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Adjunctive Pharmacotherapy Adjunctive Pharmacotherapy In SepsisIn SepsisIn SepsisIn Sepsis
“ Aim to modify host response to sepsis ”“ Aim to modify host response to sepsis ” Aim to modify host response to sepsis Aim to modify host response to sepsis
Adjunctive Pharmacotherapy In SepsisSystem Drugs Result
RCT/Systematic RCT/Systematic
Review
Endocrine Corticosteroid (low dose)
Insulin +Insulin +
Coagulation Recombinant activated protein C
A ti th bi IIIAnti-thrombin III
Tissue factor pathway inhibitor
System Drugs ResultSystem Drugs ResultRCT/Systematic
Review Immune GM-CSF
G-CSFPolyclonal IVIGAnti-endotoxinAnti-TNF Interleukin-1-receptor antagonistProstaglandin,leukotrines inhibitor : Ibuprofen, high dose steroidB d ki i t i tBradykinin antagonistElastase inhibitorNitric oxide synthase inhibitorNitric oxide synthase inhibitor
**NNT , number need to save one life**NNT , number need to save one life หมายถึงจํานวนผูปวยที่ใหรักษาเพือ่ทําใหรอดชีวติเพิม่ขึน้ หมายถึงจํานวนผูปวยที่ใหรักษาเพือ่ทําใหรอดชีวติเพิม่ขึน้ 1 1 คนคน
Russell JA. N Engl J Med Russell JA. N Engl J Med 20062006; ; 335 335 : : 16991699--713713..
Which are the appropriate adjunctiveWhich are the appropriate adjunctivepp p jpp p j
pharmacotherapies for this patients ?pharmacotherapies for this patients ?p p pp p p
ActionActionI b f t hilI b f t hilIncrease number of neutrophilsIncrease number of neutrophilsEnhance chemotaxis Enhance chemotaxis and bactericidal activityand bactericidal activityyyIncrease circulating monocyte and plateletIncrease circulating monocyte and platelet
Bilgin K. Pediatrics 2001; 107:36–41.
GMGM CSFCSFGMGM--CSFCSF•• RCTRCT•• RCT RCT •• 60 60 cases of neonatal sepsis with cases of neonatal sepsis with
neutropenianeutropenia ((ANC<ANC<11,,500500))••ResultResult decrease mortalitydecrease mortality••Result Result -- decrease mortalitydecrease mortality
GMGM--CSF : Placebo = CSF : Placebo = 1010% : % : 3030%%-- increase number of neutrophil, increase number of neutrophil, eosinophil monoc te and plateleteosinophil monoc te and plateleteosinophil,monocyte and plateleteosinophil,monocyte and platelet
Neutralize toxinNeutralize toxinNeutralize toxinNeutralize toxinImmunoglobulin substitutionImmunoglobulin substitutionReduce proReduce pro--inflammatory inflammatory mediatorsmediatorsI tiI ti i fl t di ti fl t di tIncrease antiIncrease anti--inflammatory mediatorsinflammatory mediators
(RR = 0.64, 95% CI 0.51-0.80)Conclusion: all trials were small and the e idence is ins fficient to s ppo t ains fficient to s ppo t athe evidence is insufficient to support a insufficient to support a robust conclusion of benefitrobust conclusion of benefit
Alejandroa MM, etal. In The Cochrane Library Issue Alejandroa MM, etal. In The Cochrane Library Issue 22. Oxford : Update Software Ltd ; . Oxford : Update Software Ltd ; 20022002, , 44
robust conclusion of benefitrobust conclusion of benefit
Recombinant Human Activated Protein C Recombinant Human Activated Protein C ((rhAPCrhAPC))(( ))
SepsisSepsispp
Inflammatory systemInflammatory system Coagulation systemCoagulation system
Micro thrombiMicro thrombi
Multiorgan dysfunctionMultiorgan dysfunction
Protein C & Activated Protein CProtein C & Activated Protein CProtein C & Activated Protein CProtein C & Activated Protein C
Protein C & Activated Protein CProtein C & Activated Protein CProtein C & Activated Protein C Protein C & Activated Protein C In SepsisIn Sepsis
Dysfunction of Protein CDysfunction of Protein C--Activated Protein C SystemActivated Protein C System
Decrease liver PC synthesisDecrease liver PC synthesisDecrease liver PC synthesisDecrease liver PC synthesis
CytokineCytokine--induced downinduced down--regulation of endothelial regulation of endothelial thrombomodulin and endothelial PC receptorthrombomodulin and endothelial PC receptorthrombomodulin and endothelial PC receptorthrombomodulin and endothelial PC receptor
Decrease free protein S (complement activation)Decrease free protein S (complement activation)
Inhibit APC by plasminogen activator inhibitorInhibit APC by plasminogen activator inhibitor--1 1 and and PC inhibitorPC inhibitor
APC consumption in microthrombotic processAPC consumption in microthrombotic process
MMarker of clinical severity and prognosisarker of clinical severity and prognosisMMarker of clinical severity and prognosisarker of clinical severity and prognosis
PROWESS St dPROWESS St dPROWESS Study PROWESS Study
11,,690 690 adults : severe sepsis with adults : severe sepsis with ,,690690 adu ts se e e seps s tadu ts se e e seps s tat least one organ dysfunctionat least one organ dysfunction
rhAPCrhAPC 24 24 mcg/kg/hr mcg/kg/hr for for 96 96 hrs hrs
BernardBernard GR. N Engl J Med GR. N Engl J Med 20012001;;344344::699699--709709
PROWESS ResultPROWESS ResultPROWESS ResultPROWESS Resultsignifisignificcantly higher rate of survivalantly higher rate of survival ((PP 00 006006))signifisignificcantly higher rate of survival antly higher rate of survival ((PP==00..006006))
Outcomes of PROWESSOutcomes of PROWESSOutcomes of PROWESSOutcomes 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 grSerious bleeding was higher in the rhAPC gr
(3.5% vs. 2.0%, P=0.06).
Bernard GR. N Eng J Med Bernard GR. N Eng J Med 20012001; ; 344344: : 699699--709709
Contraindication of rhAPCContraindication of rhAPCขอหามใช ขอหามใช recombinant human activated protein C recombinant human activated protein C ใน ใน severe sepsissevere sepsis
Clinical trial ofClinical trial ofClinical trial of Clinical trial of rh APC in Pediatric Patientsrh APC in Pediatric Patients
Early stop this trial Early stop this trial ft it dft it d 400400 ti tti tafter recruited ~after recruited ~400 400 patientspatients
No clinical benefitNo clinical benefitNo clinical benefitNo clinical benefit
P.Eisenberg.Investigation of the efficacy and safety of drotrecogin alfa in pediatric severe sepsis.Eli Lilly P.Eisenberg.Investigation of the efficacy and safety of drotrecogin alfa in pediatric severe sepsis.Eli Lilly and Company,and Company,21 21 April April 20052005