What is the role of microcirculatory dysfunction and mitochondrial depression in the pathophysiology of multiple organ dysfunction syndrome (MODS) in sepsis?

Updated: Jan 27, 2020
  • Author: Ali H Al-Khafaji, MD, MPH, FACP, FCCP, FCCM; Chief Editor: Michael R Pinsky, MD, CM, Dr(HC), FCCP, FAPS, MCCM  more...
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Microcirculation is the key target organ for injury in sepsis since vascular endothelium is universally affected by the circulating inflammatory mediators. Although it is unclear if microcirculatory abnormalities are the cause or an innocent bystander of the end-organ injury, clear microvascular dysfunction is seen. A decrease in the number of perfused capillaries is seen, although with application of vasodilator therapies, full microvascular recruitment occurs. Mitochondrial dysfunction also occurs and is often associated with reduced mitochondrial transmembrane potential gradients, which are necessary to drive oxidative phosphorylation. The end result is an apparent inability of end-organs to extract oxygen maximally.

Debate continues as to whether this failure of energy metabolism is an adaptive cytoprotective mechanism similar to hibernation or reflects primary mitochondrial pathology. These are areas of active research but do not presently translate into clear clinical practice guidelines. Increased capillary endothelial permeability leads to widespread protein-rich tissue edema.

Septic shock and SIRS are characterized by reversible myocardial depression, which can prove resistant to catecholamine and fluid administration. Circulating “myocardial depressant factor”—probably representing the synergistic effects of TNF-α, IL-1β, other cytokines, and NO—is implicated in pathogenesis. The two characteristics of this acute stress myocardial depression are impaired adrenergic responsiveness and diastolic dysfunction leading to relative catecholamine resistance and small rather than dilated hearts. Macrovascular myocardial ischemia and hypoperfusion are unlikely contributors.

In severe sepsis and septic shock, microcirculatory dysfunction and mitochondrial depression cause regional tissue distress, and regional dysoxia therefore persists. This condition is termed microcirculatory and mitochondrial distress syndrome (MMDS). [7] Sepsis-induced inflammatory autoregulatory dysfunction persists, and oxygen need is not matched by supply, leading to MODS.

Redistribution of intravascular fluid volume resulting from reduced arterial vascular tone, diminished venous return from venous dilation, and release of myocardial depressant substances causes hypotension.

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