SEPSIS-3: THE NEW DEFINITIONS

WHAT THEY SHOULD MEAN TO YOU

MERVYN SINGER
BLOOMSBURY INSTITUTE OF INTENSIVE CARE MEDICINE
UNIVERSITY COLLEGE LONDON, UK
https://www.youtube.com/watch?v=1S8l5D2xr6w
IN THE BEGINNING
THERE WAS “SEPSIS-1”
AND “SEPSIS-2” COULDN’T
R E A L LY A D D T O I T
WE’VE COME TO RECOGNISE MANY ISSUES WITH “OLD” SEPSIS

▪ ‘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 +++++

SEPSIS-3
THERE IS NO RIGHT ANSWER …

.. SO WE TRIED TO DEVELOP - AS BEST WE COULD -

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 / W A R D PAT I E N T I N M I N D
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 A V 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 !
 sepsis isn’t just a systemic does SIRS
what does
pro-inflammatory response really fit within the
1991/2002 ‘shock’ mean?
sepsis construct??

organ CV collapse not

≥2 of 4 SIRS
dysfunction responding to fluid

severe septic
infection sepsis
sepsis shock

too much overlap between what does

‘infection’ and ‘sepsis’ ‘organ dysfunction’

mean?
 sepsis isn’t just a systemic
pro-inflammatory
1991/2002 response

organ CV collapse not

≥2 of 4 SIRS
dysfunction responding to fluid

severe septic
infection sepsis
sepsis shock
 bioenergetic
anti-
immune
inflammatory
metabolic

pro- inflammatory hormonal

cardiovascular

neural endothelial

coagulation
1991/2002

organ CV collapse not

≥2 of 4 SIRS
dysfunction responding to fluid

severe septic
infection sepsis
sepsis shock

too much overlap between

‘infection’ and ‘sepsis’
“ 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

▪ 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

D ATA S P E A K S V O L U M E 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)
 does SIRS
really fit within the
1991/2002
sepsis construct??

organ CV collapse not

≥2 of 4 SIRS
dysfunction responding to fluid

severe septic
infection sepsis
sepsis shock
 SIRS???

• 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 —> SENSITIVE (-ISH) BUT POOR SPECIFICITY

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

n.b. SIRS still has a place when considering possibility of infection but NOT ‘sepsis’
 what does
1991/2002 ‘shock’ mean?

organ CV collapse not

≥2 of 4 SIRS
dysfunction responding to fluid

severe septic
infection sepsis
sepsis shock

what does
‘organ dysfunction’
mean?
 781,725

118,676
??? under-reported

??? over-reported

300,270 213,124
WHAT IS ‘SEPSIS’?

Electronic questionnaire:
94 experienced clinicians (most ICU)

‘unequivocal’ septic shock + MOF

due to Gm- bacteraemia
WHAT IS ‘SEPSIS’?

Electronic questionnaire:
94 experienced clinicians (most ICU)

‘unequivocal’ septic shock + MOF

due to Gm- bacteraemia
SYSTEMATIC REVIEW OF CRITERIA USED FOR SEPTIC SHOCK

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)
SEPTIC SHOCK
V A R I A B LY D E F I N E D — >
4 - F O L D V A 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

n = 44 observational studies

Shankar-Hari et al, JAMA 2016

A DEFINITION —> WHAT SOMETHING ‘IS’,
THE ‘ESSENCE’ OF SOMETHING ..

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

 BETTER-DEFINED TERMINOLOGY

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

BETTER-DEFINED TERMINOLOGY

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

i on? ? ?
ot e n s
to elevate MAP≥65 mmHg despite adequatehfluid
R y p resuscitation
e m ia O
l a c tata
e u s e
id n ’t w
w h y d
Septic shock is defined as a subset of sepsis where

underlying circulatory and cellular/metabolic abnormalities

are profound enough to substantially increase mortality

 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

• 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

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 ? ?

90 day mortality (%) ED enrolled

TRISS ICU enrolled
50 ALBIOS

40 PHOENIX
SEPSISPAM ProMISe
30

ProCESS
20

ARISE
10

0
0 2 4 6 8

lactate (mmol/l)
NICE - GUIDELINES ON SEPSIS (2016)
 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 DIAGNOSTIC FOR SEPSIS
neurological
cardiovascular
dysfunction?
dysfunction? low systolic BP (≤100 mmHg)

qSOFA altered mentation

respiratory ±
metabolic
tachypnoea (≥22/min) dysfunction?

qSOFA mortality (%)

0 ~1
1 ~3
2 ~8-10
3 >20
Dr currently called at NEWS 5 (or 4)
SUMMARY

▪ 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!!!