Effects of impaired microvascular flow regulation on metabolism-perfusion matching and organ function

Abstract

Impaired tissue oxygen delivery is a major cause of organ damage and failure in critically ill patients, which can occur even when systemic parameters, including cardiac output and arterial hemoglobin saturation, are close to normal. This review addresses oxygen transport mechanisms at the microcirculatory scale, and how hypoxia may occur in spite of adequate convective oxygen supply. The structure of the microcirculation is intrinsically heterogeneous, with wide variations in vessel diameters and flow pathway lengths, and consequently also in blood flow rates and oxygen levels. The dynamic processes of structural adaptation and flow regulation continually adjust microvessel diameters to compensate for heterogeneity, redistributing flow according to metabolic needs to ensure adequate tissue oxygenation. A key role in flow regulation is played by conducted responses, which are generated and propagated by endothelial cells and signal upstream arterioles to dilate in response to local hypoxia. Several pathophysiological conditions can impair local flow regulation, causing hypoxia and tissue damage leading to organ failure. Therapeutic measures targeted to systemic parameters may not address or may even worsen tissue oxygenation at the microvascular level. Restoration of tissue oxygenation in critically ill patients may depend on restoration of endothelial cell function, including conducted responses.

Keywords: conducted responses; critical illness; heterogeneity; microvascular networks; oxygen transport.

FIGURE 1

Representative microvascular network derived from observations of rat mesentery illustrating structural heterogeneity. A, Main arteriolar inflow. V: Main venular outflow (reprinted from Roy et al.)

FIGURE 2

Schematic diagrams indicating how lack of ventilation-perfusion matching or metabolism-perfusion matching can cause hypoxia. A, (a) In the lungs, if poorly ventilated alveoli (indicated by small shaded shape) receive high perfusion, then blood may be poorly oxygenated. Thicknesses of lines represent relative distribution of blood flow. (b) In the systemic circulation, if tissue regions with high metabolic demand by mitochondria (represented by large shaded shape) receive low perfusion, then oxygen supply may be inadequate. B, (c) Redistribution of flow in the lungs, for example, by hypoxic vasoconstriction, reduces flow to poorly ventilated regions, improving overall blood oxygenation. (d) Redistribution of flow in peripheral circulation, for example, by local metabolic regulation of blood flow, increases flow to regions of high metabolic demand, improving tissue oxygenation (represented by large unshaded shape). C, Effects of heterogeneous capillary flow rates on oxygen delivery. Oxygen saturation in arteriole A is set to 1. In the homogeneous case, capillaries C1-C4 all have flow of 2.5 (arbitrary units). Saturation in venule V is 0.2, that is, 80% extraction. In the heterogeneous case, the same flow is distributed (1, 2, 3, 4) to capillaries C1-C4. Mixed saturation in V is 0.3 (dashed line), that is, 70% extraction. C1 is anoxic along its downstream half, implying tissue hypoxia. For simplicity, oxygen delivery per unit length is held constant if saturation is above zero

FIGURE 3

Schematic illustrating the “dimensional problem.” A, Network supplying a two-dimensional region. B. Network supplying a three-dimensional region