Adjunctive Pharmacotherapy In Sepsis

Host Response To Sepsis Immune System Coagulation System Endocrine System Autonomic Nervous System

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

Adjunctive Pharmacotherapy Aim to modify host response to sepsis

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

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

Which are the appropriate adjunctivepharmacotherapies for this patients ?

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

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)

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

Recombinant Human Activated Protein C (rhAPC)Sepsis

Inflammatory systemCoagulation systemMicro thrombiMultiorgan dysfunction

Protein C & Activated Protein C

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

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

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

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

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

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

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

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