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

1. inciting microbe
2. host immune response
3. inflammatory pathway
4. 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)