Abstract
Severe sepsis is a systemic response to infection that results in organ dysfunction. Microvascular dysregulation characterized by hyporesponsive and heterogeneous blood flow is implicated in the pathogenesis of organ failure. Although the renin-angiotensin system (RAS) has known effects on the microvasculature and is activated in sepsis, the relationships between RAS and organ injury in human sepsis remain unclear. We hypothesized that systemic RAS mediators are associated with microvascular hyporesponsiveness and organ dysfunction in human sepsis. We studied 30 severe sepsis subjects, and healthy volunteers served as controls. Septic subjects were studied 24 hours after the initial recognition of organ dysfunction; 12 subjects were enrolled such that an initial study was also performed 8 hours after organ dysfunction. Plasma was analyzed for plasma renin activity (PRA) and angiotensin II (Ang II) concentration. Organ failure was assessed quantitatively with the Sequential Organ Failure Assessment (SOFA) score. Using near-infrared spectroscopy, we measured the rate of increase in the oxygen saturation of microvascular hemoglobin in thenar muscles after 5 minutes of forearm ischemia. In so doing, we assessed bulk arteriolar and capillary hemoglobin influx to the tissue during reactive hyperemia. At 8 hours, Ang II was markedly elevated and significantly correlated with the extent of organ failure in septic subjects. After 24 hours of resuscitation to achieve clinically defined end points of preload and arterial pressure, Ang II remained elevated in septic subjects. There was a strong linear relationship between PRA and Ang II in the systemic circulation. Notably, both PRA and Ang II significantly and negatively correlated with the rate of microvascular reoxygenation during reactive hyperemia in septic subjects. We conclude that RAS is activated in severe sepsis, and systemic RAS mediators correlate with measures of microvascular dysregulation and organ failure.