Sepsis and Septic Shock, 2008

Prof J Cohen

Sepsis and Septic Shock

Definitions
Epidemiology
Pathogenesis
Principles of management

Definitions
Infection: microbial phenomenon
characterised by an inflammatory
response to the presence of micro
organisms or the invasion of normally
sterile host tissue by these organisms
Bacteraemia: the presence of
bacteria in the bloodstream
Septicaemia: no longer used
ACCP/SCCM Consensus Conference: Bone et al, Chest 1992 101:1644

Definitions
Sepsis: systemic response to infection
manifested by 2 of:

Temp > 38oC or < 36oC

HR > 90 bpm
RR > 20 bpm or PaCO2 < 32 mmHg
WBC > 12 x 109/L, < 4 x 109/L or >10% band form

Septic shock: sepsis with hypotension

despite adequate fluid resuscitation, with
perfusion abnormalities that could include,
but are not limited to, lactic acidosis,
oliguria, and/or acute mental status.
ACCP/SCCM Consensus Conference: Bone et al, Chest
1992 101:1644

SIRS and Sepsis

SIRS: Systemic Inflammatory
Response Syndrome
Fever, leucocytosis, organ failure
Recognises difficulty of always
identifying infection, but
As a result, high sensitivity but low
specificity

Parasite

Virus

Infection

Severe
Sepsis Sepsis

SIRS

Fungus

shock

Bacteria
BSI

Adapted from SCCM ACCP Consensus Guidelines

Severe
SIRS Trauma

Burns

Epidemiology

Wheres the infection ?

Bernard & Wheeler NEJM 336:912, 1997

Whats the infection?

Pure isolates, total n = 444 pts, 61% micro documented

Cohen et al, J Infect Dis 1999 180:116

Martin et al: N Engl J Med 2003:348:1546

Severe sepsis incidence and

mortality increase with age

Mortality

Incidence

Angus Crit Care Med 29:1301, 2001

Organ dysfunction at time of

severe sepsis recognition

Bernard NEJM 344:699, 2001

Relationship between mortality on ICU

and
the number of failed organs

From Brealey & Singer, 2000

Pathogenesis

HOST
PRR
Pathogen recognition
receptor

PARASITE
PAMP
Pathogen associated
Molecular pattern

Sepsis and septic shock

Bacterial infection
Excessive host response
Host factors lead to cellular damage
Organ damage
Death

Molecular architecture of the IR to

sepsis

Bacterial factors
Cell wall components
Extracellular products
Effector mechanisms
Lymphokine storm
Chemokine activation
Neutrophil migration
Vascular inflammation

Host factors
Acquired immunity
Innate immunity
Genetic susceptibility

Cohen, Nature: 2002 420:885

mmune activation and immunosuppression in sepsis

Hotchkiss et al, NEJM 2003 348:138

Management

Management of Sepsis
Recognition
Supportive care
Source control
Antibiotics
Specific (adjunctive)
therapy

How likely is it that the diagnosis of

sepsis is being missed? Is it...
Total (n=497)

Extremely likely
Very likely
Somewhat likely
Not very likely
Not likely at all
Not sure
Ramsay, Crit Care 2004 8:R409.

Intensive Care Physicians (n=237)

Initial resuscitation of sepsis:

therapeutic goals

Central venous pressure: 8 12

mmHg
Mean arterial pressure: 65 mmHg
Urine output: 0.5 mL/kg/h
Central venous (SVC) or mixed
venous oxygen saturation: 70%

Dellinger, Crit Care Med, 2003 31:946

Dellinger, Crit Care Med, 2003 31:946

Issues in the rational choice of

antibiotics
EFFICACY
Spectrum of activity
Pharmacokinetics &
pharmacodynamics
Patterns of resistance
TOXICITY
COST

Choosing antibiotics in sepsis

There is no, single, best regimen
Consider the site of the infection
Consider which organisms most often
cause infection at that site
Choose antibiotic(s) with the appropriate
spectrum
After obtaining cultures, give antibiotics
quickly and empirically at
appropriate dose

Inadequate treatment of bloodstream infections

increases ICU mortality

Ibrahim et al, Chest 2000 118:146

Non-antibiotic therapy for sepsis

Low dose steroids
Intensive insulin therapy
tight glycaemic control
Activated protein C
Goal directed therapy

Effect of steroids on 28 day mortality

RR 0.88 (0.78 to 0.99) p = 0.03

Favours treatment Favours control

Annane et al, BMJ 2004 329:480

Effect of steroids on shock reversal

RR 1.6 (1.27 to 2.03) p < 0.0001

Favours control
Annane et al, BMJ 2004 329:480

Favours treatment

CORTICUS
International, prospective doubleblind RCT of hydrocortisone in
patients with moderate severe
septic shock
HC 50 mg q6h for 5 d then tapering
to d 11. No fludrocortisone.
Primary EP 28 d mortality in
nonresponders
Sprung et al, N Engl J Med 2008 358:111

CORTICUS - Results
No effect on 28 day mortality in
whole population or pre-identified
subgroups
Did not reverse shock in whole
population or pre-identified
subgroups
Did reduce the time to shock reversal
No significant problem with superinfection
Sprung et al, N Engl J Med 2008
358:111

Intensive insulin therapy in critically ill

patients

Tight glycaemic control=

80-110 mg/dl (4.4-6.1 mmol/l)

Van den Berghe et al, NEJM 2001 345:1359

Intensive insulin therapy in medical patients

on ICU

Van den Berghe et al, N Engl J Med 2006 354:449

Intensive insulin therapy in medical

patients on ICU for > 3 days
ARR (%)

OR (95% CI)

P value

0.69 (0.50-0.95)

0.02

ICU mortality

38.1--- 31.3
6.8%

In hospital
mortality

52.5 --- 43.0 0.63 (0.46-0.89)

9.5%

OR and p value corrected for type & severity of illness

Van den Berghe et al, N Engl J Med 2006
354:449

0.003

The VISEP study of intensive insulin

therapy and colloid resuscitation in
sepsis

Study terminated at first safety analysis becaus

significant hypoglycaemia in intensive group
12.1% vs 2.1% p < 0.001

Brunkhorst et al, N Engl J Med 2008 358:125

PROWESS Drotrecogin alfa (activated)

[activated protein C] in sepsis
mortality (%)
Placebo

Absolute reduction
aPC
in risk (%)

P
value

All treated pts

30.8

24.7

6.1

0.005

All treated pts

stratified

32.1

25.7

6.4

0.009

All randomised
pts

31.3

24.8

6.5

0.003

Bernard et al, N Engl J Med 2001 344:699

Drotrecogin alfa (activated) is not effective

in adults with severe sepsis and a low risk of
death*, and is associated with an increased
rate of serious bleeding

* APACHE II < 25 or
Single organ failure

Abraham et al, NEJM 2005 353: 1332. ADDRESS trial group

PROWESS Continuing debate

Is there confidence in the baseline
comparability of the populations
especially the subpopulations?
There are variable outcomes
depending on the severity marker
used (IL6, APII, SOFA)
There is no confirmatory study
ADDRESS severe subgroup did not
show benefit

Early goal directed therapy

Purpose: to adjust cardiac preload,
afterload and contractility to balance
oxygen delivery with oxygen demand
Entry criteria: patients in the
emergency dept with severe sepsis &
shock
Plan: randomise to 6h of EGDT before
transfer to ICU
Rivers et al, N Engl J Med 2001 345:1368

Early Goal Directed Therapy

A/E admissions with severe
sepsis/shock treated for 6 h before
ICU transfer
Protocol designed to achieve:
CVP 8 12 mmHg
MAP 65 mmHg
ScvO2 70%
Urine output 0.5 ml/kg.hr
Rivers et al, N Engl J Med 2001 345:1368-77

Early goal-directed therapy in sepsis

Standard
therapy
n=133

Active
therapy
n=130

But.
Unexpectedly high placebo mortality
In hospital mortality (%)
Unusual (ER) population
All patients
46.5
30.5
0.009
Single centre
non-blinded
study
design
Severe sepsis

30.0

14.9

0.06

Septic shock

56.8

42.3

0.04

Rivers et al, N Engl J Med 2001 345:1368

Current controversies
Low dose steroids ? / Not
confirmed
Intensive insulin therapy ? / Not
confirmed safety concerns
Activated protein C Licensed but
? requires confirmation
Goal directed therapy ?/ Requires
confirmation

On microbes
Nor do I doubt if the most formidable armies
ever heere upon earth is a sort of soldiers who
for their smallness are not visible

Sir William Petty, 1640