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Adjunctive Pharmacotherapy In Sepsis

Adjunctive Pharmacotherapy In Sepsis. นายแพทย์ เฉลิมไทย เอกศิลป์ สถาบันสุขภาพเด็กแห่งชาติมหาราชินี. Host Response To Sepsis. Immune System Coagulation System Endocrine System Autonomic Nervous System. Conventional Treatment of Sepsis. - Antimicrobial therapy

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Adjunctive Pharmacotherapy In Sepsis

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  1. Adjunctive Pharmacotherapy In Sepsis นายแพทย์ เฉลิมไทย เอกศิลป์ สถาบันสุขภาพเด็กแห่งชาติมหาราชินี

  2. Host Response To Sepsis • Immune System • Coagulation System • Endocrine System • Autonomic Nervous System

  3. Conventional Treatment of Sepsis - Antimicrobial therapy - Get rid source of infection - Respiratory support - Hemodynamic support - Other organ support

  4. Adjunctive Pharmacotherapy “ Aim to modify host response to sepsis ”

  5. Adjunctive Pharmacotherpy With Positive Results • GM-CSF • Polyclonal IVIG • Recombinant human activated protein C • Insulin Therapy • Low dose corticosteroid

  6. Outcomes of Treatment on Severe Sepsis & Septic Shock Russell JA. N Engl J Med 2006; 335 : 1699-713.

  7. Which are the appropriate adjunctive pharmacotherapies for this patients ?

  8. Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) Action Increase number of neutrophils Enhance chemotaxis and bactericidal activity Increase circulating monocyte and platelet Bilgin K. Pediatrics 2001; 107:36–41.

  9. GM-CSF • RCT • 60 cases of neonatal sepsis with • neutropenia (ANC<1,500) • Result - decrease mortality • GM-CSF : Placebo = 10% : 30% • - increase number of neutrophil, eosinophil,monocyte and platelet • - no adverse effects . Bilgin K. Pediatrics 2001; 107:36–41

  10. Polyclonal Intravenous Immunoglobulin (IVIG) Sepsis : endotoxin, exotoxin Action Neutralize toxin Immunoglobulin substitution Reduce pro-inflammatory mediators Increase anti-inflammatory mediators Tugrul S,et al. Crit Care 2002, 6 : 357-362

  11. Polyclonal IVIG Systematic review 27 RCTs N = 492 Reduce overall mortality (RR = 0.64, 95% CI 0.51-0.80) Conclusion: all trials were small and the evidence is insufficient to support a robust conclusion of benefit Alejandroa MM, etal. In The Cochrane Library Issue 2. Oxford : Update Software Ltd ; 2002, 4

  12. Recombinant Human Activated Protein C (rhAPC) Sepsis Inflammatory system Coagulation system Micro thrombi Multiorgan dysfunction

  13. Protein C & Activated Protein C

  14. Protein C & Activated Protein C In Sepsis • Dysfunction of Protein C-Activated Protein C System • Decrease liver PC synthesis • Cytokine-induced down-regulation of endothelial thrombomodulin and endothelial PC receptor • Decrease free protein S (complement activation) • Inhibit APC by plasminogen activator inhibitor-1 and PC inhibitor • APC consumption in microthrombotic process • Marker of clinical severity and prognosis

  15. PROWESS Study • Multicenter, RCT • 1,690 adults : severe sepsis with at least one organ dysfunction • rhAPC 24 mcg/kg/hr for 96 hrs BernardGR. N Engl J Med 2001;344:699-709

  16. PROWESS Result significantly higher rate of survival (P=0.006)

  17. Outcomes of PROWESS • Decreased mortality 6.1% MR-rhAPC vs Control = 30.8 % vs 24.7 %,P=0.005 • Decreased D-dimer and Interleukin-6 • Serious bleeding was higher in the rhAPC gr (3.5% vs. 2.0%, P=0.06). Bernard GR. N Eng J Med 2001; 344: 699-709

  18. Bernard GR. N Eng J Med 2001; 344: 699-709

  19. Indication for rhAPC in Severe Sepsis • DIC • Septic shock • APACHE II ≥ 25 • Multiorgan dysfunction • Acute respiratory distress syndrome

  20. Contraindication of rhAPC

  21. Clinical trial of rh APC in Pediatric Patients • Early stop this trial after recruited ~400 patients • No clinical benefit P.Eisenberg.Investigation of the efficacy and safety of drotrecogin alfa in pediatric severe sepsis.Eli Lilly and Company,21 April 2005

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