Vitamin C, Corticosteroid and Thiamine

Wallaga University
Institute of Health Sciences

Department of Pharmacy
Clinical Pharmacy Program
Title: Current evidence for use of Vitamin C, Thiamine and Corticosteroids in Patients
with Septic Shock
• By : Dinka Dugassa
• Moderator:Gemechis Belay(B.Pharm,Msc in Clinical Pharmacy and HDoP)
June 21, 2023

Nekemte, Ethiopia
Ambulatory Medicine Seminar Presentation June, 2023
Wallaga University
Presentation outlines
o Introduction
o Epidemiology and Burden
o Corticosteroid
o Vitamin
o Thiamine
o References
o Acknowledgement
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• Introduction
– Sepsis is a life-threatening condition that occurs due to a
dysregulated host response to infection .
– There were approximately 49 million cases of sepsis and
11 million sepsis-related deaths worldwide annually .
– Septic shock, a subset of sepsis, is characterized by
circulatory and cellular/metabolic abnormalities that are
associated with a higher risk of mortality .

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• Introduction
– Sepsis is recognized as a life-threatening biological
condition that induces systemic tissue and organ
dysfunction and
– is associated with 5.3 million annual deaths worldwide.
– Standardized management and care for septic shock has
improved sepsis-related mortality from 40% to
approximately 20%,
• but the overall disease burden remains high.

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– At present, there are no treatments directly targeting the
pathogenesis of sepsis;
– therefore, management relies on early identification and

treatment of infection through appropriate antibiotic
therapy and/or source control, as well as the reversal of
hemodynamic instability through fluid resuscitation and
vasopressors, if necessary .
– Therefore, safe, effective, affordable adjuvant interventions

that focus on mitigating dysregulated host responses in
addition to standard therapy are urgently required.
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• Ascorbic acid….
– Helps repair vascular endothelial cells that are damaged by inflammatory
mediators and oxidative stress and is therefore administered to patients with
sepsis .
– Despite receiving standard enteral and parenteral ascorbic acid
supplementation,
• 88% of patients with sepsis have hypovitaminosis C.
• 38% of these patients have severe ascorbic acid deficiency (<11 μmol/l) ,
• Which is associated with impaired catecholamine synthesis as well as an
attenuated vasomotor response to α-adrenergic stimulation and
• May increase the mortality risk.

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• Thiamine ….
– inhibits the metabolism of ascorbic acid to oxalic acid,

• which is a reducing substance.
– 1/3rd of all patients with sepsis have thiamine

deficiency.
– Although thiamine deficiency is not associated with
mortality of these patients,
– thiamine supplementation improves lactate clearance.

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• Hydrocortisone….
– Facilitates expression of sodium-dependent
ascorbate cotransporter (SVCT) that increases
cellular uptake of ascorbic acid , and
– Thus plays an essential role in enhancing the
function of ascorbic acid.
– Furthermore, approximately 60% of patients with
severe sepsis have adrenal insufficiency and
critical illness-related corticosteroid insufficiency
(CIRCI),
– Which is due to decreased glucocorticoid receptor
activity.
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• HAT therapy
– Because both ascorbic acid and thiamine deficiencies
and CIRCI occur frequently in patients with severe
sepsis,
• the use of hydrocortisone in combination with
ascorbic acid and thiamine (HAT therapy)
• constitutes a rational strategy for the treatment of
patients with sepsis.

VITAMIN C AND THIAMINE FOR SEPSIS
AND SEPTIC SHOCK
Vitamin C levels in Critically ill
patients
– Vitamin C levels fall in critical illness due to reduced intake
and increased oxidative consumption.
– Septic shock patients have significantly depleted vitamin C

levels compared with septic shock patients.
– Humans and Guniea pig can not synthesize vitamin C in

their body
Car Critical Care 2017
Previously in Clinical Research
• Phase I Trial Safety Trial

– Focus on the safety of administering IV vitamin C to
patients with severe sepsis.
Fowler
Transitional
Journal 2014
Vitamin C Cocktail Therapy
• Vitamin C, Thiamine and Corticosteroids in Patients with septic
shock: A Retrospective Before - After Study
45.00%
– Single center Before - After Study 40.00% 40.4%
35.00%
– Patients with severe sepsis or septic shock 30.00%
25.00%
20.00%
– Before (47 patients) 15.00%
10.00% Series1
• 60% of patients received hydrocortisone 5.00%
0.00%
8.5 Series2
Series3
– After (47 patients) %
il
Co ty
eta
i
tal
ck
• All patients received vitamin C cocketail.
or
M
ed
Marik Chest 2017
t
eic
Pr
What was the Vitamin C cocketail?
– Vitamin c 1.5g 6 hourly
– Hydrocortisone 50mg 6 hourly
– Thiamine 200mg 6 hourly
Marik Chest 2017

Potential Synergistic Effects: Vitamin
C and Steroid
• Vitamin C need transporter SCVT2, to enter into cell.
• In infection,
– The expression of SCVT2 is decreased
– Corticosteroid receptor is oxidized by inflammatory mediator
• Corticosteroid increases the expression of SCVT2
• Vitamin C help to reverse the oxidized Corticosteroid

receptor.
Fuji critical Care Resusc 2019
Thiamine May help of
• 1/3rd of critically ill patients –thiamine deficiency in the early phase
of acute illness.
Donnenio Critical Care 2020

• Thiamine deficiency increases the conversion of glycolate to oxalate resulting to
hyperoxalosis.
• The extra oxalate accumulates and can cause kidney organ damage
– Oxalate Nephropathy
• Supplementation with thiamine

– To reduce the risk of acute kidney injury.
Buecher Journal Burn Care Respiratory 2016

Hydrocortisone for Septic
Shock :Adrenal Trail
3800 Patients with septic shock
Hydrocortisone 200mg Placebo

/day
– Intravenous infusion for a maximum of 7 days or until ICU

Discharge or death
– Median time of resolution of shock 3 (2-5) Vs 4 (2-9)
days ,p<0.001
Effect of Ascorbic Acid, Corticosteroids, and Thiamine on Organ
Injury in Septic Shock
The ACTS Randomized Clinical Trial
• Conclusions and Relevance
• In patients with septic shock, the combination of ascorbic acid,
corticosteroids, and thiamine, compared with placebo, did not
result in a statistically significant reduction in SOFA score
during the first 72 hours after enrollment.

– These data do not support routine use of this combination therapy for
patients with septic shock.
• Trial Registration
• ClinicalTrials.gov Identifier: NCT03389555

Conclusions
• In patients with septic shock,
– the combination of
• ascorbic acid,
• corticosteroids, and
• thiamine, compared with placebo, did not result in a

statistically significant reduction in SOFA scores during the
first 72 hours after enrollment.
– These data do not support routine use of this

combination therapy for patients with septic shock.
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• Methods and materials
• Study setting and period
• The study was conducted at Shecha Health
Center, Arbaminch town, SNNP region, South
West Ethiopia which is found 505 km from
Addis Ababa.
• The study was conducted from December 2022
to March 2023

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• Methods and materials…..
• Study design: an invivo open label clinical trial
was conducted
• Source population: All patients diagnosed with
Malaria at Shecha Health Center.
• Study population: A Malaria patient diagnosed
with P.V Mono Infection from December 2022 to
March 2023 at Shecha Health Center,Malaria
Treatment Center clinic within the study period
and fulfills the inclusion criteria.
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• Inclusion Criteria:Age > 6 months,Slide confirmed
infection with P. vivax with > 250 asexual
forms/μl,Lives within 5 km of the enrolling health
facility,Weight ≥ 5.0 kg,Ability to swallow oral
medication,Ability and willingness to comply with
the protocol for the duration of the study and to
comply with the study visit schedule, Able to give
Informed consent from patient or from a parent or
guardian in the case of children.

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• Exclusion Criteria: Sever malaria with complication sign
and symptoms,Signs or symptoms of severe
malnutrition,,Mixed plasmodium infection Severe
anemia, defined as hemoglobin (Hb) < 8 g/dl,Presence of
febrile conditions caused by diseases other than malaria
(e.g. measles, acute lower,respiratory tract infection,
severe diarrhea with dehydration),Serious or chronic
medical condition (e.g. cardiac, renal, hepatic diseases,
sickle cell disease,,HIV/AIDS),Positive pregnancy test or
breastfeeding,Unable or unwilling to take contraceptives
for women of child-bearing age

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• Dependent Variable: Therapeutic Efficacy of CQ+PQ
• Independent Variables:Axillary temperature,
leukocyte count, asexual and/ or sexual parasites
count,age,sex,weight
• Sample Size: For therapeutic efficacy studies, which
were recommended by the Technical Expert Group
on Malaria Chemotherapy in 2008, sample size
should be determined using classical statistical
methods
Technical Expert Group on Malaria Chemotherapy in 2008

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• Result and Discussion

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• Result and Discussion…..

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• Limitation of the study

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• Conclusion

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• Recommendation

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• Sample references

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• Acknowledgement
• First of all my thanks goes to GOD!
• Special thanks to Malaria Treatment Unit of Shecha Health
Center for the proper documentation of patients information
and treatment outcome and for their guideline assistance
during data collection.
• I am in the great thanks Ethiopian Public Health Institute,
Malaria Team Director and research office of Wollega
University, being as source and base in order to prepare this
research.
• At the last but not least, I would like to extend my
appreciation to Busha Gamachu and Bockretsion Gidey for
their invaluable cooperation.

Wallaga University
Thank you!

Vitamin C, Corticosteroid and Thiamine

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Wallaga University

Institute of Health Sciences

• Moderator:Gemechis Belay(B.Pharm,Msc in Clinical Pharmacy and HDoP)

June 21, 2023

– Sepsis is a life-threatening condition that occurs due to a

dysregulated host response to infection .

– There were approximately 49 million cases of sepsis and

11 million sepsis-related deaths worldwide annually .

– Septic shock, a subset of sepsis, is characterized by

circulatory and cellular/metabolic abnormalities that are

associated with a higher risk of mortality .

Ambulatory Medicine Seminar Presentation June, 2023

– Sepsis is recognized as a life-threatening biological

condition that induces systemic tissue and organ

– is associated with 5.3 million annual deaths worldwide.

– Standardized management and care for septic shock has

improved sepsis-related mortality from 40% to

• but the overall disease burden remains high.

– therefore, management relies on early identification and

– Therefore, safe, effective, affordable adjuvant interventions

– Helps repair vascular endothelial cells that are damaged by inflammatory

mediators and oxidative stress and is therefore administered to patients with

– Despite receiving standard enteral and parenteral ascorbic acid

• 88% of patients with sepsis have hypovitaminosis C.

• Which is associated with impaired catecholamine synthesis as well as an

attenuated vasomotor response to α-adrenergic stimulation and

• May increase the mortality risk.

– inhibits the metabolism of ascorbic acid to oxalic acid,

– 1/3rd of all patients with sepsis have thiamine

Ambulatory Medicine Seminar Presentation June, 2023

Ambulatory Medicine Seminar Presentation June, 2023

– Septic shock patients have significantly depleted vitamin C

– Humans and Guniea pig can not synthesize vitamin C in

• Phase I Trial Safety Trial

– Vitamin c 1.5g 6 hourly

– Hydrocortisone 50mg 6 hourly

– Thiamine 200mg 6 hourly

Marik Chest 2017

• Corticosteroid increases the expression of SCVT2

• Vitamin C help to reverse the oxidized Corticosteroid

Donnenio Critical Care 2020

• Supplementation with thiamine

Buecher Journal Burn Care Respiratory 2016

3800 Patients with septic shock

Hydrocortisone 200mg Placebo

– Intravenous infusion for a maximum of 7 days or until ICU

• Conclusions and Relevance

• In patients with septic shock, the combination of ascorbic acid,

corticosteroids, and thiamine, compared with placebo, did not

result in a statistically significant reduction in SOFA score

during the first 72 hours after enrollment.

patients with septic shock.

• ClinicalTrials.gov Identifier: NCT03389555

• thiamine, compared with placebo, did not result in a

– These data do not support routine use of this

Ambulatory Medicine Seminar Presentation June, 2023

Ambulatory Medicine Seminar Presentation June, 2023

Ambulatory Medicine Seminar Presentation June, 2023

Ambulatory Medicine Seminar Presentation June, 2023

Ambulatory Medicine Seminar Presentation June, 2023

Ambulatory Medicine Seminar Presentation June, 2023

Ambulatory Medicine Seminar Presentation June, 2023

Ambulatory Medicine Seminar Presentation June, 2023