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

And prognostication can happen as early as the Emergency Department …

n=1886 CAP patients

C O R O L L A R Y

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

2)&2&

7

2&

( -6 A

4E E C 4E A4 -6 A

2

1 B4

146C 6 7

2(

-4C I1 B

- E4 71 B

0 6A CI/ 4

2 4E6 7 6A ECAE 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

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

controlsurvivornon-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

controlsurvivornon-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 )

controlsurvivornon-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 )

controlsurvivornon-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 )

controlsurvivornon-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 )

controlsurvivornon-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 )

OK, so we can predict death, … what can we do about it?

Can we ‘beat’ nature?

mouse CLP model bloods taken 6h post-CLP

- 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

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

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2&

( -6 A

4E E C 4E A4 -6 A

2

1 B4

146C 6 7

2(

-4C I1 B

- E4 71 B

0 6A CI/ 4

2 4E6 7 6A ECAE E AA7 4 B

Survivors

Non-survivors

EsmololPlacebo

EsmololPlacebo

Davide Andreis and Vic Khaliq

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 ?

placeboesmolol

100

80

60

40

20

00 12 24 36 48 60 72

Predicted survivorsSurvival (%)

Time (h)

100

80

60

40

20

00 12 24 36 48 60 72

Predicted non-survivorsSurvival (%)

Time (h)

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