Endothelin in septic patients:: Effects on cardiovascular and renal function and its relationship to proinflammatory cytokines

Objective: To determine the time course of big-endothelin (big-ET) and its relationship to proinflammatory cytokines and organ function in sepsis. Design: Prospective analysis in patients meeting criteria of severe sepsis as part of a multicenter study (RAMSES) with an anti-tumor necrosis factor monoclonal antibody F(ab')(2) fragment (afelimomab). Setting: University hospital intensive care unit. Patients: A total of 23 nontrauma patients with severe sepsis or septic shock and ten multiple trauma patients. Septic patients were randomized for additional experimental treatment when initial interleukin (IL)-6 serum level was above 1000 pg/mL. Interventions: Randomized patients received 1.0 mg/kg afelimomab or placebo three times daily over 3 days in addition to standard treatment. In each patient, serial blood samples for plasma big-ET and cytokine determination as well as clinical data were collected over 28 days. Measurements and Main Results: Significantly increased concentrations of circulating big-ET were found in patients with severe sepsis as compared with healthy subjects. In septic papatients, and were more elevated in randomized than in nonrandomized patients. At study entry (day 0), big-ET reached a peak concentration and significantly correlated with IL-6 (r(2) =.43) and IL-8 (r(2) =.44) in patients with severe sepsis. Moreover, big-ET levels in septic patients, pooled over all observation days, correlated positively with pressure-adjusted heart rate, central venous pressure, pulmonary artery pressure, and pulmonary Vascular resistance and correlated inversely with creatinine clearance (r(2) = .54, .54, .59, .40, and .51, respectively, p = .0001). In all randomized septic patients, pressure-adjusted heart rate decreased from day 0 to day 2 in parallel with big-ET; however, a significant decrease in big-ET (day 0 to day 2) was only found in patients additionally treated with afelimomab. Conclusions: In patients with severe sepsis, big-ET plasma levels are markedly increased, even above those of multiple trauma patients, in close relationship to IL-6 and IL-8, and with significant correlation to renal function and pulmonary vascular tone.