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.


METHODS
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).


METHODS
University hospital intensive care unit.


METHODS
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.


METHODS
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.


RESULTS
Significantly increased concentrations of circulating big-ET were found in patients with severe sepsis as compared with healthy subjects. In septic patients, big-ET plasma levels were higher than in multiple trauma patients, 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 (r2 = .43) and IL-8 (r2 = .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 (r2 = .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.
Tschaikowsky
K
K
Department of Anesthesiology, University of Erlangen-Nürnberg, Erlangen, Germany. klaus.tschaikowsky@rzmail.uni-erlangen.de
Sägner
S
S
Lehnert
N
N
Kaul
M
M
Ritter
J
J
D000328:Adult; D002319:Cardiovascular System / Q000503:physiopathology; D019332:Endothelin-1; D016232:Endothelins / Q000097:blood*; D005260:Female; D006801:Humans; D007668:Kidney / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011498:Protein Precursors / Q000097:blood*; D018805:Sepsis / Q000097:blood* / Q000503:physiopathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D014409:Tumor Necrosis Factor-alpha