adjunctive pharmacotherapy in sepsis
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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Adjunctive Pharmacotherapy In Sepsis
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Host Response To Sepsis Immune System Coagulation System Endocrine System Autonomic Nervous System
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Conventional Treatment of Sepsis- Antimicrobial therapy- Get rid source of infection- Respiratory support- Hemodynamic support- Other organ support
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Adjunctive Pharmacotherapy Aim to modify host response to sepsis
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Adjunctive Pharmacotherpy With Positive Results GM-CSF Polyclonal IVIG Recombinant human activated protein C Insulin Therapy Low dose corticosteroid
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Outcomes of Treatment on Severe Sepsis & Septic Shock Russell JA. N Engl J Med 2006; 335 : 1699-713.
TreatmentIndicationMortality (%)NTT**Px grControl grEarly goal-directed therapy
Activated protein C
Low dose corticosteroid
Low tidal volume ventilation
Insulin therapySevere sepsis and septic shock
Severe sepsis at increased risk for deathSevere sepsis with > one organ failure
Septic shock with adrenal insufficiency
Sepsis with ARDS
Critically ill surgical patients33
3125
53
31
4.649
4431
63
40
86
7.716
10
11
29**NNT , number need to save one life 1
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Which are the appropriate adjunctivepharmacotherapies for this patients ?
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Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF)ActionIncrease number of neutrophilsEnhance chemotaxis and bactericidal activityIncrease circulating monocyte and plateletBilgin K. Pediatrics 2001; 107:3641.
- GM-CSF RCT 60 cases of neonatal sepsis with neutropenia (ANC
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Tugrul S,et al. Crit Care 2002, 6 : 357-362Sepsis : endotoxin, exotoxinAction Neutralize toxin Immunoglobulin substitution Reduce pro-inflammatory mediators Increase anti-inflammatory mediatorsPolyclonal Intravenous Immunoglobulin(IVIG)
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Alejandroa MM, etal. In The Cochrane Library Issue 2. Oxford : Update Software Ltd ; 2002, 4Polyclonal IVIGSystematic review 27 RCTsN = 492Reduce 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
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Recombinant Human Activated Protein C (rhAPC)Sepsis
Inflammatory systemCoagulation systemMicro thrombiMultiorgan dysfunction
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Protein C & Activated Protein C
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Dysfunction of Protein C-Activated Protein C SystemDecrease liver PC synthesisCytokine-induced down-regulation of endothelial thrombomodulin and endothelial PC receptorDecrease free protein S (complement activation)Inhibit APC by plasminogen activator inhibitor-1 and PC inhibitorAPC consumption in microthrombotic processMarker of clinical severity and prognosisProtein C & Activated Protein C In Sepsis
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PROWESS Study Multicenter, RCT1,690 adults : severe sepsis with at least one organ dysfunctionrhAPC 24 mcg/kg/hr for 96 hrs Bernard GR. N Engl J Med 2001;344:699-709
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PROWESS Result significantly higher rate of survival (P=0.006)
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Outcomes of PROWESSDecreased mortality 6.1% MR-rhAPC vs Control = 30.8 % vs 24.7 %,P=0.005Decreased 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
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Bernard GR. N Eng J Med 2001; 344: 699-709
rhAPC ( % )rhAPCControl retroperitoneum 12.53.51.10.40.70.50.20.20.20.22.012.12.01.10.50.100.1000.23.0
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Indication for rhAPC in Severe Sepsis DIC Septic shock APACHE II 25 Multiorgan dysfunction Acute respiratory distress syndrome
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Contraindication of rhAPC
recombinant human activated protein C severe sepsis U.S.regulationHemorrhagic stroke 3 2 , epidural catheter European regulation heparin 15 international unit/kg/hr acute coagulopathy sepsis 30,000/ 13
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Clinical trial of rh APC in Pediatric PatientsEarly stop this trial after recruited ~400 patientsNo clinical benefitP.Eisenberg.Investigation of the efficacy and safety of drotrecogin alfa in pediatric severe sepsis.Eli Lilly and Company,21 April 2005