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American Journal of  Medical 
Science and Innovation (AJMSI) 

Systematic Review: Impact of  Vitamin C, Hydrocortisone, and Thiamine Therapy on 
Sepsis and Septic Shock Patients

Manal Rashid Al-Khaldi1*

Volume 2 Issue 2, Year 2023
ISSN: 2836-8509 (Online)

DOI: https://doi.org/10.54536/ajmsi.v2i2.1938
https://journals.e-palli.com/home/index.php/ajmsi

Article Information ABSTRACT

Received: July 17, 2023
Accepted: August 21, 2023
Published: September 06, 2023

Systematic Inflammatory Response Syndrome and Sepsis are inflammatory responses to 
many health manifestations. Sepsis mortality is high despite global treatment standards, with 
metabolic resuscitation being a novel approach for managing Sepsis. The purpose of  this 
systematic review is to assess the effectiveness of  the critical care combination comprising 
hydrocortisone, Vitamin C, and thiamine in potentially mitigating Sepsis, reducing mortality 
associated with septic shock, and alleviating organ failure. In order to execute this scoping 
review, recent research based on the effect of  vitamin C, hydrocortisone, and thiamine 
therapy in Sepsis and Septic Shock was identified. Data was gathered from Google Scholar, 
PubMed, NCBI, Hindawi, Scirp, Journal of  Immunology, and Critical Care Medicine. Studies 
selected from different years ranging between 2017 to 2023 using keywords ‘Severe Sepsis,’ 
‘Septic Shock,’ ‘Effect of  Vitamin C on Sepsis, ‘Effect of  Thiamine on Sepsis Treatment,’ 
‘Hydrocortisone Therapy in Sepsis,’ ‘SIRS,’ ‘Septic Shock Criteria.’ Access was made to the 
whole texts of  the articles that were found. This review could provide fundamental strategic 
plans dealing with specific risk factors and managing accordingly. The systemic review 
has been completed according to the guidelines regulated by Preferred Reporting Items 
for Systemic Research and Meta-Analysis. The initial search for publications on vitamin 
C, hydrocortisone, and thiamine in Sepsis and septic shock retrieved 1710 papers, from 
which 265 were selected. The reviews’ articles were further evaluated to assess vitamin C, 
hydrocortisone, and thiamine’s effects on Sepsis. Over 80 references were considered for 
their potential use in medical diagnosis and therapy. This review has included ten recent 
articles for the last seven years. Intravenous vitamin C, corticosteroids, hydrocortisone, and 
thiamine prevent organ failure, reduce vasopressor use, and decrease mortality in severe 
Sepsis and septic shock patients.  

Keywords
Septic Shock, 
Immunomodulatory Therapy, 
Innate Immune Response

1 King Hamad University Hospital: Muharraq, Bahrain, BH, Bahrain
* Corresponding author’s e-mail: manalrashid268@outlook.com

INTRODUCTION
Systematic Inflammatory Response Syndrome (SIRS) is 
an inflammatory response to various clinical disorders. 
(Davies & Hagen, 1997) The intensity of  SIRS impacts 
the host’s susceptibility to infection through the innate 
immune system. (Robertson & Coopersmith, 2006; J. 
Wang et al., 2023) The innate immune response can be 
defined as the first line of  defense against a microbial 
intruder and characterized as a non-specific response that 
takes only a few minutes to activate. Pathogen-Associated 
Molecular Patterns (PAMPS) were recognized via Pattern 
Recognition Receptors (PRRs) prevalent in innate cell 
types, including neutrophils and macrophages. (Beutler et 
al., 2004) The adaptive immune system is more effective 
than the innate immune system in protecting the host 
from various microorganisms. (Davies & Hagen, 1997) 
Similarly, Systematic inflammatory response syndrome 
is a body’s defence response to a noxious stressor 
(infection, trauma, surgery, acute inflammation, ischemia 
or reperfusion, or malignancy) (Chakraborty & Burns, 
2019; Nyström, 1998) to localize and then eliminate 
the exogenous and endogenous source of  insult. 
(Chakraborty & Burns, 2019) Furthermore, SIRS can be 
diagnosed by observing abnormalities such as heart rate, 

temperature, respiratory rate, and white blood cell (WBC) 
count. (Davies & Hagen, 1997) 
Moreover, SIRS is a multifaceted condition, classified 
into two primary categories: Sepsis and non-infectious 
inflammation. (Davies & Hagen, 1997) SIRS, when 
associated with infection, can progress to Sepsis. The 
term ‘Sepsis’ encompasses a range of  conditions (Lever 
& Mackenzie, 2007), all stemming from the intrusion of  
microbial agents from a local infectious source into the 
bloodstream. (Henriquez-Camacho & Losa, 2014) These 
conditions can manifest with mild signs and symptoms 
of  systemic infection, including traditional indicators 
like fever, tachycardia, tachypnea, and leukocytosis. 
(Nyström, 1998) In more severe cases, they can lead to 
shock and organ dysfunction. (Henriquez-Camacho 
& Losa, 2014; Lever & Mackenzie, 2007) In addition, 
the pathophysiology of  Sepsis primarily results from 
the host’s innate immune system response (Lever & 
Mackenzie, 2007), and SIRS occurs at an exceptionally 
elevated rate. 
Numerous research indicated that one-third of  patients 
admitted to ICU (Intensive Care Unit) suffer from 
SIRS. (Brun-Buisson, 2000) Hemodynamic instability 
despite intravascular volume resuscitation is referred to 



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as Septic shock, while severe Sepsis is defined as Sepsis 
accompanied by one or more instances of  end-organ 
failure. (Chakraborty & Burns, 2019) These conditions 
illustrate a physiological continuum marked by an 
imbalance between the body’s pro and anti-inflammatory 
responses. Consequently, for immune-compromised 
septic patients meeting two or more Sequential Organ 
Failure Assessment (SOFA) SIRS criteria, the term 

Multiple Organ Dysfunction (MOD) is applied, 
signifying altered organ function. (Kaukonen et al., 2015; 
Nyström, 1998) This definition was established during a 
sepsis definitions consensus conference sponsored by the 
American College of  Chest Physicians and the Society 
of  Critical Care Medicine. (Chakraborty & Burns, 2019; 
Suárez-de-la-Rica et al., 2023)
The execution of  any two of  the following conditions 

Figure 1: Showing the symptoms of  Sepsis

Figure 2: Showing the stages of  Sepsis

constitutes the objective measurement of  SIRS 
(Chakraborty & Burns, 2019) SIRS with a source of  
infection:

• Above 38 or below 36 degrees Celsius for body 
temperature.

• Heart beats per minute greater than 90.
• Respiration more than 20 times per minute or Partial 

CO2 pressure under 32 mmHg.
• Over 10% immature forms or bands, Leukocyte 

Count/White Blood Cells (WBC) greater than 12000, or 

fewer than 4000/microliter. (Chakraborty & Burns, 2019)
Severe sepsis criteria (Hypotension, Hypo perfusion, 

and Organ Dysfunction): (Herzum & Renz, 2008; B. 
Liang et al., 2023)

• Lactic acidosis, SBP greater than 90 or SBP lesser 
than or equal to 40 mmHg of  normal.

Septic Shock Criteria
• Hypotension with severe Sepsis despite receiving 

enough fluid support.



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MODS Criteria
• Indications of  less than or equal to two organ failures. 

(Herzum & Renz, 2008)
The level of  organ system damage can be measured using 
a variety of  measures. (Chakraborty & Burns, 2019) A 
few examples include the Multiple Organ Dysfunction 
(MOD) (Chakraborty & Burns, 2019) scores, Sequential 
Organ Failure Assessment (SOFA), Acute Physiology and 
Chronic Health Evaluation (APACHE) score versions II 
and III, and Logistic Organ Dysfunction (LOD) score. 
(Chakraborty & Burns, 2019)

LITERATURE REVIEW
Epidemiology of  Septic Syndrome
Sepsis is a significant public health concern, with Septic 
syndrome being the leading cause of  mortality in the 
United States. (Giamarellos-Bourboulis, 2008) Globally, it 
affects many individuals annually, with estimates ranging 
from 15 to 19 million cases. (Litwak et al., 2019; Marik et 
al., 2017; K. Wang et al., 2023) 

Treatment Options for SIRS, Severe Sepsis, and 
Septic Shock
SIRS, Severe Sepsis, and Septic Shock are severe disease 
states that require effective treatment strategies. One 
therapeutic approach involves the administration of  
Vitamin C, Hydrocortisone, and Thiamine (Vitamin 
B1). (Sprung et al., 2008) Studies have suggested a 
regimen of  these agents administered every six to twelve 
hours for patients with severe Sepsis and septic shock, 
demonstrating potential mortality benefits. (Litwak et al., 
2019; Marik et al., 2017) 

Depletion of  Vitamin C in Sepsis
Research has indicated that Sepsis can lead to a depletion 
of  Vitamin C, an essential cofactor for producing 
catecholamines and cortisol, hormones critical for shock 
survival. (Balakrishnan et al., 2018)  Studies have explored 
the safety and efficacy of  Vitamin C supplementation 
to counteract this depletion, with doses as high as 6g 
reported to be safe and without adverse side effects. 
(Balakrishnan et al., 2018)  

Metabolic Resuscitation as an Effective Treatment 
Option
To mitigate the adverse effects of  high-dose Vitamin 
C intake, intravenous thiamine has been administered 
alongside hydrocortisone to enhance endogenous 
catecholamine synthesis. (Balakrishnan et al., 2018) 
This combination of  metabolic resuscitation has been 
investigated and found to be an effective adjuvant 
treatment for septic shock and Sepsis (Fujii et al., 2022), 
emerging as a viable therapeutic option.(Kuhn et al., 2018; 
Shi & Tie, 2020).

Immunomodulatory Therapies for Sepsis: Efficacy 
and Mechanisms
Patients with Sepsis treated with high doses of  vitamin 

C, hydrocortisone, and thiamine discovered a substantial 
reduction in mortality and improved disease prevention. 
(Balakrishnan et al., 2018; Mohamed et al., 2023; Shi & Tie, 
2020) Ascorbic acid, or vitamin C, is an anti-inflammatory 
and cellular anti-oxidant. (Fujii et al., 2019) Water-soluble 
vitamin C produces cortisol, catecholamines, and 
vasopressin, essential disease-process mediators. Because 
of  its antioxidant characteristics, vitamin C also helps 
reduce inflammation. Emerging findings support the use 
of  vitamin C in addition to standard therapy for patients 
with Sepsis and septic shock to decrease inflammation 
and improve hemodynamic stability (Teng et al., 2018). 
Another study (Sprung et al., 2008) demonstrated that 
patients with septic shock frequently utilize hydrocortisone 
(Sprung et al., 2008), which decreases infection resistance 
by reducing inflammation. (Suffredini, 2018).
Additionally, having anti-endo-toxic and antipyretic 
properties, corticosteroids and hydrocortisone have been 
demonstrated to affect vascular reactivity in a way that 
may be advantageous to the infected person. (Suffredini, 
2018)  Moreover, another study stated the beneficial 
effect of  thiamine as therapy for Sepsis. (Moskowitz 
& Donnino, 2020) The study estimated the correlation 
between thiamine, rapid lactate clearance, and lower 
mortality. (Moskowitz & Donnino, 2020) Nevertheless, 
these immunomodulatory therapies showed significance 
for Sepsis, effectively lowering the mortality risk and 
treating this infection’s symptoms. (Vincent et al., 2002)
This scoping review aims to assess the association 
between Vitamin C, Thiamin, and Hydrocortisone effect 
as a therapy for Sepsis and Septic Shock. This unique 
association has not been addressed earlier in the scientific 
literature. It suggests a novel approach to metabolic 
resuscitation, potentially adding value to medical sciences 
and diagnostic research. This approach will add value 
and new insights to the medical sciences and diagnostic 
research field.

METHODOLOGY
Search Strategy
In order to execute this scoping review, recent research 
and review articles/publications are based on the effect 
of  vitamin C, hydrocortisone, and thiamine therapy in 
Sepsis and Septic Shock were identified. 

Study Selection and Eligibility
The databases used to collect articles include Google 
Scholar, PubMed, Web of  Science, NCBI, Hindawi, 
Scirp, Journal of  Immunology, Critical Care Medicine, 
PLoS ONE, Journal of  Sepsis and Blood Infection, 
National Library of  Medicine, Frontiers in Medicine, 
ResearchGate, Internal Medicine Journal, Journal of  
Medical Internet Research, MEDLINE, EMBASE 
database, and BioMed.
For this study, we searched through the literature to 
find articles that addressed the role of  vitamin C, 
hydrocortisone, and thiamine in treating Sepsis and 
septic shock. Search strategy based on the use of  MeSH 



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terminologies which were related to the topic, studies 
were selected from different years ranging between 
2017 to 2023 using keywords’ ‘Sepsis,’ ‘Severe Sepsis,’ 
‘Septic Shock,’ ‘Effect of  Vitamin C on Sepsis,’ ‘Effect 
of  Vitamin C in Septic Shock Treatment,’ ‘Vitamin C 
in Sepsis,’ ‘Effect of  Thiamine on Sepsis Treatment,’ 
‘Hydrocortisone Therapy in Sepsis,’ ‘SIRS,’ ‘Septic Shock 
Criteria,’ ‘Response Syndrome Septic Shock,’ ‘Patients 
with Septic Shock,’ ‘Epidemiology of  Sepsis,’ ‘Markers 
of  Sepsis,’ ‘Inflammatory Markers of  Septic Shock,’ 
‘Systematic Inflammatory Response Syndrome,’ ‘Sepsis 

Response to Infection,’ ‘Innate Immunity in Sepsis,’ 
‘Adaptive Immune Response in Sepsis,’ ‘Sepsis Diagnosis,’ 
‘Immunity in Sepsis Mechanism,’ ‘Anti-inflammatory 
Therapy in Sepsis,’ ‘Sepsis Immunomodulatory Therapy,’ 
‘Antioxidant Therapy Severe Sepsis,’ ‘Review on Sepsis 
Therapy,’ ‘Correlation between Vitamin C Therapy and 
Sepsis.’ Access was made to the whole texts of  the articles 
that were found. Furthermore, the systemic review has 
been completed according to the guidelines regulated by 
Preferred Reporting Items for Systemic Research and 
Meta-Analysis (PRISMA). 

Table 1: Data selection strategy
Years Search Engines Keywords

2017- 2023

Google Scholar Sepsis
Severe Sepsis
Septic Shock
Correlation between Vitamin C Therapy and 
Sepsis
Epidemiology of  Sepsis
Sepsis Immunomodulatory Therapy
Hydrocortisone Therapy in Sepsis

PubMed
NCBI
Hindawi
Scirp
Frontiers in Medicine
BioMed
Journal of  Immunology
PLoS ONE
Journal of  Sepsis and Blood Infection

Inclusion Criteria
The following addition and omission criteria were 
used to filter the titles rather than study relevance. We 
only selected those studies submitted to peer-reviewed 
journals for approval that were already published. These 
studies were taken into consideration to understand the 
research criteria better. 
• Papers in English and articles published in recent years 
were preferred. 
• Studies describing Sepsis and its types were included.
• Studies related to Sepsis diagnostics and treatments 
were included. 
• Studies related to the effect of  vitamin C on Sepsis were 
also considered.
• Studies of  the correlation between antioxidants, anti-
inflammatory therapy, and Sepsis were also considered. 
• Roadmap report on Sepsis was included in this review.
• Reviews of  recent developments in Sepsis diagnostic 
systems. 

• The role of  Vitamin C, Hydrocortisone, and Thiamin in 
the therapy of  Sepsis, Severe Sepsis, *Septic Shock, and 
• MODS was also reviewed.

Exclusion Criteria
The exclusion criteria involve; 
• Papers written in languages other than English were 
excluded. 
• Studies focusing solely on the impact of  Sepsis on 
Cardio-logical health were excluded.
• Studies on Sepsis-associated hyperlactatemia were 
excluded. 
• Papers not aimed at Sepsis and the advancement of  its 
treatment were excluded from the review. The objective 
was not related to Sepsis and its diagnosis.
• Papers related to Sepsis but whose main objective was 
not related to the effect of  Vitamin C and its therapy in 
Sepsis and Septic Shock were excluded from the review.                      
• Duplicate studies were excluded.                                                                                                    

Table 2: Indicating the Inclusion and Exclusion Criteria of  Studies
Included Articles Excluded Articles
Articles in the English language Articles were written other than in the English language
Articles of  recent years Studies that focused on the impact of  Sepsis on Cardio-logical health
Relevant to Sepsis and types Studies related to Sepsis-associated hyperlactatemia
Relevant to Sepsis diagnostics and 
treatments

Not aimed at the therapy of  Sepsis, advancement, and scopes in its 
diagnostics

Roadmap Report on Sepsis The objective was not related to Sepsis and its treatment
Reviews of  recent developments in 
Sepsis diagnostic systems

Not aimed at the effect of  Vitamin C in Sepsis and Septic Shock 
treatment



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• Studies lacking predefined findings’ supporting data.
Among the 1710 research, 265 were retrieved, and 1445 
papers were eliminated due to their no direct relevance 
to the study’s main goal and were written primarily in 
languages other than English, most commonly Arabic, 
French, Spanish, and Dutch.

Data Extraction and Risk of  Bias
Using Microsoft Excel, the researcher extracted and 
sorted the sample size, study type, duplicates, full-text 
articles, and empirical studies, making the systematic 
review approach practicable. The two authors reviewed 
and decided to include all reviews independently based on 
the eligibility criteria. Information of  variables includes 
the author, year of  publication, and number of  studies. 
The two reviewers assessed the methodological qualities 
by using the 7-item scale of  risk of  bias developed by 
the Cochrane Bias Methods Group. This review used the 
PRISMA guideline and flow diagram to lower the risk of  
bias. The sources of  bias assessed included outcomes, 
population, study selection process, incompleteness of  
data, and time frame and setting.

Quality of  Systematic Reviews
The expert team members assessed the quality of  the 
systematic reviews, including questions regarding the 
degree to which the systematic reviewers had evaluated 
the risk of  bias in individual studies. Systematic reviews 
with major limitations were excluded. The Authors have 
assessed the methodological quality of  studies in Sepsis 

and septic shock based on the review authors’ assessments 
of  risk of  bias in the primary studies they had included.

Summary Measures and Synthesis of  Results
The authors analyzed the data collected by the members 
of  the expert team. Due to the expected heterogeneity of  
studies regarding participants, interventions, outcomes 
and study designs, a quantitative summary measure of  the 
results was not planned. We did a qualitative and narrative 
summary of  the results of  the systematic reviews. The 
literature review results were presented and discussed in 
two workshops intending to validate results.

RESULTS
The initial search for publications concerning the 
significance of  vitamin C, hydrocortisone, and thiamine 
in treating Sepsis and septic shock yielded 1710 papers, 
from which 265 were selected. The reviews’ articles 
were further analyzed to ensure they were pertinent to 
assessing the impact of  vitamin C, hydrocortisone, and 
thiamine in sepsis treatment. Around 80 references were 
examined for their potential applicability to the medical 
field as a treatment. A total of  10 articles were included, 
with preference given to those published during the last 
seven years. Figure 3 illustrates the Preferred Reporting 
Items for Systemic Research and Meta-Analysis guidelines 
(PRISMA) flowchart of  article identification, displaying 
the many stages of  the systematic review applied in 
identifying studies.  

Figure 3: PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses

DISCUSSION
Effectiveness of  Vitamin C, Hydrocortisone, and 
Thiamine in Sepsis and Septic Shock Treatment
Numerous studies have explored the efficacy of  
immunomodulatory therapies as a potential treatment for 

Sepsis and Septic shock, yielding a range of  findings and 
perspectives. This systematic review aims to consolidate 
and analyze the research in this field, highlighting areas of  
agreement and divergence among various studies. 
An unrestrained immune reaction to the microorganisms 



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is one of  the defining characteristics of  blood infection, 
often known as Sepsis. As a result, inflammation 
develops throughout the body. Sepsis is a potentially 
life-threatening condition that can develop when an 
infection is not properly diagnosed and treated promptly. 
A widely acknowledged notion is that the hydrocortisone, 
vitamin C, and Thiamine (HVT) combination could 
help restore the imbalanced immune response, correct 
oxidative mitochondrial function, and enhance energy 
production. However, current clinical practice has an 
ongoing debate regarding using the HVT strategy (Sun et 
al., 2023). In addition to the potential combined benefits, 
the rationale for employing HVT includes its minimal 
risk, affordability, and easy availability. Any minor clinical 
side effects, like hydrocortisone-induced hyperglycemia, 
hypertension, or hypernatremia, may occur but are 
generally inconsequential and can be effectively managed 
in the intensive care unit. (Briegel et al., 2018; Marik, 2018; 
Shi & Tie, 2020; J. Wang et al., 2023)

Vitamin C as an Anti-Inflammatory Agent
Studies such as  (Lv et al., 2021), (Wei et al., 2020), and 
(Fujii et al., 2019) have all suggested the potential benefits 
of  vitamin C in the treatment of  Sepsis (Marik et al., 
2017). Moreover, it was examined that Sepsis patients 
have shown benefits from vitamin C in addition to 
conventional treatment (Marik et al., 2017). According 
to the Surviving Sepsis Guidelines, the same therapy 
was administered to every patient in this trial. (Lv et al., 
2021) The vitamin C group began using vitamin C on 
the day they entered the intensive care unit, and patients 
received IV injections of  3.0 g of  vitamin C dissolved in 
5% dextrose (100 ml each time, twice a day) until they 
were released from the hospital. In contrast, intravenous 
5% dextrose (100 ml/time, twice a day) was given to 
the control group as a placebo. A significant vitamin C 
deficiency typically results in an overactive inflammatory 
response. (Lv et al., 2021) Vitamin C has multiple roles 
in treating patients with severe Sepsis and septic shock 
due to its anti-inflammatory properties, anti-oxidation 
properties, inhibition of  nitric oxide synthesize, cortisol 
retention effect, and increased catecholamine synthesis 
in the brain and adrenal medulla. (Long, Du, Ouyang, 
Zhong, & Zeng, 2023; Lv et al., 2021)

Combination Therapy: Role in Treating Sepsis
In addition, another study (Wei et al., 2020) showed that a 
potential cure for Sepsis would be exogenous vitamin C 
supplementation. Li (2018) conducted a meta-analysis that 
showed vitamin C use could dramatically lower sepsis-
related mortality (Yao et al., 2021a). The study’s findings 
determined that a vitamin C infusion could shorten the 
time that vasopressors were administered. Catecholamines 
were also synthesized with the assistance of  vitamin C 
(Wei et al., 2020). Furthermore, another study by (Fujii 
et al., 2019) stated that vitamin C is an anti-inflammatory 
and cellular antioxidant. It was undetermined whether 
hydrocortisone, thiamine, and vitamin C combination 

therapy in septic shock lower vasopressor reliance. (Fujii 
et al., 2019) The Vitamins trial would assess whether 
combination therapy consisting of  vitamin C, thiamine, 
and hydrocortisone, when compared with hydrocortisone 
alone, boosts the amount of  vasopressor-free hours in 
critically sick patients suffering from septic shock. (Fujii 
et al., 2022; Fujii et al., 2019)
Moreover, in another study (Mohamed et al., 2020), 
researchers investigated the combination therapy of  
vitamin C, thiamine, and hydrocortisone. It was evaluated 
that administering a combination of  hydrocortisone, 
thiamine, and ascorbic acid did not lower all-cause in-
hospital mortality in patients suffering from septic shock 
within six hours of  receiving a diagnosis of  septic shock. 
Patients diagnosed with septic shock who were given 
intravenous vitamin C, thiamine, and hydrocortisone at 
the dose and for the duration prescribed had no impact 
on the hospital mortality rate. The treatment with vitamin 
C appeared to be risk-free. There was evidence to suggest 
that the inflammatory process had been mitigated. 
(Mohamed et al., 2020)
Furthermore, in other research conducted at Zhujiang 
Hospital of  Southern Medical University in Guangdong 
Province, China, a single-centre, single-blind, randomized, 
parallel, controlled trial was undertaken. The study found 
that combining hydrocortisone, vitamin C, and thiamine 
did not significantly reduce mortality among Sepsis and 
Septic shock patients. This outcome aligns with a prior 
retrospective study conducted by Litwak et al., 2019. 
(Chang et al., 2020; Litwak et al., 2019)

Combination Therapy and Mortality Rate
Furthermore, according to the findings of  another meta-
analysis conducted by (Yao et al., 2021b), a significant 
decrease in SOFA score and vasopressor duration among 
patients with Sepsis and septic shock was associated with 
vitamin C and thiamine, either alone or in conjunction 
with hydrocortisone administration; however, it did not 
affect short-term mortality (Mitchell et al., 2020). In the 
meantime, the findings demonstrated that combination 
therapy did not impact death rates in intensive care units 
or hospitals. (Yao et al., 2021b) It was further described 
that a deficit in vitamins C and B1 could lead to several 
disorders with pathophysiological features similar to those 
of  Sepsis. These features include peripheral vasodilation, 
coagulation problems, cardiac and endothelial 
dysfunction, and hypoxia. Hence, vitamin C and thiamine 
are recommended for organ function restoration in 
Sepsis and septic shock. (Yao et al., 2021b) Pyruvate 
dehydrogenase requires phosphorylated thiamine to 
maintain aerobic respiration. Insufficient thiamine may 
cause anaerobic pathway shift and lactate accumulation. 
Meanwhile, intravenous vitamin C treatment was safe 
even at very large dosages, and the dosage was relatively 
consistent across all studies. (Yao et al., 2021b)

Metabolic Resuscitation
Another study (Fujii et al., 2022) summarized that 



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“Metabolic resuscitation” had drawn great interest as a 
complementary treatment for septic shock and Sepsis. 
Usually, vitamin C, glucocorticoids, and vitamin B1 or 
one of  its components were mixed while executing such 
metabolic resuscitation. (Fujii et al., 2022) Prior research 
showed hydrocortisone, vitamin C, and thiamine (HVT) 
as potential adjuvant therapy for Sepsis and septic shock, 
with lower mortality and improved disease cure. (Shi & 
Tie, 2020)

Positive Impact of  Combination and Immunomodulatory 
Therapy
Consequently, another study by Marik et al., 2017 showed 
that the natural progression of  patients with severe 
Sepsis and septic shock appeared to be significantly 
changed by the intravenous administration of  vitamin C, 
hydrocortisone, and thiamine in moderate dosage. (Marik 
et al., 2017) The findings of  this study were supported 
by several experimental and clinical studies that have 
demonstrated the efficacy and prospective utility of  
moderate-dose hydrocortisone, intravenous vitamin 
C, and thiamine in critically ill patients. (Marik et al., 
2017) However, this was the initial study to examine the 
relationship between thiamine and intravenous vitamin C 
hydrocortisone, which works synergistically to reverse the 

pathophysiologic alterations of  Sepsis. (Marik et al., 2017)

Mixed Findings and Perspectives
The study by (Chang et al., 2020) demonstrated the 
combination therapy of  vitamin C, hydrocortisone, 
and thiamine. Chang et al., 2020 did not find substantial 
improvement for patients diagnosed with Sepsis with 
combination therapy, and it did not appear to improve 
the mortality rate. In contrast, another study by Long 
et al., 2023 supported the positive effect of  vitamin C 
and hydrocortisone in treating Septic shock. (Long, Du, 
Ouyang, Zhong, & Ye, 2023). Hydrocortisone showed 
antitoxic effects, and the combination of  hydrocortisone 
with vitamin C and thiamine showed significant effects in 
refractory Sepsis and Septic shock. (H. Liang et al., 2023; 
Long, Du, Ouyang, Zhong, & Ye, 2023) 
This systematic review summarizes the findings based on 
the effect of  Vitamin C, Hydrocortisone, and Thiamine 
in Sepsis and Septic shock treatment and provides 
a comprehensive overview of  the research findings 
related to immunomodulatory therapy. In comparison, 
some studies suggest potential benefits, while others 
present mixed results, underscoring the complexity 
of  this therapeutic approach and the need for further 
investigation. 

Table 3: The lists of  studies discussed in this review are relevant to the effect of  Vitamin C, Hydrocortisone, and 
Thiamine in treating Sepsis and Septic Shock
No Title Author Year Conclusion Reference No.
01 Retracted Article: 

Early use of  high-
dose vitamin C is 
beneficial in the 
treatment of  Sepsis

Lv, S. J., Zhang, G. 
H., Xia, J. M., Yu, H., 
& Zhao, F.

2021 The early treatment of  Sepsis with 
intravenous high-dose vitamin C in 
combination with standard therapy 
showed a beneficial effect on 
Sepsis in terms of  reduced 28-day 
mortality, decreased SOFA score, 
and increased clearance rate of  
procalcitonin.

Lv, S.-J., et al., 
(2021)

02 Efficacy of  vitamin 
C in patients with 
Sepsis: An updated 
meta-analysis.

Wei, X. B., Wang, Z. 
H., Liao, X. L., Guo, 
W. X., Wen, J. Y., 
Qin, T. H., & Wang, 
S. H.

2020 In conclusion, including the 
recently published retrospective 
studies in our meta-analysis could 
not reveal the beneficial effect of  
vitamin C on patients with Sepsis. 
The value of  vitamin C in Sepsis 
needs to be clarified through more 
high-quality randomized controlled 
trials in the future.

Wei, X.-b., et al., 
(2020)

03 Vitamin C, 
Hydrocortisone 
and Thiamine 
in Patients with 
Septic Shock 
(VITAMINS) trial: 
study protocol and 
statistical analysis 
plan.

Fujii, T., Udy, A. 
A., Deane, A. M., 
Luethi, N., Bailey, M., 
Eastwood, G. M., & 
Bellomo, R.

2019 Septic shock is associated 
with poor outcomes. Vitamin 
C (ascorbic acid) is a cellular 
antioxidant with anti-inflammatory 
properties. Whether the 
combination therapy of  vitamin 
C, thiamine, and hydrocortisone 
reduces vasopressor dependency in 
septic shock is unclear.

Fujii, T., et al., 
(2019)



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04 Vitamin C Therapy 
for Routine 
Care in Septic 
Shock (ViCTOR) 
trial: Effect of  
intravenous vitamin 
C, thiamine, and 
hydrocortisone 
administration on 
inpatient mortality 
among patients with 
septic shock.

Mohamed, Z. U., 
Prasannan, P., Moni, 
M., Edathadathil, F., 
Prasanna, P., Menon, 
A., & Menon, V.

2020 We conclude that intravenous 
vitamin C, thiamine, and 
hydrocortisone in the dose and 
duration used did not affect the 
hospital mortality in patients with 
septic shock. Vitamin C therapy 
seems to be safe. There is evidence 
of  a reduction in the inflammatory 
process

Mohamed, Z.U., 
et al., (2020)

05 Combination 
therapy of  
thiamine, vitamin C 
and hydrocortisone 
in treating patients 
with Sepsis and 
septic shock: a 
meta-analysis and 
trial sequential 
analysis.

Yao, R., Zhu, Y., Yu, 
Y., Li, Z., Wang, L., 
Zheng, L.,  & Yao, Y.

2021 In the current meta-analysis, the 
combination therapy of  vitamin 
C and thiamine, with or without 
hydrocortisone, had no impact on 
short-term mortality compared 
with placebo but was associated 
with a significant reduction in 
SOFA score among patients with 
Sepsis and septic shock.

Yao, R., et al., 
(2021)

06 Effect of  adjunctive 
vitamin C, 
glucocorticoids, 
and vitamin B1 
on longer-term 
mortality in adults 
with Sepsis or septic 
shock: a systematic 
review and a 
component network 
meta-analysis.

Fujii, T., Salanti, 
G., Belletti, A., 
Bellomo, R., Carr, A., 
Furukawa, T. A., & 
Young, P. J.

2022 On NMA, metabolic resuscitation 
with vitamin C, glucocorticoids, 
vitamin B1, or combinations of  
these drugs was not proven to 
reduce longer-term mortality. 
However, NMA and component 
NMA suggested an association 
between high dose and very high 
dose vitamin C and decreased 
mortality with low certainty. 
Glucocorticoid therapy was 
associated with a decreased 
duration of  vasopressor support 
and ICU therapy. Further RCTs 
evaluating very high doses of  
intravenous vitamin C therapy 
appear justified.

Fujii, T., et al., 
(2022)

07 Benefit of  
hydrocortisone, 
thiamine, and 
vitamin C for 
patients with 
Sepsis or septic 
shock? Too early to 
conclude.

Shi, R., & Tie, H. 2020 In conclusion, the beneficial 
findings of  our study support that 
HVT remains an attractive choice 
for Sepsis and septic shock, while 
results from large-scale RCTs are 
still expected before a definite 
conclusion, especially regarding the 
timing of  HVT and the severity of  
Sepsis.

Shi, R., & Tie, 
H., (2020)

08 Hydrocortisone, 
vitamin C, and 
thiamine for the 
treatment of  
severe Sepsis 
and septic shock: 
a retrospective 
before-after study.

Marik, P. E., 
Khangoora, V., 
Rivera, R., Hooper, 
M. H., & Catravas, J.

2017 Our results suggest that the early 
use of  intravenous vitamin C, 
corticosteroids, and thiamine 
effectively prevents progressive 
organ dysfunction, including acute 
kidney injury, and reduces the 
mortality of  patients with severe 
Sepsis and septic shock. Additional 
studies are required to confirm 
these preliminary findings.

Marik, P.E., et al., 
(2017)



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09 Combined 
treatment with 
hydrocortisone, 
vitamin C, and 
thiamine for Sepsis 
and septic shock: 
a randomized 
controlled trial.

Chang, P., Liao, Y., 
Guan, J., Guo, Y., 
Zhao, M., Hu, J., & 
Liu, Z.

2020 In conclusion, hydrocortisone, 
vitamin C, and thiamine did 
not appear to reduce the 28-
day mortality compared with a 
placebo in patients with Sepsis 
or septic shock. Moreover, we 
must consider side effects, such as 
severe hypernatremia. However, 
a larger sample and multi-centre, 
randomized controlled trials 
are required to validate the 
effectiveness and timing of  this 
treatment.

Chang, P., et al., 
(2020)

10 Research Progress 
on Therapeutic 
Effect and 
Mechanism of  
Hydrocortisone on 
Sepsis

Yicen Long 
Xiaoqiang Du Zhi 
Ouyang Jian Zhong 
Zeng Ye

2023 Sepsis has remained a high 
mortality rate worldwide. 
Hydrocortisone has potent 
immunological and antitoxic 
effects, and thus, it is frequently 
used in treating septic shock. In 
recent years, the combination 
of  hydrocortisone and other 
drugs, such as vitamin C and 
thiamine, has achieved promising 
outcomes in refractory septic 
shock. The present review focuses 
on the therapeutic effects of  
hydrocortisone in Sepsis and 
summarizes the mechanisms 
by which hydrocortisone acts 
on vascular endothelial cells. 
We highlighted the effect 
of  hydrocortisone on anti-
inflammation, anti-apoptosis, 
improvement of  vascular 
functions, and anti-oxidative stress.

Long, Y., et al., 
(2023)

CONCLUSION
An uncontrolled immunological response to the 
microorganisms characterizes blood infection or Sepsis. 
This causes inflammation throughout the body. Sepsis 
is typically brought on by a delay in the infection’s 
detection and treatment. Contrarily, intravenous vitamin 
C, corticosteroids, hydrocortisone, and thiamine 
successfully prevent organ dysfunction progression and 
lower the need for vasopressors and the mortality of  
patients with severe Sepsis and septic shock. Moreover, 
severe Sepsis and septic shock patients may benefit from 
vitamin C, corticosteroids, and thiamine combination. 
These therapies were medically proven and showed 
significance in treating Sepsis, lowering its symptoms’ 
effects, and preventing organ malfunctioning. However, it 
should be chosen for the proper type of  septic shock, the 
suitable patient who would benefit, and the right dosage 
and duration when treating Sepsis. Triple therapy remains 
considered to be a promising technique in this regard.
 
RECOMMENDATIONS
Researchers are encouraged to explore various avenues 

in treating Sepsis, including patient stratification, dosage, 
duration optimization, subtype specificity, long-term 
effects, and combination therapies. Precision medicine 
is crucial for optimizing treatment outcomes. Further 
refinement of  dosages and duration is necessary to 
balance efficacy and safety. Subtype specificity is also 
crucial, as a tailored approach may be required for each. 
Long-term effects of  immunomodulatory therapies in 
Sepsis survivors and combining therapies can further 
enhance their efficacy. 
Further recommendations include clinical trials, 
precision medicine approach, pharmacokinetic and 
pharmacodynamics studies, long-term follow-up studies, 
and combination therapies. It also encourages data 
sharing and collaboration among researchers, healthcare 
institutions, and pharmaceutical companies to accelerate 
research. Public awareness about early Sepsis symptoms is 
crucial for early detection and treatment. Policy advocacy 
for evidence-based immunomodulatory therapies in 
Sepsis treatment protocols is encouraged, prioritizing 
patient outcomes and safety. Moreover, international 
collaboration in Sepsis research and treatment is 



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encouraged to foster global cooperation. These 
recommendations aim to advance the understanding of  
Sepsis, improve management, and enhance the quality of  
care for Sepsis patients. 

LIMITATIONS 
• The majority of  the screened articles were not in English, 
and the majority of  the articles were unreachable. The 
limitations of  the study were these considerations.
• Publication bias, language bias, timeframe, and quality 
of  included studies are common limitations in systematic 
reviews. Acknowledging these biases and assessing 
individual studies’ quality is crucial for evaluating the 
strength of  evidence.

Strengths

• The review utilized a comprehensive search strategy, 
focusing on recent research published within the last 
seven years. 
• It followed clear inclusion and exclusion criteria, 
enhancing its credibility. 
• The discussion section effectively highlighted conflicting 
findings, demonstrating a balanced analysis. 
• The review integrated findings from various studies, 
including supportive and contradictory evidence, 
providing a holistic understanding of  the topic. 
• The review also discussed potential clinical implications, 
valuable for healthcare professionals and researchers in 
Sepsis and Septic shock treatment.

Novelty of  Research
The review focuses on the combination therapy of  vitamin 
C, Hydrocortisone, and Thiamine in treating Sepsis and 
Septic shock. It synthesizes recent studies to examine 
the potential synergic effects and clinical benefits of  
administrating them together. The review includes studies 
from 7 recent years, providing a contemporary perspective. 
The research evaluates diverse perspectives, highlighting 
the complexity of  Sepsis and Septic Shock treatment. 
It provides clear and actionable recommendations for 
future research and clinical practice, offering guidance 
on refining treatment protocols, patient selection 
criteria, and developing clinical guidelines. The research 
emphasizes a multidisciplinary approach involving 
various medical specialities and healthcare providers to 
address the multifaceted nature of  Sepsis and Septic 
shock. The novelty of  the research lies in its systematic 
and contemporary analysis, consideration of  diverse 
research perspectives, and practical recommendations for 
future research and clinical practice. 

Contribution to Knowledge
This review has made significant contributions to critical 
care medicine and immunomodulatory therapies. It 
synthesizes existing research, strengthens the evidence 
base for this therapy, and offers insights into strategies 
to improve patient care, reduce mortality rates, and 

alleviate symptoms. The research also provides valuable 
information for developing clinical guidelines and 
protocols for Sepsis and Septic shock treatment. It 
acknowledges the knowledge gap and emphasizes a 
multidisciplinary approach, recognizing the complexity 
of  these conditions. Future research directions include 
patient selection criteria, dosages, and treatment duration. 

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