Sepsis and Septic Shock 2008 Prof J Cohen

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 > 38 o. C or < 36 o. C HR > 90 bpm RR > 20 bpm or Pa. CO 2 < 32 mm. Hg 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 Bacteria BSI Adapted from SCCM ACCP Consensus Guidelines SIRS Sepsis Severe SIRS Trauma Burns

Epidemiology

Where’s the infection ? Bernard & Wheeler NEJM 336: 912, 1997

What’s the infection? 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 Mortality Incidence Angus Crit Care Med 29: 1301, 2001

Organ dysfunction at time of severe sepsis recognition Bernard NEJM 344: 699, 2001

Relationship between mortality on ICU and the number of failed organs 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) Extremely likely Very likely Somewhat likely Not very likely Not likely at all Not sure Ramsay, Crit Care 2004 8: R 409. Intensive Care Physicians (n=237)

Initial resuscitation of sepsis: therapeutic goals • Central venous pressure: 8 – 12 mm. Hg • Mean arterial pressure: ≥ 65 mm. Hg • Urine output: 0. 5 m. L/kg/h • Central venous (SVC) or mixed venous oxygen saturation: ≥ 70%

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 q 6 h 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 a. PC 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 (IL 6, 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 6 h 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 mm. Hg – MAP ≥ 65 mm. Hg – Scv. O 2 ≥ 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…. • 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 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