What are the mechanisms of cell injury and resulting organ dysfunction in sepsis/septic shock?

Updated: Oct 07, 2020
  • Author: Andre Kalil, MD, MPH; Chief Editor: Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM  more...
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Sepsis is described as an autodestructive process that permits the extension of the normal pathophysiologic response to infection (involving otherwise normal tissues), resulting in MODS. Organ dysfunction or organ failure may be the first clinical sign of sepsis, and no organ system is immune to the consequences of the inflammatory excesses of sepsis.

The precise mechanisms of cell injury and resulting organ dysfunction in patients with sepsis are not fully understood. MODS is associated with widespread endothelial and parenchymal cell injury occurring via the following proposed mechanisms:

  • Hypoxic hypoxia – The septic circulatory lesion disrupts tissue oxygenation, alters the metabolic regulation of tissue oxygen delivery, and contributes to organ dysfunction; microvascular and endothelial abnormalities contribute to the septic microcirculatory defect in sepsis; ROS, lytic enzymes, vasoactive substances (eg, NO), and endothelial growth factors lead to microcirculatory injury, which is compounded by the inability of the erythrocytes to navigate the septic microcirculation

  • Direct cytotoxicity – Endotoxin, TNF-α, and NO may cause damage to mitochondrial electron transport, leading to disordered energy metabolism; this is called cytopathic or histotoxic anoxia (ie, inability to use oxygen even when it is present)

  • Apoptosis (programmed cell death) – This is the principal mechanism by which dysfunctional cells are normally eliminated; the proinflammatory cytokines may delay apoptosis in activated macrophages and neutrophils, but other tissues, such as the gut epithelium, may undergo accelerated apoptosis; therefore, derangement of apoptosis plays a critical role in tissue injury in patients with sepsis

  • Immunosuppression – Interaction between proinflammatory and anti-inflammatory mediators may lead to an imbalance and an inflammatory reaction, immunodeficiency may predominate, or both may occur

  • Coagulopathy – Subclinical coagulopathy signified by mild elevation of the thrombin time or activated partial thromboplastin time (aPTT) or by a moderate reduction in platelet count is extremely common, but overt DIC is rare; coagulopathy is caused by deficiencies of coagulation system proteins, including protein C, antithrombin III, and TF inhibitors

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