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

SEPSIS IN 45 MINUTES

WHAT IS SEPSIS?

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

S E P S I S - 2 R E C O G N I S E D P R O B L E M S W I T H S E P S I S - 1 … … B U T L A C K E D E V I D E N C E T O S U P P O R T C H A N G E

R E C O G N I S E D I S S U E S W I T H T H E O L D D E F I N I T I O N S . .

Bad coldPneumonia Peritonitis..

50% of inpatients

1-in-8 ICU patients with sepsis-related MOF

Not very life-threatening!

IMPRECISE!

IMPRECISE!

V E R Y VA G U E C R I T E R I A F O R S E V E R E S E P S I S , S E P T I C S H O C K …

n = 44 observational studies

Shankar-Hari et al, JAMA 2016

‘ O L D ’ 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 AT I O N I N M O R TA L I T Y 1 0 - F O L D VA R I AT I O N I N I N C I D E N C E

▪ Sepsis is a syndrome with no perfect diagnostic test

▪ .. but the science has moved on considerably since 2001

▪ Sepsis is much, much more than systemic inflammation

▪ Patients don’t die of infection per se, but from the consequent

organ dysfunction

▪ Organ dysfunction relates to an abnormal host response

▪ A small minority of people with infection develop ‘bad’ infection

▪ How many people who die from sepsis are/should be salvageable?

. . A N D T H E R E A R E B R O A D E R I S S U E S

A D E F I N I T I O N — >

. . W H AT 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 . .

C L I N I C A L C R I T E R I A O P E R AT I O N A L I Z E T H E D E F I N I T I O N

. . A N D O F F E R C O N S I S T E N C Y S O W E A L L TA L K T H E

S A M E L A N G U A G E

S E P S I S - 3

▪ 850,000 patients (predominantly from US) who had cultures taken and

antibiotics started

▪ ~90% from Emergency Department or Ward

C L I N I C A L C R I T E R I A D E V E L O P E D U S I N G ‘ B I G D ATA’

▪ A new definition .. and more precise clinical criteria to describe sepsis

S E P S I S - 3 P R O V I D E S …

life-threatening organ dysfunction due to a

dysregulated host response to infection

definition

I N F E C T I O Nclinical criteria

S O FA S C O R E … L O O K F O R C H A N G E I N B A S E L I N E ≥2

▪ It's not perfect

▪ .. but long established and well-validated relationship to mortality risk

▪ Uses variables routinely measured in any unwell patient in developed world

and in many LMICs

▪ Assume baseline SOFA = 0 in previously healthy people

▪ Big data analysis showed >10% risk of death if change in SOFA ≥2

▪ SOFA is an epidemiology/research tool .. not intended as a triage tool

S O FA S C O R E

▪ hypotensive

▪ hypoxaemic

▪ hypercarbic

▪ tachycardic

▪ oliguric

▪ hyperlactataemic/acidotic

▪ decreased GCS

▪ ….

. . A N D W E D O N ’ T S T O P T O C A L C U L AT E A PA C H E , S A P S , A K I S C O R E S … O R S O FA

W E T R E AT T H E PAT I E N T I N F R O N T O F U S . .

S E P S I S - 3 P R O V I D E S …

circulatory, cellular, and metabolic abnormalities

associated with greater risk of mortality than sepsis alone

definition

▪ A new definition .. and more precise clinical criteria to describe septic shock

clinical criteria

>2 mmol/l

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

after fluid resuscitation

• Hospital mortality

• 42.3% in patients having both hypotension + hyperlactataemia (>2)

• 25.7% with hyperlactataemia alone

• 30.1% with fluid-resistant hypotension alone

• 25.0% 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 patients with septic shock should have a

substantial increase in mortality above sepsis alone

T H E P R O PA G A N D A : S E P S I S I S A M A J O R K I L L E R …

▪ 34 million antibiotic prescriptions by English GPs in 2015

▪ 1.3 million hospital patient episodes with a sepsis/infection discharge code in England p.a.

▪ .. with 32,300 in-hospital deaths = 2.5% mortality rate

▪ BUT only 36,000 cases of sepsis had an ICU admission, of whom 11,000 died

P L A C I N G ‘ I N F E C T I O N ’ A N D ‘ S E P S I S ’ I N T O P E R S P E C T I V E

“Pneumonia is the old man’s friend” - Sir William Osler

Patients may be allowed to die from/with sepsis due to the severity of their

underlying comorbidity - terminal cancer, end-stage heart/kidney/lung disease,

severe stroke, severe dementia …

H O W M A N Y WA R R A N T E D L I F E - P R O L O N G I N G T H E R A P Y ± I C U A D M I S S I O N ? ? ?

D O PAT I E N T S D I E ‘ F R O M ’ O R ‘ W I T H ’ S E P S I S ?

0

200000

400000

600000

800000

0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90+

‘SUSPICION OF SEPSIS’ ADMISSIONS IN ENGLAND 2011-17N

Age

Mortality (%)

0

10

20

30

0-4 5-9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 85-89 90+

‘SUSPICION OF SEPSIS’ MORTALITY 2011-17

Age

456

115

113

208

306

396

603

933

1812

3196

5165

8359

1470

8

2476

7

3527

0

5562

6

8254

4

9592

5

9803

9

77.5% OF DEATHS 8% OF DEATHS

Dementia? Stroke? Other severe disability?

S E P S I S O U T C O M E S H AV E I M P R O V E D D R A M AT I C A L LY … ?

118,676

213,124300,270

781,725

??? under-reported

??? over-reported

PAT I E N T M A N A G E M E N T

▪ Well-intentioned exercise to raise standards by offering

a standardized, evidence-based approach to Rx

▪ But the evidence base remains poor, and the strength

of most of the recommendations is weak

▪ Multiple bundles of care have been touted … but

subsequently found wanting in prospective RCTs

▪ Today’s dogma = tomorrow’s chip paper

S U R V I V I N G S E P S I S C A M PA I G N G U I D E L I N E S

• single-centre, open study

• March 1997 - March 2000

• ER in inner-city Detroit

• n =263

• half got EGDT for 6 h

• thereafter standard care on

ICU/ward

▪ Disappointing and heavily criticized

(by Royal Colleges etc..)

▪ Evidence base over-extrapolated and

often mis-interpreted

▪ Far too complex

▪ Minimal uptake as considered non-

implementable in routine practice

N I C E ( O R N O T- S O - N I C E ) G U I D E L I N E S

S O W H AT S H O U L D W E D O ?

▪ New (more sensible) guidance hopefully emerging soon from NHS England

▪ Does this patient with suspected infection warrant antibiotic treatment?

▪ Does this patient with suspected infection likely have organ dysfunction (i.e. sepsis)?

▪ Is the unwell patient in front of me possibly septic?

A S K Y O U R S E L F …

▪ 15-30% of patients initially diagnosed as ‘septic’ have a non-infectious condition

▪ qSOFA - a suggested rapid bedside tool in Sepsis-3 for

risk-stratifying patients likely to have sepsis

Q U I C K S O FA :

n.b. qSOFA is not part of the sepsis definitions

qSOFA was never intended to be a screening tool

strong recommendation to prospectively validate qSOFA

in multiple healthcare settings

Dr called at NEWS ≥5

T H E U K N AT I O N A L E A R LY WA R N I N G S C O R E ( N E W S ) M U S T B E S U P E R I O R T O QS O FA A S I T M E A S U R E S A F U R T H E R 4 C R I T E R I A

▪ Plans to roll out NEWS as uniform national score across hospital wards, EDs, community (GPs), nursing homes and ambulance crews

▪ Antibiotics

▪ Source control - pus is poorly treated by antibiotics alone

▪ Remove likely infected lines … + metalwork etc..

I N F E C T I O N M A N A G E M E N T

E V E R Y H O U R O F A N T I B I O T I C D E L AY K I L L S

. . A N E X E R C I S E I N B I O L O G I C A L

I M P L A U S I B I L I T Y

• Multiple papers - including EVERY prospective study I’m aware of - do NOT show a correlation between a short-term delay in administering antibiotics and mortality (!!)

• Many studies also fail to show an outcome difference between appropriate and inappropriate antibiotics (!!)

• ?? under-dosing issues • ?? discordance between in vivo and in vitro sensitivities • ?? inadequate source control • ?? other - ?attributable impact of Abx

• It is reasonable to treat sepsis promptly • .. and, ideally, choose the right antibiotic • But does every second count?

… and no data on antibiotic sensitivities, adequacy of dosing, source control, etc..

0

2

4

6

8

10

12

2011-12 2012-13 2013-14 2014-15 2015-16 2016-17

% M O R TA L I T Y O F PAT I E N T S A D M I T T E D T O H O S P I TA L W I T H ‘ S U S P I C I O N O F S E P S I S ’

( T R U S T S I N N & N E L O N D O N , E S S E X A N D H E R T S )

% mortality

UCLH

UNINTENDED CONSEQUENCES

N H S S E Q U I N D ATA

n=28150 ICU patientslow BP, >6h

low BP, ≤6h

normal BP, ≤6h

normal BP, >6h

n=28150 ICU patientslow BP, >6h

low BP, ≤6h

normal BP, ≤6h

normal BP, >6h

Most septic patients need some fluids … but not too much!

SSC guidelines recommend “at least 30 ml/kg within first 3 hours

(strong recommendation, low quality of evidence)”

However, evidence suggests too much fluid is injurious

So more (physio)logical to give repeated 200-250 ml challenges,

assessing intravascular volume status after each bolus

Lactate = marker of stress .. of which hypovolaemia is but one cause

Rapid normalisation of lactate associated with better prognosis

F L U I D M A N A G E M E N T ( 1 )

What fluid? Currently synthetic colloids are out of favour (though this

relates to many litres of fluid) - importantly, no evidence of benefit

Balanced (e.g. Hartmann’s) or unbalanced (e.g. n-saline) solution.

- no clear evidence to show difference (watch plasma chloride level)

Albumin - mixed evidence base

F L U I D M A N A G E M E N T ( 2 )

Catecholamines recommended as 1st line

.. though increasing evidence of an association with harm

Groundswell for ‘decatecholaminization’ - use lowest possible dose

VA S O A C T I V E D R U G S

Catecholamines recommended as 1st line

.. though increasing evidence of an association with harm

Groundswell for ‘decatecholaminization’ - use lowest possible dose

Target an adequate BP for that patient (NO magic number)

Target adequate organs perfusion

VA S O A C T I V E D R U G S

No proven magic bullet

Steroid controversy still rages … maybe useful in sicker patients??

No alternative pressor shown to be superior to catecholamines

Novel strategies being tested - beta-blockers, nivolumab ….

O T H E R

identify early

resuscitate promptly … but don’t overdo it

antibiotics are additive

.. but does every hour count?

.. 3 hour window adequate for most cases (but shouldn’t unnecessarily delay)

.. not a panacea

.. stop EARLY (4-5 days for most infections)

early source control

target reasonable BP for that patient .. and titrate to response

minimize use of catecholamines (as generally evil)

minimize use of sedatives (as generally evil)

C U R R E N T M A N A G E M E N T ( S I N G E R D O G M A )