M E R V Y N S I N G E R B L O O M S B U R Y I N S T I T U T E O F I N T E N S I V E C A R E M E D I C I N E

U N I V E R S I T Y C O L L E G E L O N D O N , U K

S E P S I S - 3 : T H E N E W D E F I N I T I O N S W H A T T H E Y S H O U L D M E A N T O Y O U

https://www.youtube.com/watch?v=1S8l5D2xr6w

I N T H E B E G I N N I N G T H E R E W A S “ S E P S I S - 1 ”

A N D “ S E P S I S - 2 ” C O U L D N ’ T R E A L LY A D D T O I T

▪ ‘Sepsis’ means different things to different people

▪ It’s a syndrome with no perfect diagnostic test

▪ .. though the science has moved on since 2001

▪ Is SIRS still fit for purpose to define ‘sepsis’?

▪ No specified criteria to describe ‘organ dysfunction’ or ‘shock’

▪ .. so the epidemiology is a complete mess

▪ Sepsis is a killer .. but is it a mass murderer? Hype +++++

W E ’ V E C O M E T O R E C O G N I S E M A N Y I S S U E S W I T H “ O L D ” S E P S I S

S E P S I S - 3

. . S O W E T R I E D T O D E V E L O P - A S B E S T W E C O U L D - N E W D E F I N I T I O N S B A S E D O N S C I E N C E , D R I V E N B Y D ATA , A N D W H I C H C O U L D B E E A S I LY A N D C O N S I S T E N T LY A P P L I E D . . A N D W I T H T H E E D / WA R D PAT I E N T I N M I N D

T H E R E I S N O R I G H T A N S W E R …

P L E A S E D O R E A D T H E PA P E R S F O R Y O U R S E LV E S

. . S O M E E D I T O R I A L I S T S / T W E E T E R S H AV E C L E A R LY N O T

… A N D G O T I T B A D LY W R O N G !

infection

1991/2002

≥2 of 4 SIRS

severe sepsis

septic shocksepsis

organ dysfunction

CV collapse not responding to fluid

sepsis isn’t just a systemic

pro-inflammatory response

too much overlap between

‘infection’ and ‘sepsis’

does SIRS

really fit within the

sepsis construct??

what does

‘organ dysfunction’

mean?

what does

‘shock’ mean?

infection

1991/2002

≥2 of 4 SIRS

severe sepsis

septic shocksepsis

organ dysfunction

CV collapse not responding to fluid

sepsis isn’t just a systemic

pro-inflammatory response

pro- inflammatory

anti-

inflammatory

cardiovascular

hormonal

metabolic

bioenergetic

endothelial

coagulation

neural

immune

infection

1991/2002

≥2 of 4 SIRS

severe sepsis

septic shocksepsis

organ dysfunction

CV collapse not responding to fluid

too much overlap between

‘infection’ and ‘sepsis’

▪ predominantly taken from large US hospital EHR databases

▪ ~ 5 million patient encounters in wide range of hospitals

▪ ~ 850,000 patients with suspected infection (cultures/Abx)

▪ ~ 90% outside the ICU

“ B I G D ATA ” U S E D T O U N D E R P I N R E C O M M E N D AT I O N S

▪ 12 Pittsburgh/W Pennsylvania hospitals (big + small)

▪ 1.3M patient encounters

▪ 11% (149K) suspected infection (89% ED/ward)

▪ … of these, only 4% (6347) died

▪ … ?? from or with infection (e.g. COPD, cancer)

▪ … how many of these suspected cases were truly infected??

▪ i.e. at most, only 1 in 200 of the entire population died of/with

sepsis (infection + organ dysfunction)

D ATA S P E A K S V O L U M E S

infection

1991/2002

≥2 of 4 SIRS

severe sepsis

septic shocksepsis

organ dysfunction

CV collapse not responding to fluid

does SIRS

really fit within the

sepsis construct??

• SIRS usually represents an appropriate body response to infection .. even a bad cold

• .. but does this make the infection “sepsis” ????

• Need to clearly differentiate straightforward infection from a life-threatening “bad” infection

• SIRS has both sensitivity and specificity issues

SIRS???

n.b. SIRS still has a place when considering possibility of infection but NOT ‘sepsis’

Am J Respir Crit Care Med 2015; 192:958-964

S I R S — > S E N S I T I V E ( - I S H ) B U T P O O R S P E C I F I C I T Y

infection

1991/2002

≥2 of 4 SIRS

severe sepsis

septic shocksepsis

organ dysfunction

CV collapse not responding to fluid

what does

‘organ dysfunction’

mean?

what does

‘shock’ mean?

118,676

213,124300,270

781,725

??? under-reported

??? over-reported

‘unequivocal’ septic shock + MOF due to Gm- bacteraemia

Electronic questionnaire:

94 experienced clinicians (most ICU)

W H A T I S ‘ S E P S I S ’ ?

W H A T I S ‘ S E P S I S ’ ?

‘unequivocal’ septic shock + MOF due to Gm- bacteraemia

Electronic questionnaire:

94 experienced clinicians (most ICU)

S Y S T E M A T I C R E V I E W O F C R I T E R I A U S E D F O R S E P T I C S H O C K

hypotension (SAP <90, MAP <60 or <70, fall in SAP >40) AND/OR

.. that persists despite adequate fluid resuscitation (either unspecified or after challenges of either 20 ml/kg OR 1000 ml)

AND/OR biochemical variables (e.g. lactate >2 or >4, or base deficit >5)

AND/OR use of inotropes and/or vasopressors [±dose specified]

AND/OR new onset organ dysfunction (defined variably using APACHE II, APACHE III,

or SOFA cardiovascular component)

n = 44 observational studies

Shankar-Hari et al, JAMA 2016

S E P T I C S H O C K VA R I A B LY D E F I N E D — > 4 - F O L D VA R I A T I O N I N M O R TA L I T Y 1 0 - F O L D VA R I A T I O N I N I N C I D E N C E

A D E F I N I T I O N — > W H A T S O M E T H I N G ‘ I S ’ , T H E ‘ E S S E N C E ’ O F S O M E T H I N G . .

Sepsis is defined as life–threatening organ dysfunction due to a

dysregulated host response to infection

Septic shock is defined as a subset of sepsis where underlying

circulatory and cellular/metabolic abnormalities are profound

enough to substantially increase mortality

B E T T E R - D E F I N E D T E R M I N O L O G Y

Organ dysfunction is characterized by a rise in total SOFA ≥2

- assume SOFA = 0 unless patient known to have abnormal score prior

- SOFA ≥2 associated with >10% chance of dying in hospital

- For formal characterisation of ‘sepsis’ SOFA can be scored retrospectively …

… but actively treat patient in interim

B E T T E R - D E F I N E D T E R M I N O L O G Y

Shock is characterised by lactate >2 mmol/l and vasopressors needed

to elevate MAP≥65 mmHg despite adequate fluid resuscitation

Septic shock is defined as a subset of sepsis where

underlying circulatory and cellular/metabolic abnormalities

are profound enough to substantially increase mortality

why didn’t we use lactataemia OR hypotension???

• 28,150 infected patients with ≥2 SIRS criteria + ≥1 organ dysfunction

after fluid resuscitation

• Hospital mortality

• 42.3% in patients having both hypotension + hyperlactataemia

• 25.7% with hyperlactataemia alone

• 30.1% with fluid-resistant hypotension alone

• 25% with organ dysfunction but lactate ≤2 and MAP ≥65

S U R V I V I N G S E P S I S C A M PA I G N ( S S C ) R E G I S T R Y

0

10

20

30

40

50

0 2 4 6 8

ARISE

ALBIOS

ProCESS

TRISS

PHOENIXSEPSISPAM

lactate (mmol/l)

90 day mortality (%) ED enrolled ICU enrolled

ProMISe

I S I C U L A C TA T E T H E S A M E A S E D L A C TA T E ? ?

N I C E - G U I D E L I N E S O N S E P S I S ( 2 0 1 6 )

Q S O FA = Q U I C K B E D S I D E S T R A T I F I C A T I O N T O O L . . NOT A D I A G N O S T I C F O R S E P S I S

tachypnoea (≥22/min)

low systolic BP (≤100 mmHg)

altered mentationqSOFA

qSOFA mortality (%)0 ~11 ~32 ~8-103 >20

cardiovascular dysfunction?

neurological dysfunction?

respiratory ± metabolic

dysfunction?

Dr currently called at NEWS 5 (or 4)

S U M M A R Y

▪ SEPSIS-3 offers (we hope) objectivity, reproducibility and

generalizability for research, for coding, for epidemiology ..

▪ qSOFA may be a useful bedside prompt to highlight at-risk patients

▪ needs prospective validation

▪ embedded within NEWS (standard-of-care EWS in UK)

▪ NOT the final word - it’s an iterative process ..

▪ … Sepsis-4 will improve on Sepsis-3

▪ .. but I do hope it is progress!!!