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

Abstract

In caring for the critically ill, clinicians may face the conundrum of a patient with normal ventilation, cardiac output, and arterial oxygen saturation, but with evidence of renal 1 or hepatic 2 failure.Conventional clinical decision-making in these situations is often based on macroscopic parameters such as heart rate and blood pressure that do not provide insight into conditions at the microvascular level. As a result, therapeutic decisions may not address the underlying pathophysiological derangements leading to organ failure.Normal tissue function depends on adequate oxygen supply.Although cellular hypoxia can result from defects anywhere along the oxygen transport pathway (pulmonary uptake, blood flow, uptake by mitochondria), deficits not attributable to impairment of overall ventilation or blood flow can result from heterogeneous oxygen transport at the microvascular level. Tissue oxygen levels vary widely over short length scales (tens of microns). Microvascular networks are heterogeneous in structure (diameter, length of flow pathways) and function (flow velocity, oxygen content). This heterogeneity can result in impaired oxygen extraction, 3 and regions of hypoxia or anoxia can occur even in tissue that receives an adequate overall oxygen supply. 4,5 This review addresses the role of local regulation of blood flow in overcoming this heterogeneity and matching perfusion to metabolic demand under normal and pathological conditions.

Functional implications of microvascular heterogeneity for oxygen uptake and utilization

“…In the clinical setting, treatment approaches are often based on global parameter values without consideration of conditions at the microscopic level, where high levels of heterogeneity may exist. In pathophysiological conditions, as for example in sepsis, compromise of the regulatory mechanisms designed to compensate for heterogeneity can lead to organ dysfunction or failure (Bateman et al, 2015; Ellis et al, 2002; Roy & Secomb, 2021). Simply increasing cardiac output by increasing intravascular volume and stroke volume may not address issues of heterogeneity at the microvascular level.…”

Isolated Fragments of Intact Microvessels: Tissue Vascularization, Modeling, and Therapeutics

“…A common misperception, however, is that the more vascularized the tissue, the more perfused the tissue will be, and consequently more functional. However, microvascular perfusion is a function of not only the number of microvessels in the network but also the microvessel phenotypes present and their arrangement relative to each other [13][14][15]. As such, the addition of more and more microvessel segments without subsequent network re-organization and adaptation can instead compromise tissue perfusion and create a pathological state.…”

Microcirculatory dysfunction in cardiogenic shock

“…Indeed, some of the vessels of the microcirculation are supported by vascular smooth muscle (VSM) and others are not. The VSM tone is partly modulated by local concentrations of vasoactive metabolites and mediators, autonomic influences (sympathetic stimulation causes vasoconstriction), and hemodynamic factors, but also by conducted responses from downstream vessels [ 48 ]. Increases in transmural pressure also activate mechanosensitive ion channels in VSM leading to vasoconstriction, known as the myogenic response [ 49 ].…”

“…EC sensed increases in shear stress, which leads to vasodilation due to the release of mediators including nitric oxide (NO), prostaglandins, and EDHF (endothelium-derived hyperpolarizing factor). Under hypoxic conditions, EC can also release adenosine, a potent vasodilator [ 48 ].…”