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

Sepsis

SIRS
Severe SIRS Trauma

Bacteria
BSI

Burns

Adapted from SCCM ACCP Consensus Guidelines

Epidemiology

Wheres the infection ?

Abdomen 15% Urine 10% Other 8% Culture Negative 20%

Lung 47%

Bernard & Wheeler NEJM 336:912, 1997

Whats the infection?

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

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 35 30 25 15 10 5 0 20 15

Incidence per 100,000

25 20

Incidence
1-4 5-9 <1 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 >8 5

10 5 0

Angus Crit Care Med 29:1301, 2001

Mortality %

Mortality

Organ dysfunction at time of severe sepsis recognition

80 70
Shock Respiratory Renal Metabolic Coag DIC

Percent of Patients

60 50 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
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) Intensive Care Physicians (n=237)

Extremely likely Very likely Somewhat likely Not very likely Not likely at all Not sure

3% 27% 51% 17% 0% 2%

3% 29% 51% 16% 1% 0%

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 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 (%)
ICU mortality 38.1--- 31.3 6.8%

OR (95% CI)
0.69 (0.50-0.95)

P value
0.02

In hospital mortality

52.5 --- 43.0 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 All treated pts All treated pts stratified All randomised pts 30.8

Absolute reduction aPC in risk (%)

6.1

P value
0.005

24.7

32.1

25.7

6.4

0.009

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. mortality (%) high placebo mortality Unexpectedly In hospital Unusual (ER) population 46.5 30.5 0.009 All patients centre non-blinded study design Single
Severe sepsis 30.0 56.8 14.9 42.3 0.06 0.04

Septic shock

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