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

InfectionInfection

ParasiteParasite

VirusVirus

FungusFungus

BacteriaBacteriaTraumaTrauma

BurnsBurns

SepsisSepsis SIRSSIRSSevereSevereSepsisSepsis

SevereSevereSIRSSIRS

Adapted from SCCM ACCP Consensus Guidelines

shock

BSIBSI

Epidemiology

Where’s the infection ?Abdomen

15%

Culture Negative

20%

Lung47%

Urine 10%

Other8%

Bernard & Wheeler NEJM 336:912, 1997

What’s the infection?

0

10

20

30

40

50

60

70

80

Gram pos Gram neg Fungal

EarlyLate

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

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

Inci

denc

e pe

r 100

,000

0

5

10

15

20

25

30

35

40

45

Mor

talit

y %

Angus Crit Care Med 29:1301, 2001

Mortality

Incidence

Organ dysfunction at time of severe sepsis recognition

0

10

20

30

40

50

60

70

80Pe

rcen

t of P

atie

nts

ShockRespiratoryRenalMetabolicCoagDIC

Bernard NEJM 344:699, 2001

Relationship between mortality on ICU and the number of failed organs

0102030405060708090

100

0 1 2 3 4 5 6

From Brealey & Singer, 2000

Pathogenesis

HOST PARASITE

PAMPPathogen associated

Molecular pattern

PRRPathogen recognition

receptor

Bacterial infection

Sepsis and septic shock

Excessive host response

Host factors lead to cellular damage

Organ damage

Death

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

Cohen, Nature: 2002 420:885

Hotchkiss et al, NEJM 2003 348:138

Immune activation and immunosuppression in sepsis

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...

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.

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 TOXICITYCOST

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 infectionsincreases 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

Favours treatment Favours control

RR 0.88 (0.78 to 0.99) p = 0.03

Annane et al, BMJ 2004 329:480

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

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

Van den Berghe et al, NEJM 2001 345:1359

Tight glycaemic control=80-110 mg/dl (4.4-6.1 mmol/l)

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

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

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

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

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

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 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

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

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

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 whofor their smallness are not visible”

Sir William Petty, 1640