased pulmonary vascular permeability, increased lung
weight, and loss of aerated lung tissue with hypoxemia and
bilateral radiographic opacities’’ [53]. Sepsis is the most
common cause of ARDS [54] and results from intra-alveolar
macrophage activation with elaboration of a diverse array of
bioactive mediators including proteases, ROS, cytokines, and
chemokines [13]. Because ARDS is caused by the excess
production of proinflammatory mediators, HAT therapy
rapidly reverses the pathogenic mechanism of ARDS [52,55].
Multi-System Organ Failure
Multi-system organ failure is the most common cause of
death in patients with sepsis. These patients usually develop
progressive and irreversible organ failure requiring the in-
creasing use of advanced life support measures. Because of
the high burden of ongoing treatment with the extremely
grave prognosis families will often elected to limit care al-
lowing for a more peaceful death.
What is the mechanism of MSOF in sepsis? The prevailing
theory suggests that MSOF results from impaired oxygen
delivery at the cellular level because of altered microcircu-
latory blood flow [56,57]. Although global oxygen delivery is
typically increased in sepsis, proponents of this theory sug-
gest that many tissue capillary beds do not receive adequate
oxygen supplies because of microvascular endothelial dys-
function. However, there are few data that tissue hypoxia
 4 MARIK
occurs in patients with sepsis. Multiple experimental models
have failed to demonstrate cellular hypoxia in sepsis [58–61].
Increasing oxygen delivery in patients with sepsis does not
increase oxygen consumption [62–64]. A number of ran-
domized controlled trials have failed to demonstrate an im-
provement in outcome in patients with sepsis who received
therapy that aimed to increase oxygen delivery compared with
those who received conventional therapy [65–67]. These
studies suggest that microcirculatory impairment with shunting
and maldistribution of blood flow are unlikely to be central to
the pathophysiology of sepsis-induced organ failure.
Metabolic failure as a cause of sepsis-related MOSF
In patients with sepsis who die of MSOF histopathologic
examination of the heart, liver, and kidneys have failed to
demonstrate necrotic or apoptotic cell death [68,69]. Takasu
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et al. [69] performed rapid postmortem cardiac and renal
harvest in 44 patients with sepsis and compared the immu-
nohistochemistry features with those of control organs. Im-
munohistochemistry demonstrated low levels of apoptotic
cardiomyocytes in septic and control subjects, however,
electron microscopy showed hydropic mitochondria in the
septic specimens. It is noteworthy that per milligram of tis-
sue, the heart and kidney consume the most oxygen and
possess the greatest abundance of mitochondria [70]. The
authors of these studies have concluded that the degree of cell
injury and death does not account for severity of sepsis-
induced organ dysfunction. Similarly, animal models have
failed to reveal widespread cell death in sepsis despite pro-
gressive organ failure [71]. To explain these findings
Hotchkiss et al. [72] have suggested that these features are
consistent with cell stunning or hibernation and that these
changes may represent a short-term adaptive response.
Multiple defects in mitochondrial function have been de-
scribed in animal models and patients with sepsis. These
include abnormal autophagy, decreased biogenesis (mito-
chondrial numbers), decreased activity of the components of
the electron transport chain (particularly complex I), and
uncoupling of oxidation phosphorylation [73–80]. Altera-
tions in fatty acid metabolism with decreased b-oxidation and
abnormalities of the citric acid cycle appear to be a charac-
teristic feature of the mitochondrial dysfunction in sepsis
[81,82]. These changes lead to decreased adenosine tri-
phosphate (ATP) production. Furthermore, damaged mito-
chondria undergo mitophagy, i.e., autophagy directed at the
removal of damaged mitochondria [83,84]. Matkovich et al.
[85] measured messenger RNA (mRNA) alterations in hearts
from patients who died from sepsis and compared these with
mRNA expression in non-failing and failing human hearts. In
this study, mRNA expression levels for 198 mitochondrially
localized energy production components, including Krebs
cycle and electron transport genes, were reduced on average
by 43%. Except for mitochondrial isocitrate dehydrogenase,
all of the other 19 genes involved in the tricarboxylic acid
(TCA) cycle were decreased. In a sepsis model, Arulkumaran
et al. [61] demonstrated that sepsis-induced renal dysfunction
was associated with reduced nicotinamide adenine dinucle-
otide (NADH) and mitochondrial membrane potential
(MMP) with increased renal ROS production. In this study,
4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl, a free rad-
ical scavenger was protective against renal tubule injury. It is
likely that the unbalanced production of mitochondrial re-
active oxygen species (mtROS) impairs mitochondrial
structure, enzymatic function and biogenesis and play a role
in the mitochondrial dysfunction of sepsis. These data sug-
gest that the bioenergetic failure in sepsis leads to organ
failure particularly in those organs with a high metabolic
demand and high mitochondrial concentration [79–84,86].
The bioenergetic failure does not lead to widespread cell
necrosis or apoptosis but rather a state of cellular hibernation
[72]. Furthermore, the mitochondrial oxidative injury re-
leases mitochondrial DNA (mtDNA), which amplifies the
inflammatory injury leading to further immune paresis and
PICS syndrome [87].
Prevention of MSOF with HAT treatment
Critically ill patients with sepsis typically have low or
undetectable serum levels of vitamin C resulting in an acute
scorbutic condition [52,88–90]. Recently Carr et al. [91]
demonstrated that 100% of patients with sepsis had low
vitamin C levels. Low plasma concentrations are associated
with the severity of organ failure and mortality [89]. Fur-
thermore, low vitamin C levels have been demonstrated to be
predictive of the development of MSOF [90].
The overlapping anti-inflammatory properties of gluco-
corticoids and vitamin C reduce the production of proin-
flammatory mediators and ROS, which are linked to the
development of MSOF. In experimental models, parenteral
vitamin C attenuates organ injury and improves survival in
mice with sepsis [92–94]. Dehydroascorbic acid is trans-
ported via the GLUT1 transporter into mitochondria, where it
converted to ascorbic acid and acts as a potent antioxidant
limiting mitochondrial oxidant injury [95,96]. In an experi-
mental model, Dhar-Mascareno et al. [97] demonstrated that
oxidant-induced mitochondrial damage and apoptosis in
human endothelial cells were inhibited by vitamin C. Studies
using N-acetylcysteine have proven to be ineffective and
potentially harmful in patients with sepsis possibly because
of the limited ability of this drug to enter into the mito-
chondria and its inability to regenerate BH4 [25,98,99]. As-
corbic acid is required for the synthesis of carnitine, which is
required for the transport of fatty acids into the mitochondrial
matrix and for b-oxidation [81,95].
Thiamine is the precursor of thiamine pyrophosphate, the
essential coenzyme of several decarboxylases required for
glucose metabolism, the Krebs cycle, the generation of ATP,
the pentose phosphate pathway, and the production of
NADPH. Thiamine pyrophosphate (TPP) is a critical coen-
zyme for the pyruvate dehydrogenase complex, the rate-
limiting step in the citric acid cycle. Thiamine deficiency is
common among patients with sepsis, with a range in preva-
lence between 20% and 70%, depending on measurement
techniques and inclusion criteria [100–105]. A deficiency in
thiamine leads to decreased activity of thiamine-dependent
enzymes that triggers a sequence of metabolic events leading
to energy compromise and decreased ATP production. It is
likely that thiamine deficiency compounds the mitochondrial
injury and bioenergetic failure caused by vitamin C deple-
tion. In a pilot randomized controlled trial, Donnino et al.
[105] randomly assigned 88 patients with septic shock to
receive 200 mg thiamine twice daily for seven days. In the
pre-defined subgroup of patients with thiamine deficiency,
 HAT THERAPY AND SEPSIS
those in the thiamine treatment group had statistically sig-
nificantly lower lactate levels at 24 hours and a lower mor-
tality at 30 days. Furthermore, in a secondary analysis of this
study the need for renal replacement therapy and the serum
creatinine were greater in the placebo group [106]. The ob-
servation that thiamine was reno-protective is an important
observation considering the high metabolic demand of the
kidney and the postulated role of thiamine in improving en-
ergy metabolism. This finding is all the more important be-
cause correction of mean arterial pressure and macrovascular
blood flow is not restorative in septic acute kidney injury
(AKI), and supports of the concept that mitochondrial dys-
function and injury may be a critical feature of septic AKI [84].
Several studies suggest that vitamin C alone and when
combined with glucocorticoids and thiamine reduce the risk
of MSOF. Nathens et al. [107] randomly assigned 595 sur-
gical intensive care (ICU) patients to receive intravenous
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vitamin C and vitamin E for up to 28 days. The vitamin
combination was associated with a significant reduction in the
incidence of MSOF (p = 0.04). The Sepsis-Related Organ
Failure Assessment (SOFA) score has been used to quantify
the severity of organ dysfunction in patients with sepsis [14]. In
a pilot study of 24 patients with severe sepsis and septic shock,
Fowler et al. [88] demonstrated a significant decrease in the
SOFA score in patients randomly assigned to receive intrave-
nous vitamin C. Similarly in our observational study in which
we compared treatment with HAT therapy versus standard
treatment, we demonstrated a rapid decrease in the SOFA score
in patients who received HAT therapy (Fig. 3) [52].
Persistent Inflammation-Immunosuppression
and Catabolism Syndrome
Patients with MSOF who survive the first two weeks of
sepsis often have a protracted clinical trajectory and exhibit
FIG. 3. Time course of the Sepsis-Related Organ Failure
Assessment (SOFA) score over the four-day treatment pe-
riod in the treatment group and in the control group survi-
vors and non-survivors. *p < 0.001 for comparison of
treatment group vs control group. (Reproduced with per-
mission from Marik PE, Khangoora V, Rivera R, et al.
Hydrocortisone, vitamin C and thiamine for the treatment of
severe sepsis and septic shock: A retrospective before-after
study. Chest 2017;151:1229–1238).
5
both chronic immune suppression and inflammation. This
syndrome has been termed the persistent inflammation/
immunosuppression and catabolism syndrome (PICS) [15,108].
This persistent inflammation is characterized by increased
concentration of plasma interleukin (IL)-6, a persistent acute
phase response, neutrophilia, with increased immature
granulocyte count, anemia, lymphopenia, and, often, tachy-
cardia [108]. Although these patients are profoundly im-
munosuppressed, inflammation is ongoing. While the exact
pathophysiology of PICS syndrome is unclear, PICS is prob-
ably driven by DAMPs and alarmins that are produced by
injured organs and tissues, such as mtDNA, nucleosides, his-
tones, HMGB1, protein S100A, ATP, adenosine and/or hya-
luronan products. The paradoxical immunosuppression and
infectious complications in patients with sepsis compound as
sepsis progresses, with a shift to infection by opportunistic
organisms. Torgersen et al. [16] studied both clinical and
postmortem records of patients (n = 235) who died from sepsis
or septic shock in their institution over a period of 10 years.
Multiple organ dysfunction syndrome (MODS) was consid-
ered the main cause of death in 52% of patients. An unresolved
infectious focus was present at autopsy in 77% of patients.
Moreover, 90% of the patients with prolonged intensive care
exceeding seven days had persistent infectious foci.
Prevention of PICS with HAT therapy
The use of HAT therapy reduces the proinflammatory re-
sponse and the development of MSOF and as such limits
progression to PICS syndrome. Moreover, HAT therapy
specifically decreases the immunosuppression associated
with sepsis. It has been known for more than 60 years that
vitamin C has immune-enhancing properties. In 1949. Fred
Klenner from Reidsville, North Carolina, reported on the use
of intravenous vitamin C in the treatment of polio and other
viral illnesses [109]. It was initially assumed that vitamin C
was directly viricidal (in vivo) and this mistaken belief un-
derlies the recommendations of Linus Pauling who promoted
the use of large doses of oral vitamin C (up to 18 g/d) for the
prevention and treatment of the common cold [110]. How-
ever, a number of randomized controlled trials have reported
that vitamin C supplementation had no effect on the inci-
dence of the common cold [111]. Whereas high-dose vitamin C
has in vitro viricidal properties [112,113], there are no data or
physiologic rationale to suggest that this occurs in vivo.
Rather, the anti-viral effects of vitamin C are likely because
vitamin C has specific immune-enhancing effects. Vitamin C
is concentrated in leucocytes, lymphocytes, and macro-
phages, reaching high concentrations in these cells [114].
Vitamin C improves chemotaxis, enhances neutrophil
phagocytic capacity and oxidative killing, stimulates inter-
feron production, and supports lymphocyte proliferation
[115–117]. In addition, vitamin C has been demonstrated to
attenuate the formation of neutrophil-extracellular-traps
(NETs) [94,118]. Vitamin C stimulates dendritic cells to
secrete IL-12 and thereby drive naı̈ve CD4+ T cells to dif-
ferentiate into TH1 cells [118]. Vitamin C improves the
generation of NK-cell progenitors from T/NK-cell progeni-
tors [119]. Vitamin C promotes T-cell maturation, possibly
by epigenetic mechanisms [120]. In a CLP sepsis model, Gao
et al. [121] demonstrated that parenteral vitamin C improved
the outcome of sepsis and sepsis-induced MODS in wild-type
 6 MARIK
as well as Gulo-/- mice. In this study negative immuno-
regulation by CD4+CD25+ regulatory T cells (Tregs) and the
secretion of inhibitory cytokines (TGF-b and IL-10) were
inhibited and T-cell–mediated immunosuppression was im-
proved in those mice treated with vitamin C.
Many physicians are reluctant to prescribe a short course
of low-dose glucocorticoid on the basis that these drugs in-
crease the risk of infections. The prolonged (>10 d) use of
moderate- to high-dose glucocorticoids (>400 mg hydrocor-
tisone per day) is well known to increase the risk of oppor-
tunistic infections. In a landmark study, Keh et al. [122]
performed a randomized, cross-over study that evaluated the
clinical and immunologic effects of low-dose glucocorticoids
in patients with septic shock. These investigators demon-
strated that hydrocortisone simultaneously decreased circu-
lating levels of both pro- and anti-inflammatory cytokines.
Hydrocortisone downregulated the proinflammatory immune
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response but did not inhibit the TH1-related response and
concentrations of IL-12 and interferon-g were not sup-
pressed. Paradoxically, by enhancing macrophage function
and the innate immune system and blunting the anti-
inflammatory response short-term glucocorticoids may re-
duce the risk of infection and the development of PICS
syndrome (Fig. 2). Roquilly et al. [123] randomly assigned
149 multi-trauma patients to receive a continuous infusion of
hydrocortisone (200 mg/d for 5 d) or placebo (the HYPO-
LYTE Study). The primary end point of this study was
hospital-acquired pneumonia within 28 days. In the intention
to treat analysis, 35% of the patients treated with hydrocor-
tisone and 51% of those treated with placebo developed
pneumonia (p = 0.007). In the three recent large randomized
controlled trials, low-dose short-duration treatment with
glucocorticoids was not associated with an increased risk of
secondary infections [124–126]. These data suggest that the
combination of vitamin C and low-dose glucocorticoids may
simultaneously and synergistically blunt both the excessive
proinflammatory and immunosuppression response charac-
teristic of sepsis and thereby prevent PICS syndrome.
Conclusions
The major pathogenetic mechanisms whereby patients with
sepsis die include refractory vasodilatory shock, ARDS,
MSOF, and PICS syndrome. Because of their overlapping and
synergistic immunomodulating effects, HAT therapy may re-
store the dysregulated immune system and thereby prevent or
limit vasoplegic shock, ARDS, and the bioenergetic failure that
characterizes sepsis and reduce the risk of death.
Author Disclosure Statement
The author has no real or potential conflicts of interest
concerning this manuscript.
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Address for correspondence:
Dr. Paul E. Marik
Division of Pulmonary and Critical Care Medicine
Eastern Virginia Medical School
825 Fairfax Avenue, Suite 410
Norfolk, VA 23517
E-mail: marikpe@evms.edu