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"Management of Sepsis"

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  • Fig. 56.2 Positive blood cultures in severe sepsis. Data from Bochud et al.42
  • Fig. 56.1 Potential risk factors leading to sepsis.
  • Transcript

    • 1. Sepsis and Septic Shock, 2008 Prof J Cohen
    • 2. Sepsis and Septic Shock • Definitions • Epidemiology • Pathogenesis • Principles of management
    • 3. 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
    • 4. Definitions • Sepsis: systemic response to infection manifested by ≥ 2 of: – Temp > 38o C or < 36o C – 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
    • 5. 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
    • 6. InfectionInfection ParasiteParasite VirusVirus FungusFungus BacteriaBacteria TraumaTrauma BurnsBurns SepsisSepsis SIRSSIRSSevereSevere SepsisSepsis SevereSevere SIRSSIRS Adapted from SCCM ACCP Consensus Guidelines shock BSIBSI
    • 7. Epidemiology
    • 8. Where’s the infection ? Abdomen 15% Culture Negative 20% Lung 47% Urine 10% Other 8% Bernard & Wheeler NEJM 336:912, 1997
    • 9. 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
    • 10. Martin et al: N Engl J Med 2003:348:1546
    • 11. 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 Incidenceper100,000 0 5 10 15 20 25 30 35 40 45 Mortality% Angus Crit Care Med 29:1301, 2001 Mortality Incidence
    • 12. Organ dysfunction at time of severe sepsis recognition 0 10 20 30 40 50 60 70 80 PercentofPatients Shock Respiratory Renal Metabolic Coag DIC Bernard NEJM 344:699, 2001
    • 13. Relationship between mortality on ICU and the number of failed organs 0 10 20 30 40 50 60 70 80 90 100 0 1 2 3 4 5 6 From Brealey & Singer, 2000
    • 14. Pathogenesis
    • 15. HOST PARASITE PAMP Pathogen associated Molecular pattern PRR Pathogen recognition receptor
    • 16. Bacterial infection Sepsis and septic shock Excessive host response Host factors lead to cellular damage Organ damage Death
    • 17. Molecular architecture of the IR to sepsis Bacterial factors Cell wall components Extracellular products Host factors Acquired immunity Innate immunity Genetic susceptibility Effector mechanisms Lymphokine storm Chemokine activation Neutrophil migration Vascular inflammation
    • 18. Cohen, Nature: 2002 420:885
    • 19. Hotchkiss et al, NEJM 2003 348:138 Immune activation and immunosuppression in sepsis
    • 20. Management
    • 21. Management of Sepsis • Recognition • Supportive care • Source control • Antibiotics • Specific (adjunctive) therapy
    • 22. 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.
    • 23. 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%
    • 24. Dellinger, Crit Care Med, 2003 31:946 Dellinger, Crit Care Med, 2003 31:946
    • 25. Issues in the rational choice of antibiotics EFFICACY • Spectrum of activity • Pharmacokinetics & pharmacodynamics • Patterns of resistance TOXICITY COST
    • 26. 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
    • 27. Inadequate treatment of bloodstream infections increases ICU mortality Ibrahim et al, Chest 2000 118:146
    • 28. “Non-antibiotic” therapy for sepsis • Low dose steroids • Intensive insulin therapy – tight glycaemic control • Activated protein C • Goal directed therapy
    • 29. 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
    • 30. 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
    • 31. 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
    • 32. 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
    • 33. 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)
    • 34. Intensive insulin therapy in medical patients on ICU Van den Berghe et al, N Engl J Med 2006 354:449
    • 35. Intensive insulin therapy in medical patients on ICU for > 3 days ICU mortality In hospital mortality ARR (%) OR (95% CI) P value 38.1--- 31.3 Δ 6.8% 52.5 --- 43.0 Δ 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
    • 36. 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 of significant hypoglycaemia in “intensive” group 12.1% vs 2.1% p < 0.001
    • 37. 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 randomised pts 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
    • 38. 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 or Single organ failure
    • 39. 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
    • 40. 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
    • 41. 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
    • 42. Early goal-directed therapy in sepsis Standard therapy n=133 Active therapy n=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
    • 43. 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
    • 44. “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

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