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
Fungus
Severe
Sepsis
shock
SIRS
Sepsis
Severe
SIRS Trauma
Bacteria
BSI
Adapted from SCCM ACCP Consensus Guidelines
Burns
Epidemiology
Where’s the infection ?
Abdomen
15%
Urine
10%
Lung
47%
Bernard & Wheeler NEJM 336:912, 1997
Other
8%
Culture
Negative
20%
What’s the infection?
Pure isolates, total n = 444 pts, 61% micro documented
80
70
60
50
Early
Late
40
30
20
10
0
Gram pos
Gram neg
Cohen et al, J Infect Dis 1999 180:116
Fungal
Martin et al: N Engl J Med 2003:348:1546
Severe sepsis incidence and mortality
increase with age
45
40
25
35
Mortality
20
30
25
15
20
10
15
10
Incidence
5
5
0
Angus Crit Care Med 29:1301, 2001
>8
5
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
5-9
1-4
<1
0
Mortality %
Incidence per 100,000
30
Organ dysfunction at time of severe
sepsis recognition
80
Percent of Patients
70
60
50
40
30
20
10
0
Bernard NEJM 344:699, 2001
Shock
Respiratory
Renal
Metabolic
Coag
DIC
Relationship between mortality on ICU and
the number of failed organs
100
90
80
70
60
50
40
30
20
10
0
0
From Brealey & Singer, 2000
1
2
3
4
5
6
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
Immune 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
3%
3%
Very likely
51%
51%
Not very likely
Not sure
29%
27%
Somewhat likely
Not likely at all
Intensive Care Physicians (n=237)
16%
17%
0%
2%
Ramsay, Crit Care 2004 8:R409.
1%
0%
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
Annane et al, BMJ 2004 329:480
Favours control
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 double-blind
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
ICU mortality
38.1--- 31.3
Δ 6.8%
0.69 (0.50-0.95)
0.02
In hospital
mortality
52.5 --- 43.0
Δ 9.5%
0.63 (0.46-0.89)
0.003
OR and p value corrected for type & severity of illness
Van den Berghe et al, N Engl J Med 2006 354:449
The VISEP study of intensive insulin therapy and
colloid resuscitation in sepsis
Study terminated at first safety analysis because of
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
p
But….
•
Unexpectedly
high
placebo
mortality
In hospital mortality (%)
• Unusual (ER) population
46.5
30.5 design
0.009
All patients
• Single centre non-blinded
study
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