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
Severe
Infection Sepsis SIRS
Sepsis
Fungus
shock Severe
SIRS Trauma
Bacteria
BSI
Burns

Adapted from SCCM ACCP Consensus Guidelines

Epidemiology
 Where’s the infection ?
Abdomen
15%
Urine
10%

Other
Lung 8%
47%
Culture
Negative
20%

Bernard & Wheeler NEJM 336:912, 1997

 What’s the infection?
Pure isolates, total n = 444 pts, 61% micro documented
80
70
60
50
40 Early
Late
30
20
10
0
Gram pos Gram neg Fungal

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
30 45
40
Incidence per 100,000

25
35
Mortality

Mortality %
20 30
25
15
20
10 15
10
5 Incidence
5
0 0
1-4
5-9
<1

5
-14
-19
-24
-29
-34
-39
-44
-49
-54
-59
-64
-69
-74
-79
-84
>8
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
Angus Crit Care Med 29:1301, 2001
 Organ dysfunction at time of severe
sepsis recognition
80
Shock
70 Respiratory
Renal
Percent of Patients

60 Metabolic
Coag
50 DIC

40
30
20
10
0

Bernard NEJM 344:699, 2001

 Relationship between mortality on ICU and
the number of failed organs

100
90
80
70
60
50
40
30
20
10
0
0 1 2 3 4 5 6

From Brealey & Singer, 2000

Pathogenesis
HOST PARASITE

PRR PAMP
Pathogen recognition Pathogen associated
receptor 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
Host factors
Acquired immunity
Effector mechanisms
Innate immunity
Lymphokine storm
Genetic susceptibility
Chemokine activation
Neutrophil migration
Vascular inflammation
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) Intensive Care Physicians (n=237)

Extremely likely 3% 3%

Very likely 27% 29%

Somewhat likely 51% 51%

Not very likely 17% 16%

0% 1%
Not likely at all
2% 0%
Not sure

Ramsay, Crit Care 2004 8:R409.

 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 Favours treatment

Annane et al, BMJ 2004 329:480
 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 super-
infection

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 0.69 (0.50-0.95) 0.02

Δ 6.8%

In hospital 52.5 --- 43.0 0.63 (0.46-0.89) 0.003

mortality Δ 9.5%

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 (%)
Absolute reduction P
Placebo aPC in risk (%) value

All treated pts 30.8 24.7 6.1 0.005

All treated pts

32.1 25.7 6.4 0.009
stratified

All randomised
31.3 24.8 6.5 0.003
pts

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 Active
therapy therapy p
n=133 n=130
But….
• Unexpectedly
In hospital mortality (%)
high placebo mortality
• Unusual (ER) population
All patients 46.5
• Single centre non-blinded 30.5 design
study 0.009

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