Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis

Abstract

Introduction: Microvascular dysregulation characterized by hyporesponsive vessels and heterogeneous bloodflow is implicated in the pathogenesis of organ failure in sepsis. The renin-angiotensin system (RAS) affects the microvasculature, yet the relationships between RAS and organ injury in clinical sepsis remain unclear. We tested our hypothesis that systemic RAS mediators are associated with dysregulation of the microvasculature and with organ failure in clinical severe sepsis.

Methods: We studied 30 subjects with severe sepsis, and 10 healthy control subjects. Plasma was analyzed for plasma renin activity (PRA) and angiotensin II concentration (Ang II). Using near-infrared spectroscopy, we measured the rate of increase in the oxygen saturation of thenar microvascular hemoglobin after five minutes of induced forearm ischemia. In so doing, we assessed bulk microvascular hemoglobin influx to the tissue during reactive hyperemia. We studied all subjects 24 hours after the development of organ failure. We studied a subset of 12 subjects at an additional timepoint, eight hours after recognition of organ failure (early sepsis).

Results: After 24 hours of resuscitation to clinically-defined endpoints of preload and arterial pressure, Ang II and PRA were elevated in septic subjects and the degree of elevation correlated negatively with the rate of microvascular reoxygenation during reactive hyperemia. Early RAS mediators correlated with microvascular dysfunction. Early Ang II also correlated with the extent of organ failure realized during the first day of sepsis.

Conclusions: RAS is activated in clinical severe sepsis. Systemic RAS mediators correlate with measures of microvascular dysregulation and with organ failure.

Figure 1

Circulating RAS mediators are prevalent in the septic circulation. Plasma renin activity (Panel A) and the plasma concentration of angiotensin II (Panel B) were assessed in control (n = 10) and septic subjects. At eight hours following the recognition of organ dysfunction, both PRA and Ang II were elevated in septic subjects (n = 12). Despite resuscitation to clinical endpoints, median values for PRA (7.4 ng/mL/hr, range 0.1 to 49.7 ng/mL/hr) and Ang II (29.8 pg/mL, range 3.1 to 242.8 pg/mL) remained elevated at 24 hours (n = 30). Data depict median, interquartile range, and range for each column. * P < 0.05, ** P < 0.01 compared to control, Kruskal-Wallis test, and Dunn's Multiple Comparison post-hoc test.

Figure 2

Plasma renin activity correlates with plasma concentration of angiotensin II in septic patients. PRA and Ang II were measured 24 hours after the recognition of organ dysfunction in 30 septic patients. Correlation analysis showed a significant relationship between these factors (Spearman r = 0.75; P < 0.0001).

Figure 3

Microvascular responses to reactive hyperemia correlate inversely with organ dysfunction in severe sepsis. The microvascular response to reactive hyperemia was assessed by NIRS measures of thenar reoxygenation rates following induced forearm ischemia in 28 subjects. Correlation analysis showed a significant inverse relationship between microvascular reoxygenation rates and the degree of organ failure as assessed with the Sequential Organ Failure Assessment (SOFA) score (Pearson r = -0.50, P = 0.007).

Figure 4

Circulating RAS mediators correlate inversely with the microvascular responses to reactive hyperemia. Circulating RAS mediators were assessed by radioimmune assay of plasma from septic subjects 24 hours following the clinical onset of organ dysfunction. Correlation analysis showed both plasma renin activity (Panel A; Spearman r = -0.52, P = 0.005) and plasma angiotensin II concentration (Panel B; Spearman r = -0.41, P = 0.03) had significant inverse linear relationships with thenar reoxygenation rates, or microvascular responses to reactive hyperemia.

Figure 5

Early RAS activation correlates with microvascular dysfunction. Plasma renin activity was assessed by radioimmune assay of plasma from a subset of 12 subjects studied eight hours following the recognition of organ failure. Correlation analysis showed PRA had a significant inverse relationship (Spearman r = -0.83, P = 0.0009) with microvascular reoxygenation rates.

Figure 6

Early plasma angiotensin II concentration correlates with organ failure in severe sepsis. Plasma angiotensin II concentration was measured eight hours after the recognition of organ failure in 12 septic subjects. Panel A: Correlation analysis of these 12 subjects showed a significant relationship (Spearman r = 0.66; *P = 0.019) between Ang II and the extent of organ failure realized during the first day of ICU care as determined by the Sequential Organ Failure Assessment (SOFA) Score. Data shown includes subjects that died (black triangles) or survived hospitalization (open circles). Panel B: Early Ang II concentrations in those that ultimately survived hospitalization (mean 36.0 pg/mL, SD 36 pg/mL) were lower than those in subjects that died (mean 105.8 pg/mL, SD 36.4 pg/mL; ** normality test P > .1; Student t-test P = 0.016).