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  1. 1. Sepsis - the use of modulators of the inflammatory response Dr CM Shevlin August 2013
  2. 2. Sepsis Characterised by systemic cytokine-mediated pro- inflammatory response to invading pathogen Extensive research/clinical trials New targets in pro-inflammatory response emerging at rapid rate Increasing evidence for extensive cross-talk between pro-inflammatory response, anti- inflammatory response, immunomodulation and coagulation cascade
  3. 3. • While PAMPs initiate, dysregulated host response amplifies = cellular injury, SIRS and MOF • Rich source of potential targets Cohen, J. Clin Microbiol Infect 2009; 15: 302–307
  4. 4. Targets for modification The established...corticosteroids... And the aspirational... Cytokines Activated Protein C Renal replacement therapies And many others...
  5. 5. Corticosteroids Substantial evidence that inability to mount appropriate HPA axis response plays a role in systemic inflammation and host inability to suppress Still controversial benefit vs risk...? Not clear whether our current approach to steroid therapy is evidence-based, aimed at “replacement therapy” or modest immunosuppression
  6. 6. Rationale for steroids Evidence for over-activity of pro-inflammatory pathways relative to endogenous glucocorticoid activity Glucocorticoids molecular mechanism of action fits with the pathophysiology of sepsis... Restores cardiovascular stability in sepsis retention of sodium and water synergistic with inotropes
  7. 7. Evidence for steroids Schumer (1976): short course of high dose steroids Cronin et al (1995), Bollaert PE et all (1998), Briegel et al (1999): meta-analyses and large double blind trials = lower dose of hydrocortisone Annane (multiple, 2000-2006)... Became standard of care [fludrocortisone, ACTH test] CORTICUS (2008) Now...? Surviving sepsis guidelines (2013)
  8. 8. Where do we stand? Which patients? Should we performing an ACTH test? When should they given? How long for? How should it be given? IV/PO...Bolus/Infusion
  9. 9. Cytokines Functional class of small protein mediators which affect activation of immune response “Pro-inflammatory” (TNF, IL-1, IL-6, IL12, MIF) activate innate/adaptive immune response and ‘cytokine cascade’ “Anti-inflammatory” (IL-10, TGF, IL-4) attempt to restore immunological equilibrium Redundancy in the system may make targeted therapy ineffective... not simple division into pro- and anti but complex network
  10. 10. Specific cytokine targets TNF probably best example of mediator that has been extensively investigated as a therapeutic target encouraging preclinical evidence, several large phase III clinical trials - no strategy has succeeded IL-1, IL-6 and MIF Anti-inflammatory cytokines - IL10, IL4, TGF
  11. 11. Specific cytokine targets II New players: IL-17 high-mobility group box-1 protein myeloid related proteins Unclear why human trials so far unsuccessful
  12. 12. Activated Protein C aPC developed on basis of Protein C - naturally occurring anticoagulant -consumed in sepsis (correlated with outcome) Additional anti-inflammatory action = preventing excessive generation of thrombin. May prevent production of pro-inflammatory cytokines PROWESS and PROWESS-SHOCK The PROWESS phase 3 clinical trial subsequently showed that the treatment of severe sepsis with rhAPC reduced the relative and absolute death risk by 19.4 and 6.1%, respectively. By what mechanism?
  13. 13. Renal replacement therapies If targeted therapies don’t work... would whole “blood purification”? Rationale: non-selective removal of inflammatory mediators/bacterial products Promising results (case series only) with all techniques - haemofiltration/dialysis, variety adsorption mediums... Ongoing randomised trials
  14. 14. Renal replacement therapies II No large-scale studies with answers to timing, duration, frequency of therapies At least 1 RCT did not demonstrate improvement in clearance or outcome Currently insufficient data to support use of haemofiltration in absence of renal failure
  15. 15. Targets still under investigation Toll-like receptors Beta-adrenergic modulation Anti-microbial peptides Gene inhibition Statin therapy Melatonin Selenium
  16. 16. Conclusion Reducing mortality in sepsis a clinical need that remains unmet Designing appropriate therapies has been particularly challenging Many contributing factors to this Approaching fifty years of widespread knowledge of existence of inflammatory response to sepsis Still only one licensed drug available - corticosteroids