Adaptation in Sepsis 2

Question 1

Why are there no new sepsis therapies in the last 30 years

Answer 1

High failure rate of treatments in clinical trials
Very expensive
Time consuming
Very complex and multifactorial disease

Question 2

What is eritoran

Answer 2

A MD-TL4 antagonist that is a synthetic lipid A antagonist (similar to lipopolysaccharide

Question 3

What does eritoran do

Answer 3

Block lipopolysaccharide binding to MD2-TLR4

Question 4

Does eritoran work

Answer 4

Not significantly different for 28 day mortality

However- favourable trend to lower mortality on 105mg dose so went to phase 3 trial

Question 5

What is thrombomodulin and how does it work

Answer 5

Involved in the activation of activated protein C and limits thrombin generation so good for DIC

Question 6

Does thrombomodulin work

Answer 6

Only works if severe DIC patients as decreases mortality but for those with mild coagulopathy it kills them as increases bleeding risk.

Question 7

What is thymosin alpha 1

Answer 7

Immunomodulatory peptide which induces T cell modulation

Question 8

What is ulinastatin

Answer 8

Serine protease inhibitor/ urinary trypsin inhibitor

Question 9

Where do urlinastatin and thymosin alpha 1 work

Answer 9

Used in immune deficiency disorders and aim was to combat immunosuppressive side of sepsis
Works on antigen presenting cells.

Question 10

Does urlinastatin and thymosin alpha 1 work

Answer 10

Preclinical trial - reduced mortality in sepsis
Failed in clinical trial

Question 11

What did the chinese meta-analysis study find regarding sepsis treatment

Answer 11

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

Question 12

What is melatonin

Answer 12

Good antioxidant that regulates sleep and wake cycles.
Its reaction products produce further antioxidants
Can be given orally.

Question 13

Give 3 properties of melatonin

Answer 13

Amphiphilic - gets everywhere
Anti-oxidant
Anti-inflammatory actions

Question 14

Where does melatonin accumulate

Answer 14

Mitochondria - good as site of the most oxidative stress occurs during sepsis

Question 15

How does melatonin preform in pre-clinical trials

Answer 15

LPS (gram negative) and PepG (gram positive) PAMPs given to rats.

Reduced pro-inflammatory cytokines
Reduced mitochondrial damage
Decreased organ dysfunction

Question 16

What side effects were shown with melatonin in DAMSEL1

Answer 16

Drowsiness

Question 17

What is DAMSEL 2

Answer 17

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

Question 18

What was the findings in DAMSEL2

Answer 18

20mg is best dose
No major adverse events

Question 19

Give some other noted benefits of melatonin

Biancatelli et al 2020

Answer 19

Prevents mitochondrial dysfunction
Anti-inflammatory properties (reduced TNF-alpha)
Antioxidant properties
Reduced hepatic injury
Preventing septic cardiomyopathy
Regulates circadian rhythm
Safe

Question 20

What happens to thrombomodulin during sepsis

WIDER READING - Ito et al 2019

Answer 20

Downregulated and function impaired

Question 21

Other than severe DIC induced sepsis, where has thrombomodulin worked in the lungs

WIDER READING - Takahashi 2016

Answer 21

ARDS - HMGB-1 was lowered by rTM administration in mice

Question 22

Other than severe DIC induced sepsis, where has thrombomodulin worked in the kidneys

WIDER READING - Honda 2013

Answer 22

HUS - 5% caused by TM gene mutations.

Used rTM on 3 patients in hapan which stopped thrombocytopenia, haemolysis and renal dysfunction in 3 patients

Question 23

Other than severe DIC induced sepsis, where has thrombomodulin worked in blood vessels

Wider reading - wei 2011

Answer 23

TM when administered reduced atherosclerosis