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Sepsis and Septic Shock, 2008
Prof J Cohen
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Sepsis and Septic Shock
• Definitions
• Epidemiology
• Pathogenesis
• Principles of management
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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
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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
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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
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InfectionInfection
ParasiteParasite
VirusVirus
FungusFungus
BacteriaBacteriaTraumaTrauma
BurnsBurns
SepsisSepsis SIRSSIRSSevereSevereSepsisSepsis
SevereSevereSIRSSIRS
Adapted from SCCM ACCP Consensus Guidelines
shock
BSIBSI
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Epidemiology
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Where’s the infection ?
Abdomen15%
Culture Negative
20%
Lung47%
Urine 10%
Other8%
Bernard & Wheeler NEJM 336:912, 1997
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What’s the infection?
0
10
20
30
40
50
60
70
80
Gram pos Gram neg Fungal
Early
Late
Pure isolates, total n = 444 pts, 61% micro documented
Cohen et al, J Infect Dis 1999 180:116
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Martin et al: N Engl J Med 2003:348:1546
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Severe sepsis incidence and mortality increase with age
0
5
10
15
20
25
30
<1 1-4
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
Inc
ide
nc
e p
er
10
0,0
00
0
5
10
15
20
25
30
35
40
45
Mo
rta
lity
%
Angus Crit Care Med 29:1301, 2001
Mortality
Incidence
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Organ dysfunction at time of severe sepsis recognition
0
10
20
30
40
50
60
70
80
Perc
en
t o
f P
ati
en
ts
Shock
Respiratory
Renal
Metabolic
Coag
DIC
Bernard NEJM 344:699, 2001
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Relationship between mortality on ICU and the number of failed organs
0102030405060708090
100
0 1 2 3 4 5 6
From Brealey & Singer, 2000
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Pathogenesis
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HOST PARASITE
PAMPPathogen associated
Molecular pattern
PRRPathogen recognition
receptor
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Bacterial infection
Sepsis and septic shock
Excessive host response
Host factors lead to cellular damage
Organ damage
Death
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Molecular architecture of the IR to sepsis
Bacterial factorsCell wall componentsExtracellular products
Host factorsAcquired immunityInnate immunityGenetic susceptibility
Effector mechanismsLymphokine storm
Chemokine activationNeutrophil migration
Vascular inflammation
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Cohen, Nature: 2002 420:885
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Hotchkiss et al, NEJM 2003 348:138
Immune activation and immunosuppression in sepsis
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Management
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Management of Sepsis
• Recognition• Supportive care• Source control• Antibiotics• Specific (adjunctive) therapy
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How likely is it that the diagnosis of sepsis is being missed? Is it...
17%
27%
51%
2%
0%
3%
0%
1%
16%
51%
29%
3%Extremely likely
Very likely
Somewhat likely
Not very likely
Not likely at all
Not sure
Total (n=497) Intensive Care Physicians (n=237)
Ramsay, Crit Care 2004 8:R409.
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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%
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Dellinger, Crit Care Med, 2003 31:946
Dellinger, Crit Care Med, 2003 31:946
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Issues in the rational choice of antibiotics
EFFICACY• Spectrum of activity• Pharmacokinetics & pharmacodynamics• Patterns of resistance
TOXICITY
COST
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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
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Inadequate treatment of bloodstream infectionsincreases ICU mortality
Ibrahim et al, Chest 2000 118:146
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“Non-antibiotic” therapy for sepsis
• Low dose steroids
• Intensive insulin therapy
– tight glycaemic control
• Activated protein C
• Goal directed therapy
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Effect of steroids on 28 day mortality
Favours treatment Favours control
RR 0.88 (0.78 to 0.99) p = 0.03
Annane et al, BMJ 2004 329:480
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Effect of steroids on shock reversal
Favours treatmentFavours control
RR 1.6 (1.27 to 2.03) p < 0.0001
Annane et al, BMJ 2004 329:480
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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
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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 super-
infection
Sprung et al, N Engl J Med 2008 358:111
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Intensive insulin therapy in critically ill patients
Van den Berghe et al, NEJM 2001 345:1359
Tight glycaemic control=80-110 mg/dl (4.4-6.1 mmol/l)
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Intensive insulin therapy in medical patients on ICU
Van den Berghe et al, N Engl J Med 2006 354:449
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Intensive insulin therapy in medical patients on ICU for > 3 days
ICU mortality
In hospitalmortality
ARR (%) OR (95% CI) P value
38.1--- 31.3Δ 6.8%
52.5 --- 43.0Δ 9.5%
0.69 (0.50-0.95) 0.02
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
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The VISEP study of intensive insulin therapy and colloid resuscitation in sepsis
Brunkhorst et al, N Engl J Med 2008 358:125
Study terminated at first safety analysis because ofsignificant hypoglycaemia in “intensive” group12.1% vs 2.1% p < 0.001
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PROWESS – Drotrecogin alfa (activated)[activated protein C] in sepsis
P value
Absolute reduction in risk (%)aPCPlacebo
mortality (%)
All treated pts
All treated pts stratified
All randomisedpts
30.8
32.1
31.3
24.7
25.7
24.8
6.1
6.4
6.5
0.005
0.009
0.003
Bernard et al, N Engl J Med 2001 344:699
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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
Abraham et al, NEJM 2005 353: 1332. ADDRESS trial group
* APACHE II < 25 orSingle organ failure
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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
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Early goal directed therapyEarly 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
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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
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Early goal-directed therapy in sepsis
Standardtherapyn=133
Activetherapyn=130
p
In hospital mortality (%)
All patients
Severe sepsis
Septic shock
46.5 30.5 0.009
30.0 14.9 0.06
56.8 42.3 0.04
Rivers et al, N Engl J Med 2001 345:1368
But….• Unexpectedly high placebo mortality• Unusual (ER) population• Single centre non-blinded study design
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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
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“On microbes”
Nor do I doubt if the most formidable armies ever heere upon earth is a sort of soldiers whofor their smallness are not visible”
Sir William Petty, 1640
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