Mervyn Singer discusses the use of biomarkers in critical care. Multiple biomarkers - physiological, biochemical, biological - can prognosticate early in critical illness, even in the ED. These biomarkers are numerous - lipids, progesterone, troponin, thyroid stimulating hormone, inflammatory cytokines, mitochondrial dysfunction… so on and so forth! Prognostication can happen as early as the Emergency Department. Studies from the States have found high levels of inflammatory cytokines can predict death, separately from clinical presentation. Therefore, we can predict when critically ill patients are destined to die. So, does this mean that we are just prolonging the life of those destined to die in critical care? Perhaps. Mervyn discusses this being the possible reason for many failed ICU studies. Concurrently, the only progress in critical care in the past 20 years may be due only to less iatrogenic harm. Furthermore, he explains his experiments with rats demonstrating the use of cardiovascular parameters, cytokines, troponins and even cholesterol being accurate prognostic biomarkers. Then, Mervyn goes on to identify the use of steroids in sepsis. He talks about research that demonstrates a benefit to steroid use, but only in those patients predicted to die using the aforementioned biomarkers. This could be a key to selecting an appropriate patient group to allocate a specific treatment too. Furthermore, we examine treating sepsis with beta blockers. Giving beta blockers to everyone has no effect at best and a harmful effect at worst. However, giving beta-blockers to those who were predicted to die conferred benefit! In conclusion, we can predict outcome early in disease. This may allow better selection of patients for certain treatments! We thus need to adopt a completely different strategy for such patients predetermined to die. This also applies to trial design, especially where survival is the endpoint. For more like this, head to our podcast page. #CodaPodcast

1. A R E PAT I E N T S P R E D I C AT E D T O L I V E O R D I E ?
Mervyn Singer
Bloomsbury Institute of Intensive Care Medicine
University College London, UK

5. And prognostication can happen as early as
the Emergency Department …

6. n=1886 CAP patients

9. C O R O L L A RY
Does this explain the failure of so many ICU studies?
Progress in critical care in last 20 years relates to doing
less iatrogenic harm to the patient
Critically ill patients are predestined to survive/die.
And this can even be predicted as early as the ED
Modern medicine supports those predicted to live..
.. but prolongs death in those predicted to die

10. 2)&2&
7
2&
( -6 A
4E E C 4E A
4 -6 A
2
1 B
4
146C 6 7
2(
-4C I
1 B
- E4 7
1 B
0 6A CI
/ 4
2 4E6 7 6A ECA
E E AA7 4 B
FA E C A L P E R I T O N I T I S R AT M O D E L
Vic Khaliq

11. FA E C A L P E R I T O N I T I S R AT M O D E L
40-50% mortality
… which occurs between 18-36h
survivors show marked clinical improvement by 72h
at 6 hours post-insult, clinical severity = mild
- eventual survivors indistinguishable from non-survivors
6 hour sampling of blood and tissue:
controls vs. predicted survivors vs. non-survivors

12. control
survivor
non-survivor
FA E C A L P E R I T O N I T I S R AT ( 6 H O U R S )
heart rate stroke volume
PAT I E N T D ATA

13. control
survivor
non-survivor
IL-6 IL-10
PAT I E N T D ATA
FA E C A L P E R I T O N I T I S R AT ( 6 H O U R S )

14. control
survivor
non-survivor
troponin BNP troponin
BNP
PAT I E N T D ATA
FA E C A L P E R I T O N I T I S R AT ( 6 H O U R S )

15. control
survivor
non-survivor
cholesterol triglycerides cholesterol
PAT I E N T D ATA
FA E C A L P E R I T O N I T I S R AT ( 6 H O U R S )

16. control
survivor
non-survivor
T3 glucagon T3
survivors
non-survivors
PAT I E N T D ATA
FA E C A L P E R I T O N I T I S R AT ( 6 H O U R S )

17. control
survivor
non-survivor
adrenaline noradrenaline adrenaline noradrenaline
PAT I E N T D ATA
FA E C A L P E R I T O N I T I S R AT ( 6 H O U R S )

18. OK, so we can predict death,
… what can we do about it?
Can we ‘beat’ nature?

20. mouse CLP model
bloods taken 6h post-CLP

21. - survival predicted on 6h IL-6 level
.. with a trend to harm in predicted survivors
- dexamethasone 2.5 mg/kg
given 8 and 32h post-CLP

23. sick septic shock patients
tachycardic AND high dose NE
after 24h
Esmolol (vs placebo) ->
improved cardiac function
faster fall in troponin
better recovery of eGFR
faster reduction of NEPI

24. 2)&2&
7
2&
( -6 A
4E E C 4E A
4 -6 A
2
1 B
4
146C 6 7
2(
-4C I
1 B
- E4 7
1 B
0 6A CI
/ 4
2 4E6 7 6A ECA
E E AA7 4 B
Survivors
Non-survivors
Esmolol
Placebo
Esmolol
Placebo
Davide Andreis and Vic Khaliq

25. placebo
esmolol
100
80
60
40
20
0
0 12 24 36 48 60 72
AllSurvival (%)
Time (h)
ß - B L O C K A D E ?

26. placebo
esmolol
100
80
60
40
20
0
0 12 24 36 48 60 72
Predicted survivors
Survival (%)
Time (h)
100
80
60
40
20
0
0 12 24 36 48 60 72
Predicted non-survivors
Survival (%)
Time (h)

27. F I N A L T H O U G H T S
Septic patients and animal models suggest outcome is
determined at an EARLY stage of critical illness
Does this mean we are merely delaying death in those
determined to die with current Rx paradigms??
Challenge is to use this knowledge to do something different
- and hopefully more effective - in those very likely to die
Using this to improve trial design would be a useful start