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

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


CCC 700 6

Critical Care

Compendium

Emergency physician MA (Oxon) MBChB (Edin) FACEM FFSEM with a passion for rugby; medical history; medical education; and informatics. Asynchronous learning #FOAMed evangelist. Co-founder and CTO of Life in the Fast lane | Eponyms | Books | vocortex |

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