Microvascular resuscitation as a therapeutic goal in severe sepsis

Abstract

Sepsis causes microvascular dysfunction. Increased heterogeneity of capillary blood flow results in local tissue hypoxia, which can cause local tissue inflammation, impaired oxygen extraction, and, ultimately, organ dysfunction. Microvascular dysfunction is clinically relevant because it is a marker for mortality: it improves rapidly in survivors of sepsis but fails to improve in nonsurvivors. This, along with the fact that resuscitation of mean arterial pressure and cardiac output alone fails to improve microvascular function, means that microvascular resuscitation is therefore a therapeutic goal. In animal studies of sepsis, volume resuscitation improves microvascular permeability and tissue oxygenation, and leads to improved organ function, including a reduction in myocardial dysfunction. Microvascular resuscitation strategies include hemodynamic resuscitation using the linked combination of volume resuscitation, judicious vasopressor use, and inotropes and vasodilators. Alternative vasoactive agents, such as vasopressin, may improve microcirculatory function to a greater degree than conventional vasopressors. Successful modulation of inflammation has a positive impact on endothelial function. Finally, targeted treatment of the endothelium, using activated protein C, also improves microvascular function and ultimately increases survival. Thus, attention must be paid to the microcirculation in patients with sepsis, and therapeutic strategies should be employed to resuscitate the microcirculation in order to avoid organ dysfunction and to reduce mortality.

Figure 1

Multiphoton images of CD1 mouse hind-limb extensor digitorum longus (EDL) skeletal muscle microcirculation. After blunt dissection of the EDL, mice were injected with fluorescent nanoparticles via the tail vein. Images were acquired by exciting tissue at 900 nm using a titanium sapphire laser and collecting the fluorescent signal using a Leica SP2 microscope (Lecia, Richmond Hill, Ontario, Canada). Images were pseudo colored for depth: brown represents the surface, green 75 μm depth and blue 150 μm depth. (a) The normal homogeneous appearance in control mice is disrupted (b) in mice 5 hours after endotoxin-treatment. Solid lines indicate perfused capillaries, whereas broken lines indicate stopped capillary flow.