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.


METHODS
Prospective, randomized, placebo-controlled, blinded study.


METHODS
Clinical investigation on a surgical intensive care unit of a university hospital.


METHODS
Forty surgical septic patients (noncardiac/nonneurosurgical patients).


METHODS
After inclusion in the study and after baseline data were obtained, either 0.25 mg/hr (enalaprilat group, n = 20) or saline solution as placebo (control group, n = 20) was continuously given and continued throughout the following 5 days.


RESULTS
Extensive hemodynamic monitoring was carried out in all patients. Plasma concentrations of endothelin-1, angiotensin II, soluble thrombomodulin, and soluble adhesion molecules (endothelial 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 carried out before the start of the infusion ("baseline" values) and daily during the following 5 days. All endothelial-derived substances (thrombomodulin, endothelin-1, and all soluble adhesion molecules) were similarly 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 molecules increased in the untreated control group (endothelial leukocyte adhesion molecule from 92 +/- 14 to 192 +/- 29 ng/mL; intercellular adhesion molecule-1 from 480 +/- 110 to 850 +/- 119 ng/ mL) and returned almost 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 enalaprilat-treated group.


CONCLUSIONS
The complex pathogenesis of endothelial function abnormalities in sepsis may offer a large number of pharmacologic interventions. Administration of the angiotensin-converting enzyme inhibitor enalaprilat resulted in a reduced release of soluble endothelial-derived substances into the circulating blood, which may indicate an improved endothelial function. The specific actions of enalaprilat on the endothelium have to be elucidated in further studies.
Boldt
J
J
Department of Anesthesiology and Intensive Care Medicine, Klinikum der Stadt Ludwigshafen, Germany.
Papsdorf
M
M
Kumle
B
B
Piper
S
S
Hempelmann
G
G
D000368:Aged; D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D015815:Cell Adhesion Molecules / Q000097:blood; D016638:Critical Illness; D004311:Double-Blind Method; D015773:Enalaprilat / Q000627:therapeutic use*; D019332:Endothelin-1 / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016019:Survival Analysis; D018180:Thrombomodulin / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D015815:Cell Adhesion Molecules; D019332:Endothelin-1; D018180:Thrombomodulin; D000804:Angiotensin II; D015773:Enalaprilat