The Microcirculation as a Therapeutic Target in the Treatment of Sepsis and Shock

Vanina S. Kanoore Edul, M.D.; Arnaldo Dubin, M.D., Ph.D.; Can Ince, Ph.D.


Semin Respir Crit Care Med. 2011;32(5):558-568. 

In This Article

Microvascular Dysfunction During Sepsis

Severe sepsis, septic shock, and multiorgan failure represent ongoing stages of the same illness, in which the systemic response to an infection leads to a generalized inflammatory reaction that is distant from the initial insult.[41] Microcirculatory dysfunction appears early in the course[42] of this disease and is characterized by, among other mechanisms, endothelial dysfunction as a result of the expression of adhesion molecules, leukocyte adherence, rolling and migration, glycocalyx degradation, connexin uncoupling, vascular leakage and tissue edema due to the loss of its barrier function,[43] loss of vascular reactivity associated with the downregulation of receptors, intracellular signaling, and the loss of a hyperemic response. In addition to the loss of vascular reactivity contributing to the distributive alterations seen in microcirculatory flow between and within organ systems, alterations in the hemorheological properties of RBCs (e.g., cell deformability and aggregability) occur in sepsis and are thought to contribute to microcirculatory alterations seen in sepsis.[44]

Early appreciation of the nature of microcirculatory alteration during sepsis was achieved in animal models using intravital microscopy and laser Doppler flowmetry. Lam et al found a reduction in perfused capillary density and an increase in stopped-flow capillaries along with heterogeneity of the blood flow.[45] These changes in capillaries have since been found in different tissues, such as gut villi, heart, and kidneys as well as in humans.

A key consequence of pathologically heterogeneous microcirculatory flow seen during sepsis is that oxygen transport to the tissues gets shunted from the arterioles to the venules, which leaves the microcirculation hypoxemic. This realization resulted in the so-called shunting theory of sepsis, which explained the pathophysiological mechanism underlying the reduced oxygen extraction seen in distributive shock.[11] In a study of hemorrhagic shock in the pig ileum, for example, microcirculatory pO2 decreased during shock below the level of venous pO2. The disparity was termed pO2 gap and disappeared after resuscitation.[46] This pO2 gap is a measurement of the severity of functional shunting and was found to be more severe in a model of endotoxic shock. The pO2 gap seems to reflect the shunting of oxygen from the microcirculation, particularly during sepsis.[11]

In an intravital rat study, Nakajima et al[47] found that endotoxin induced intestinal villi hypoperfusion characterized by decreased RBC velocity and flow, even in a normotensive situation. Indeed, at the same level of hypotension, the microvascular alterations were more severe in endotoxemia than in hemorrhage.[46]

The shunting theory of sepsis explaining the nature of altered oxygen extraction in sepsis was confirmed in a hallmark study of a 24-hour rat cecal ligation and perforation model of sepsis by Ellis et al. These authors studied the oxygen transport in individual capillaries of skeletal muscle[48] and hypothesized that the study of RBC oxygen saturation levels in capillaries would provide evidence of either a mitochondrial failure (unchanged oxygen saturation) or an oxygen transport derangement (decreased oxygen saturation). They found that sepsis caused (1) an increase in stopped-flow capillaries (from 10 to 38%), (2) an increase in the proportion of fast-flow to normal-flow capillaries, and (3) a decrease in capillary venular-end oxygen saturation. Importantly, capillary oxygen extraction increased threefold and was directly related to the degree of stopped flow. It was concluded that in the early stages of sepsis, impaired oxygen transport is likely the result of a microcirculatory dysfunction.[48]


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