Download Sepsis - Pathophysiology

Sepsis - Pathophysiology
22/8/10
OH
Organisms
- Bacteria
-> Gram +ve’ cocci (staphylococci, streptococci)
-> Gram –ve bacilli (E.coli, Klebsiella, Pseudomonas aeruginosa)
- Fungi (Candida)
- Viruses
- Parasites
Complex interaction between
(1)
(2)
(3)
(4)
inciting microbe
host immune response
inflammatory pathway
coagulation pathway
Jeremy Fernando (2011)
LPS = lipopolysaccharide
TRAF6 = TNF receptor-associated factor 6
NIK = nuclear factor-KB inducing kinase
NF-KB = nuclear factor-KB -> induction of immune response genes
Jeremy Fernando (2011)
- pathogen binds to toll-like receptors (TLR’s) on surface of immune cells (monocytes)
- pro-inflammatory cytokines released -> TNF-alpha, IL-1ß, IL-2, IL-6 -> increased NO
synthase activity on endothelial cells
- anti-inflammatory cytokines released -> IL-4 and IL-10
- pro-coagulation cytokines -> TF -> FVII release
-> endothelial injury and activation of coagulation cascade
Inflammation –> neutrophil chemotaxis, increased capillary permeability, macrophage
activation, lytic enzyme induction
Jeremy Fernando (2011)
Coagulation –> fibrin production
Fibrinolytic pathway suppression –> decreased APC and tPa activity -> decreased
plasmin production
= microvascular thrombosis -> ischaemia -> organ dysfunction -> death
Pro-inflammatory mediators and pathways
Cytokines – TNF, IL-1, IL-6, IL-8, IFN-y
Coagulation pathways
Macrophages, monocytes, neutrophils
Endothelial cells
Platelets
Oxygen free radicals
Proteases
NO
Anti-inflammatory mediators
IL-4, IL 10, IL-11, IL-13
Transforming growth factor Beta
CSF
Soluble TNF receptors
IL-1 receptor antagonist
Natural anticoagulants
O2 delivery in Sepsis
- DO2 increased in septic shock from increased Q
- VO2 increased c/o raised tissue metabolic activity -> mitochondrial dysfunction
Lactic acidosis in Sepsis
- impaired regional microvascular blood flow & autoregulation
- mitochondrial dysfunction with impaired pyruvate oxidation
- excess catecholamines may impair hepatic lactate extraction (by reducing regional hepatic
blood flow)
- lactate clearance is decreased because pyruvate dehydrogenase activity is reduced in both
skeletal muscle and liver.
NB:
- tissue hypoxia may not be a major mechanism & NMR spectroscopy suggests that
hyperlactaemia may occur without tissue hypoxia
- net lactate production from the hepatosplanchnic bed is uncommon in sepsis
Jeremy Fernando (2011)