INFLUENCE OF ANGIOTENSIN-CONVERTING ENZYME-INHIBITOR ENALAPRILAT ON ENDOTHELIAL-DERIVED SUBSTANCES IN THE CRITICALLY ILL

Objective: To assess the effects of the angiotensin-converting enzyme inhibitor enalaprilat on endothelial cells in septic patients. Design: Prospective, randomized, placebo-controlled, blinded study. Setting: Clinical investigation on a surgical intensive care unit of a universi ty hospital. Patients: Forty surgical septic patients (noncardiac/nonn eurosurgical patients). Interventions: After inclusion in the study an d after baseline data were obtained, either 0.25 mg/hr (enalaprilat gr oup, n = 20) or saline solution as placebo (control group, n = 20) was continuously given and continued throughout the following 5 days. Mea surements and Main Results: Extensive hemodynamic monitoring was carri ed out in all patients. Plasma concentrations of endothelin-1, angiote nsin II, soluble thrombomodulin, and soluble adhesion molecules (endot helial leukocyte adhesion molecule-1, intercellular adhesion molecule- 1, vascular cell adhesion molecule 1,and granule membrane protein-140) were measured from arterial blood samples. All measurements were carr ied out before the start of the infusion (''baseline'' values) and dai ly during the following 5 days. All endothelial-derived substances (th rombomodulin, endothelin-1, and all soluble adhesion molecules) were s imilarly increased beyond normal in both group. Endothelin-1 increased only in the untreated control patients (from 6.9 +/- 0.7 to 14.3 +/- 1.4 mg/mL). Soluble thrombomodulin increased in the untreated control patients (from 58 +/- 9 to 79 +/- 14 ng/mL [p<.05]), but significantly decreased in the enalaprilat treated patients. Soluble adhesion molec ules increased in the untreated control group (endothelial leukocyte a dhesion molecule from 92 +/- 14 to 192 +/- 29 ng/mL; intercellular adh esion molecule-1 from 480 +/- 110 to 850 +/- 119 ng/mL) and returned a lmost to normal values in the enalaprilat patients. The survival rate did not differ significantly between the two groups. Control patients developed severe sepsis and septic shock more often than the enalapril at-treated group. Conclusions: The complex pathogenesis of endothelial function abnormalities in sepsis may offer a large number of pharmaco logic interventions. Administration of the angiotensin converting enz yme inhibitor enalaprilat resulted in a reduced release of soluble end othelial derived substances into the circulating blood, which may indi cate an improved endothelial function. The specific actions of enalapr ilat on the endothelium have to be elucidated in further studies.