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 :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 PaCO 2 < 32 mmHg – WBC > 12 x 10 9 /L, 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 :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

Infection Parasite Virus Fungus Bacteria Trauma Burns Sepsis SIRS SevereSepsis SevereSIRS Adapted from SCCM ACCP Consensus Guidelines shock BSI

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 :116

Martin et al: N Engl J Med 2003:348:1546

Severe sepsis incidence and mortality increase with age Angus Crit Care Med 29:1301, 2001 Mortality Incidence

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 PARASITE PAMP Pathogen associated Molecular pattern PRR Pathogen 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 factors Cell wall components Extracellular products Host factors Acquired immunity Innate immunity Genetic susceptibility Effector mechanisms Lymphokine storm Chemokine activation Neutrophil migration Vascular inflammation

Cohen, Nature: :885

Hotchkiss et al, NEJM :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... 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 :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, :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

Adequate initial antibiotic therapy reduces mortality Kollef et al, Chest :462

Inadequate treatment of bloodstream infections increases ICU mortality Ibrahim et al, Chest :146

Impact of antibiotic choice on survival of community-acquired BSI Vallés et al, Chest :1615

“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 treatmentFavours control RR 0.88 (0.78 to 0.99) p = 0.03 Annane et al, BMJ :480

Effect of steroids on shock reversal Favours treatmentFavours control RR 1.6 (1.27 to 2.03) p < Annane et al, BMJ :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 :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 :111

Intensive insulin therapy in critically ill patients Van den Berghe et al, NEJM :1359 Tight glycaemic control= mg/dl ( mmol/l)

Intensive insulin therapy in medical patients on ICU Van den Berghe et al, N Engl J Med :449

Intensive insulin therapy in medical patients on ICU for > 3 days ICU mortality In hospital mortality ARR (%)OR (95% CI)P value Δ 6.8% Δ 9.5% 0.69 ( ) ( )0.003 OR and p value corrected for type & severity of illness Van den Berghe et al, N Engl J Med :449

Growing concerns about tight glycaemic control Uncertainty about feeding regimen and highly selected pt population in first NEJM study. Single centre study. Failure of second NEJM study to confirm clear survival benefit German VISEP study terminated because of XS hypoglycaemia & no survival benefit

The VISEP study of intensive insulin therapy and colloid resuscitation in sepsis Brunkhorst et al, N Engl J Med :125 Study terminated at first safety analysis because of significant hypoglycaemia in “intensive” group 12.1% 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 stratified All randomised pts Bernard et al, N Engl J Med :699

Drotrecogin alfa – UK NICE guidelines Drotrecogin alfa (activated) is recommended for use in adult patients who have severe sepsis that has resulted in multiple organ failure (that is, two or more major organs have failed) and who are being provided with optimum intensive care support. The use of Drotrecogin alfa (activated) should only be initiated and supervised by a specialist consultant with intensive care skills and experience in the care of patients with sepsis NICE Technology appraisal 84; September 2004

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 : ADDRESS trial group * APACHE II < 25 or Single organ failure

Meta-analysis of 28d mortality outcomes in the two RCTs of drotrecogin alfa Costa et al, BMC Anesthesiol 2007; 7:5

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 :1368

rivers Rivers et al, N Engl J Med :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 – ScvO 2 ≥ 70% – Urine output ≥ 0.5 ml/kg.hr Rivers et al, N Engl J Med :

Early goal-directed therapy in sepsis Standard therapy n=133 Active therapy n=130 p In hospital mortality (%) All patients Severe sepsis Septic shock Rivers et al, N Engl J Med :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 who for their smallness are not visible” Sir William Petty, 1640