Sepsis Pathophysiology
OVERVIEW
Organisms
- Bacteria
-> Gram +ve’ cocci (staphylococci, streptococci)
-> Gram –ve bacilli (E.coli, Klebsiella, Pseudomonas aeruginosa) - Fungi (Candida)
- Viruses
- Parasites
Complex interaction between
- inciting microbe
- host immune response
- inflammatory pathway
- coagulation pathway
LPS = lipopolysaccharide
TRAF6 = TNF receptor-associated factor 6
NIK = nuclear factor-KB inducing kinase
NF-KB = nuclear factor-KB -> induction of immune response genes
- 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
- 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
References and Links
LITFL
- CCC — Sepsis definitions
Journal articles
- Andrades MÉ, Morina A, Spasić S, Spasojević I. Bench-to-bedside review: sepsis – from the redox point of view. Critical care. 15(5):230. 2011. [pubmed] [free full text]
- Angus DC, van der Poll T. Severe sepsis and septic shock. The New England journal of medicine. 369(9):840-51. 2013. [pubmed]
- Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet (London, England). 365(9453):63-78. 2005. [pubmed]
- Bosmann M, Ward PA. The inflammatory response in sepsis. Trends in immunology. 34(3):129-36. 2013. [pubmed] [free full text]
- Chertoff J, Chisum M, Garcia B, Lascano J. Lactate kinetics in sepsis and septic shock: a review of the literature and rationale for further research. Journal of intensive care. 3:39. 2015. [pubmed] [free full text]
- Landry DW, Oliver JA. The pathogenesis of vasodilatory shock. N Engl J Med. 2001 Aug 23;345(8):588-95. Review. PubMed PMID: 11529214.
- Rittirsch D, Flierl MA, Ward PA. Harmful molecular mechanisms in sepsis. Nat Rev Immunol. 2008 Oct;8(10):776-87. doi: 10.1038/nri2402. Review. PubMed PMID: 18802444; PubMed Central PMCID: PMC2786961.
FOAM and web resources
- EMCrit — Podcast 111 – Fluids in Sepsis, A New Paradigm by Paul Marik (2013)
Critical Care
Compendium
Associate Professor Curtin Medical School, Curtin University. Emergency physician MA (Oxon) MBChB (Edin) FACEM FFSEM Sir Charles Gairdner Hospital. Passion for rugby; medical history; medical education; and asynchronous learning #FOAMed evangelist. Co-founder and CTO of Life in the Fast lane | Eponyms | Books | Twitter |