Mervyn SingerBloomsbury Institute of Intensive Care MedicineUniversity College London, UK

The mystery of MOF

How do we get from inflammation to multi-organ failure?

cardiovascular

Is this all pathological?

.. or is the body smarter than we think?

We’ve evolved - adapted - over thousands of years to get to where we are today …

Evolution didn’t happen overnight

We’ve had tens of thousands of years to evolve ...

o .. we deal with trauma, starvation ..

o .. we live in symbiotic harmony with micro-organisms

o .. we generally fight infection very effectively

o .. and we did not travel too far so got used to local conditions

Did everyone die from critical illnessbefore modern medicine came along?

Battle of Trafalgar (1805)Lasted an afternoon

Casualties and prisoners:• French & Spanish 14,000• British 1,500

HMS Victory medical report (Dr Beatty)• 57 crew killed/died soon after battle• 102 wounded:

• performed 10 amputations (mainly leg)• later deaths from gangrene & tetanus

.. only six subsequently died

Amputation in hospital tentGettysburg, July 1863

Cases DeathsFingers 7902 198Forearms 1761 198Upper arms 5540 1273Toes 1519 81Legs 5523 1790Amputation - at thigh 6369 3411

- at knee joint 195 111- at hip joint 66 55

- at ankle 161 119

29,980 amputations performed by Union doctorsduring US Civil War

• hygiene & sterility• fluid resuscitation• blood transfusion, clotting products• oxygen• antibiotics• mechanical ventilation etc ...

Many survived without the paraphernalia of modern medicine in which we trust:

• vaccination

• sanitation/public health

• antibiotics

Modern medicine has given a helping hand

intensive care

MMWR 1999; 48:621

We’re now living much longer …

.. far beyond what evolution ever intended

Life expectancy at birth in England (1540-2011)

Adult sepsis is predominantly a disease of the elderly … .. with comorbidities, altered immune function, etc..

So why do some people live, and some die, from sepsis??

STRESSOR(relative to individual)

mild

moderate

severe

SURVIVAL

SURVIVALbehavioural

physiological

MalAdAPtATioN

SURVIVAL

DEATH

ADAPTATION

hiberna

tion

estivat

ion??

recovery time

minimal organ damage seen in affected organs (both survivors and non-survivors)

organs usually recover if patients recover similar signals in survivors and non-survivors ..

.. but magnitude (up/down) varies

VO2

180±19156±22120±27

(p<0.001)

DO2

501±116515±186404± 96(p=ns)

n

15118

O2ER

0.390.330.29

(p=ns)

REE (% normal)

155±14124±12102±24(p<0.01)

Kreymann et al, Crit Care Med 1993

sepsis sepsis syndrome

septic shock

During recovery from septic shock REE rose to 161±22% baseline

O2 consumption decreases with increasing severity

Myocardial hibernation .. protects against long-lasting hypoperfusion

Survival is not guaranteed ...

.. but it does appear to be preordained to a large extent

And clear

prognostication can

happen as early as the

Emergency Room!

The signature is generally similar in critical illness….… though the writing is bigger in non-survivors

Upregulated

Downregulated

o rat model of faecal peritonitis o awake, fluid-resuscitatedo 72 hour mortality = 25% (die at 18-36h)o stroke volume at 6h predicted outcome

o <0.17 ml -> 93% mortality o ≥0.17 ml -> 20% mortality o area under ROC curve = 0.83

(p=0.033) myocardial transcriptome at 6h

controlsurvivornon-survivor

SV HR troponin BNP T3 adrenaline

IL-6 IL-10 ketonebodies

fattyacids

HDL-cholesterol

glucose

As early as 6 hours ..

So if outcome is largely preordained at an early point, the corollary is that we need to apply a very different strategy in those ‘destined to die’

o we’ve evolved to cope pretty well with critical illnesso evolution hasn’t figured on patients who are old, with

comorbidities ..o host strategy varies … initial fight … then head down if not winningo .. akin to hibernation – allows ‘fittest/best-adapting’ to surviveo need to be cognizant of iatrogenic harmo same signature, but bigger writing in non-survivors ..o .. therapeutic implications??

Summary