The document discusses ascorbic acid (vitamin C), corticosteroids (hydrocortisone), and thiamine and their potential roles in treating sepsis both individually and in combination. It notes that sepsis patients often have low vitamin C levels and outlines vitamin C's antioxidant and anti-inflammatory properties. It describes trials testing high-dose hydrocortisone in sepsis and notes risks of high doses. The document discusses thiamine deficiency in sepsis and trials of thiamine supplementation. It summarizes a study showing reduced mortality with combination hydrocortisone, vitamin C and thiamine (HAT) therapy in sepsis and notes ongoing randomized controlled trials are testing HAT therapy in severe sepsis and se

1. ASCORBIC ACID, CORTICOSTEROIDS,
AND THIAMINE
IN SEPSIS
Dr. Kaveh Kazemian
Pharm-D. BCCP. FCCP

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5. INTRODUCTION
 Sepsis is a devastating disease that carries an enormous toll in terms of
human suffering and lives lost
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7. INTRODUCTION
 long-term complications
 Post-sepsis syndrome
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9. INTRODUCTION
Alteration the expression of genes
 Genes for pro- and anti-inflammatory cytokines, chemokines, adhesion
molecules transcription factors, enzymes, clotting factors, stress proteins
and anti-apoptotic molecules
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10. INTRODUCTION
 Inflammatory mediators Consequences:
 Vasoplegic Shock
 Myocardial dysfunction
 Altered microvascular flow
 Diffuse endothelial injury
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11. HYDROCORTISONE, ASCORBIC ACID, AND
THIAMINE (HAT) IN COMBINATION
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12. INTRODUCTION
 ROS can induce injury to lipids, proteins and nucleic acids, thereby
resulting in widespread endothelial dysfunction, mitochondrial
dysfunction, cellular injury, and multiple organ dysfunction
 Mitochondria are both the target and source of ROS in sepsis
 F2-isoprostanes as the most reliable biomarkers of in vivo oxidative
stress
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13. INTRODUCTION
 In the heart, myocyte oxidative injury is accompanied by :
I. Increased proteolysis
II. Mitochondrial damage
III. Dysregulated nitric oxide metabolism
IV. Adrenoceptor down-regulation
V. Calcium mishandling
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14. INTRODUCTION
 Increase the expression of pyruvate dehydrogenase kinase isoenzymes (PDK4)
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17. THE PREMISE BEHIND HAT THERAPY
The use of a combination of readily available, safe and cheap agents that
target multiple components of the host’s response to an infectious agent such
that they synergistically restore the dysregulated host immune response,
neutralize damaging oxidants, and restore mitochondrial function
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18. VITAMIN C
 Critically ill septic patients typically have very low or undetectable serum levels of
vitamin C
 Increased vasopressor requirements, kidney injury, multiple organ dysfunction (higher
SOFA scores) and increased mortality
The underlying cause of vitamin C deficiency
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19. VITAMIN C
 Sepsis induced glomerular hyperfiltration and decreased tubular reabsorption of
filtered vitamin C
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20. VITAMIN C
 Vitamin C is a potent antioxidant, restores other cellular antioxidants, essential co-
factor for iron and copper containing enzymes
 Dehydroascorbic acid as a potent antioxidant limiting mitochondrial oxidant injury
 Antioxidants targeting the intra-mitochondrial environment could be pivotal role in
the treatment of sepsis.
 Ascorbic acid is required for the synthesis of carnitine
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21. VITAMIN C
 Inhibition of oxidant induced mitochondrial damage and apoptosis in human
endothelial cells
 Vitamin C suppresses activation of NF-ƙB
 Ascorbic acid decreases high mobility group box 1 (HMGB1) secretion
 Vitamin C may decrease the synthesis and Inactivate histamine
 Vitamin C is an essential co-factor for the synthesis of norepinephrine, epinephrine
and vasopressin
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22. VITAMIN C
 Vitamin C may decrease the immunosuppression associated with sepsis.
 Vitamin C has immune-enhancing properties
 A number of RCTs have reported that vitamin C supplementation had no effect on the
incidence of the common cold
 Vitamin C is concentrated in leucocytes, lymphocytes and macrophages
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24. VITAMIN C
 Vitamin C may paradoxically be associated with a pro-oxidant effect
 Vitamin C may generate ROS in in-vitro where free metal ions might exist
 Normally, iron is tightly bound to protein
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25. VITAMIN C
 The divalent iron atom promote the production of free radicals.
 Infusion of 30 mg/kg and 100 mg/kg of vitamin C decreased markers of oxidative
injury, whereas these markers were increased with a dose of 300 mg/kg and 1000
mg/kg
 Vitamin C in a dose of 50 mg/kg and 100 mg/kg IV decreased myocardial damage,
improved neurological outcome and the survival rate
 In the absence of free iron or heme, vitamin C acts as an oxidant only in extremely
high ( >100 g )
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26. VITAMIN C
 A single 1 g infusion of vitamin C prior to the percutaneous coronory reperfusion
 Vitamin C up to a dose of 2 g IV given pre-operatively significantly reduced the risk
of AF
 Prophylactic vitamin C (PO and IV up to a total dose of 7 g)
 The optimal daily dose appears to be approximately 6 g/day
 It is possible that delayed treatment with a higher dose may have a pro-oxidant
deleterious effect.
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27. HYDROCORTISONE
 Suppression of inflammation
 The primary anti-inflammatory action of glucocorticoids is to repress a
large number of pro-inflammatory genes
 Low-dose glucocorticoids have immune-stimulating effects
 The balance between the immune suppressing and enhancing effects of the
drug are critically dependent on the dose and duration of treatment
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28. HYDROCORTISONE
 30 mg/kg methylprednisone for up to 4 doses ( High mortality )
 (5–7 days) & “stress-doses” of glucocorticoids (200–300 mg hydrocortisone/day).
 2018 randomized controlled trials APROCCHSS & ADRENAL
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29. THIAMINE
 Thiamine is the precursor of thiamine pyrophosphate (TPP)
 Important role in many enzymatic processes involved in brain function and
interneuronal communication
 Thiamine is involved in nerve tissue repair, myelin synthesis and nerve signal
modulation
 It plays a role in the uptake of serotonin
 Thiamine deficiency prevalence between 20% and 70%,
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30. THIAMINE
 Thiamine deficiency is associated with excitotoxic-mediated neuronal cell death and
increased production of ROS
 200 mg thiamine twice daily for seven days significantly lower lactate levels at 24 h
and a lower mortality at 30 days
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32. HYDROCORTISONE, ASCORBIC ACID, AND
THIAMINE (HAT) IN COMBINATION
 In a small, retrospective, before-after-study,
Demonstrated that the combination of hydrocortisone, ascorbic acid (6 g/day)
and thiamine (HAT Rx) improved organ function (as reflected by the SOFA
score) with a significant reduction in mortality
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33. HYDROCORTISONE, ASCORBIC ACID, AND
THIAMINE (HAT) IN COMBINATION
 According to the U.S. National Library of Medicine’s ClinicalTrials.gov
website (https://clinicaltrials.gov/)
 in excess of 12 randomized controlled trials are currently underway testing
vitamin C alone and in combination with hydrocortisone and thiamine in
patients with severe sepsis and or septic shock.
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34. University of Athens Hospital mortality
60-day, 28-day mortality,
time to vasopressor
cessation, procalcitonin
clearance and change in
the SOFA score over the
first 4 days and length of
stay in the intensive care
unit (ICU)
1500 mg Vitamin C every
6 hours for 4 days
stress-dose hydrocortisone
for 4 days (250 mg on day
1; and 200 mg on days 2,
3, and 4)
September 2020
Hospital Español de
Mexico
Decreases the dose of
exogenous vasopressors in
patients with septic shock
Vitamin C 6 grams in 250
ml of 0.9% saline solution
every 24 hours, in
continuous infusion for 72
hours.
June 2020

35. New York Methodist Hos
pital
conduct a prospective bli
nded randomized control
trial to investigate wheth
er this intervention truly
effect outcomes.
IV vitamin C, 1500mg in 50
ml of normal saline every si
x hours, infused over one ho
ur and IV Thiamine 200mg
in 50ml of 5% dextrose ever
y 12 hours, for 4 days or unt
il discharge from the intensi
ve care unit, whichever com
es first.
September 15, 2021
Lakeland Health reduces the time on press
ors agents
SOFA score
procalcitonin
February 26, 2020

36. HYDROCORTISONE, ASCORBIC ACID, AND
THIAMINE (HAT) IN COMBINATION
 HAT therapy will improve both the short-term (mortality) and long-term
(post-sepsis syndrome) outcome of patients with sepsis and septic shock
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37. Thanks
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