The reoxygenation rate was lower in those subjects receiving exogenous vasoconstrictors (mean 2.6% per sec (SD 1.6)) than in those www.selleckchem.com/products/Temsirolimus.html not on vasoconstrictors (mean 4.0% per sec (SD 1.3); t-test P = 0.03). This did not appear to depend on drug dose as reoxygenation rates for those on high dose vasoconstrictors (2.6% per sec, SD 1.8) were similar to those on lower doses (2.7% per sec, SD 0.78; t-test P = 0.88). Similarly, reoxygenation rates were lower in 20 septic subjects receiving continuous sedation during mechanical ventilation (2.45% per sec, SD 1.21) compared to septic subjects that were not ventilated (4.27% per sec, SD 1.68; t-test P = 0.03). Within the subset of ventilated septic subjects, reoxygenation rates still correlated with total SOFA score (r = -0.48; P = 0.037).

A novel finding is that these microvascular responses correlated with RAS mediators in septic subjects. We found negative correlations between reoxygenation rates and both PRA (Spearman r = -0.52, P = 0.005) and Ang II (Spearman r = -0.41, P = 0.03, see Figure Figure44).Figure 3Microvascular 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 …Figure 4Circulating 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. …

In the subset of 12 subjects studied eight hours following the recognition of sepsis-induced organ dysfunction, our findings were quite similar. Three subjects (25%) studied at this early timepoint ultimately did not survive hospitalization. The median PRA was significantly elevated in early septic subjects (15.1 ng/mL/h, range 0.9 to 73 ng/mL/h) compared to controls (1.5 ng/mL/h, range 0.1 to 2.2 ng/mL/h; see Figure Figure1,1, Panel A). Circulating Ang II was also increased in sepsis subjects (median 47.2 pg/mL, range 3.7 to 146 pg/mL) at this early timepoint (control median 10.6 pg/mL, range 2.8 to 17 pg/mL; see Figure Figure1,1, Panel B). Early PRA correlated negatively with microvascular reoxygenation rates measured at the same timepoint (Spearman r = -0.83, P = 0.0009; see Figure Figure5).

5). Strikingly, the plasma concentration of Ang II early in sepsis correlated with the extent of organ dysfunction realized during the first day of ICU care (Spearman r = 0.66, P = 0.019; see Figure Figure6).6). In parallel, early Ang II concentrations in those that ultimately survived hospitalization (mean 36.0 pg/mL, Cilengitide 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).Figure 5Early RAS activation correlates with microvascular dysfunction.