The Microcirculation: the Motor of Sepsis

The microcirculation consists of a vast network of small blood vessels whose main purpose is to provide surrounding tissues with an adequate supply of oxygen and nutrients in order to maintain a constant and uninterrupted organ function Ref-1. It is comprised of structures such as arterioles, capillaries and venules, of which there are approximately 10 billion capillaries with an overall cell surface of over 0.5 km2.

structure microcirculation

The main cell types found within the microcirculation are endothelial cells, which line the inside of the microvessels, and smooth muscle cells. Interestingly, these cell types also result in the highest levels of adrenomedullin (ADM) production, with autocrine and paracrine interactions used to regulate microcirculatory blood flow in order to meet the oxygen requirements of the surrounding tissues Ref-1. The endothelial cells lining the microvessels are key to this process by controlling the release of mediators and other regulating substances Ref-2.

The structure and function of the microcirculation is highly heterogeneous between different organs Ref-3, and the number of capillaries may be related to the different functional requirements of specific organs. Microcirculatory blood flow occurs independently of systemic changes in blood pressure Ref-4, with arteriole vasodilation resulting in an increase in capillary perfusion, and arteriole vasoconstriction resulting in a decrease in the number of available capillaries.

 

The microcirculation in sepsis

In sepsis, microcirculatory function is severely disturbed due to a loss in sensitivity and tone Ref-5,6, and a breakdown in microcirculatory structure and cellular interactions, which can lead to fluid loss into the extracellular spaces Ref-7-10. There is also a significant decrease in vessel density and in the proportion of small perfused vessels, which is more severe in non-surviving patients, with alterations also related to the severity of organ dysfunction Ref-11,12. Microcirculatory function has also been shown to improve rapidly in surviving patients and those responding to therapy, even whilst global haemodynamic variables remained similar between surviving and non-surviving patients Ref-13.

Multiple mechanisms are evident in the microcirculation during sepsis, which include:

Microcirculation in sepsis

  • Redistribution of blood flow to more critical body areas
  • Endothelial cell barrier and transduction dysregulation
  • Increased microvascular permeability and capillary leakage
  • Capillary blockage and obstruction
  • Disruption of structure and cellular interactions
  • Impaired smooth muscle tone

Disruption of these mechanisms subsequently contributes to:

Microcirculation damage

  • A reduction in perfused capillaries
  • A reduction in functional capillary density
  • Abnormalities in microcirculatory blood flow
  • Increased cellular injury
  • Increased oedema
  • Developing organ dysfunction

Differences are therefore likely to exist between microcirculatory areas that have a preserved functional capillary density and a normal blood flow, to those where blood flow is impaired or completely absent. This results in an impaired ability to regulate local oxygen delivery, which may lead to the rapid onset of tissue hypoxia Ref-14 and the early stages of organ dysfunction.

The early detection of tissue hypoxia may allow corrective measures to be taken in order to limit potential organ dysfunction and improve outcome. However, tissue hypoxia is difficult to assess due to non-specific clinical signs and a lack of accurate diagnostic tests. In addition, current measurements of hemodynamic and oxygen-derived parameters do not accurately assess the microcirculation where oxygen delivery is most crucial Ref-3.

 

References to The Microcirculation: the Motor of Sepsis

Ref-1: Ince C. The microcirculation is the motor of sepsis. Crit Care. 2005;9 Suppl 4:S13-19.

Ref-2: Vallet B. Endothelial cell dysfunction and abnormal tissue perfusion. Crit Care Med. 2002;30(5 Suppl):S229-234.

Ref-3: Hernandez G, Bruhn A, Ince C. Microcirculation in sepsis: new perspectives. Curr Vasc Pharmacol. 2013;11(2):161-169.

Ref-4: Klijn E, Den Uil CA, Bakker J, Ince C. The heterogeneity of the microcirculation in critical illness. Clin Chest Med. 2008;29(4):643-654, viii.

Ref-5: Baker CH, Wilmoth FR. Microvascular responses to E. coli endotoxin with altered adrenergic activity. Circ Shock. 1984;12(3):165-176.

Ref-6: Price SA, Spain DA, Wilson MA, Harris PD, Garrison RN. Subacute sepsis impairs vascular smooth muscle contractile machinery and alters vasoconstrictor and dilator mechanisms. J Surg Res. 1999;83(1):75-80.

Ref-7: Cerwinka WH, Cooper D, Krieglstein CF, Ross CR, McCord JM, Granger DN. Superoxide mediates endotoxin-induced platelet-endothelial cell adhesion in intestinal venules. Am J Physiol Heart Circ Physiol. 2003;284(2):H535-541.

Ref-8: Martins PS, Kallas EG, Neto MC, Dalboni MA, Blecher S, Salomao R. Upregulation of reactive oxygen species generation and phagocytosis, and increased apoptosis in human neutrophils during severe sepsis and septic shock. Shock. 2003;20(3):208-212.

Ref-9: Victor VM, Rocha M, De la Fuente M. Immune cells: free radicals and antioxidants in sepsis. Int Immunopharmacol. 2004;4(3):327-347.

Ref-10: Fink MP. Intestinal epithelial hyperpermeability: update on the pathogenesis of gut mucosal barrier dysfunction in critical illness. Curr Opin Crit Care. 2003;9(2):143-151.

Ref-11: De Backer D, Creteur J, Preiser JC, Dubois MJ, Vincent JL. Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med. 2002;166(1):98-104.

Ref-12: Trzeciak S, Dellinger RP, Parrillo JE, et al. Early microcirculatory perfusion derangements in patients with severe sepsis and septic shock: relationship to hemodynamics, oxygen transport, and survival. Ann Emerg Med. 2007;49(1):88-98, 98 e81-82.

Ref-13: Sakr Y, Dubois MJ, De Backer D, Creteur J, Vincent JL. Persistent microcirculatory alterations are associated with organ failure and death in patients with septic shock. Crit Care Med. 2004;32(9):1825-1831.

Ref-14: Ellis CG, Jagger J, Sharpe M. The microcirculation as a functional system. Crit Care. 2005;9 Suppl 4:S3-8.

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