Adaptation in Sepsis 2 Flashcards
Why are there no new sepsis therapies in the last 30 years
High failure rate of treatments in clinical trials
Very expensive
Time consuming
Very complex and multifactorial disease
What is eritoran
A MD-TL4 antagonist that is a synthetic lipid A antagonist (similar to lipopolysaccharide
What does eritoran do
Block lipopolysaccharide binding to MD2-TLR4
Does eritoran work
Not significantly different for 28 day mortality
However- favourable trend to lower mortality on 105mg dose so went to phase 3 trial
What is thrombomodulin and how does it work
Involved in the activation of activated protein C and limits thrombin generation so good for DIC
Does thrombomodulin work
Only works if severe DIC patients as decreases mortality but for those with mild coagulopathy it kills them as increases bleeding risk.
What is thymosin alpha 1
Immunomodulatory peptide which induces T cell modulation
What is ulinastatin
Serine protease inhibitor/ urinary trypsin inhibitor
Where do urlinastatin and thymosin alpha 1 work
Used in immune deficiency disorders and aim was to combat immunosuppressive side of sepsis
Works on antigen presenting cells.
Does urlinastatin and thymosin alpha 1 work
Preclinical trial - reduced mortality in sepsis
Failed in clinical trial
What did the chinese meta-analysis study find regarding sepsis treatment
thymosin alpha 1 alone or with ulinastatin appears to reduce 28 day mortality but no effect on ICU mortality
However poor quality trials - Lack of double blind RCT
What is melatonin
Good antioxidant that regulates sleep and wake cycles.
Its reaction products produce further antioxidants
Can be given orally.
Give 3 properties of melatonin
Amphiphilic - gets everywhere
Anti-oxidant
Anti-inflammatory actions
Where does melatonin accumulate
Mitochondria - good as site of the most oxidative stress occurs during sepsis
How does melatonin preform in pre-clinical trials
LPS (gram negative) and PepG (gram positive) PAMPs given to rats.
Reduced pro-inflammatory cytokines
Reduced mitochondrial damage
Decreased organ dysfunction
What side effects were shown with melatonin in DAMSEL1
Drowsiness
What is DAMSEL 2
Trial to look at the dose assessment for melatonin in sepsis
Only sepsis induced by pneumonia
Stage 1 is open label
Stage 2 is double blind RCT
What was the findings in DAMSEL2
20mg is best dose
No major adverse events
Give some other noted benefits of melatonin
Biancatelli et al 2020
Prevents mitochondrial dysfunction
Anti-inflammatory properties (reduced TNF-alpha)
Antioxidant properties
Reduced hepatic injury
Preventing septic cardiomyopathy
Regulates circadian rhythm
Safe
What happens to thrombomodulin during sepsis
WIDER READING - Ito et al 2019
Downregulated and function impaired
Other than severe DIC induced sepsis, where has thrombomodulin worked in the lungs
WIDER READING - Takahashi 2016
ARDS - HMGB-1 was lowered by rTM administration in mice
Other than severe DIC induced sepsis, where has thrombomodulin worked in the kidneys
WIDER READING - Honda 2013
HUS - 5% caused by TM gene mutations.
Used rTM on 3 patients in hapan which stopped thrombocytopenia, haemolysis and renal dysfunction in 3 patients
Other than severe DIC induced sepsis, where has thrombomodulin worked in blood vessels
Wider reading - wei 2011
TM when administered reduced atherosclerosis
