enalaprilat-anhydrous and Critical-Illness

To assess the effects of the angiotensin-converting enzyme inhibitor enalaprilat on endothelial cells in septic patients.. Prospective, randomized, placebo-controlled, blinded study.. Clinical investigation on a surgical intensive care unit of a university hospital.. Forty surgical septic patients (noncardiac/nonneurosurgical patients).. 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.. 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.. 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.

Topics: Aged; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Cell Adhesion Molecules; Critical Illness; Double-Blind Method; Enalaprilat; Endothelin-1; Endothelium, Vascular; Female; Hemodynamics; Humans; Inflammation; Male; Middle Aged; Prospective Studies; Sepsis; Survival Analysis; Thrombomodulin

Several components are responsible for circulatory control at the central, regional, and microcirculatory level. Angiotensin-converting enzyme (ACE) inhibitors are known to act beneficially on circulation by various mechanisms. The influence of continuous i.v. administration of the ACE inhibitor enalaprilat on regulators of circulation was studied in 45 critically ill patients. According to a prospective randomized sequence, either 0.25 mg/h (group 1, n = 15) or 0.5 mg/h (group 2, n = 15) of enalaprilat or saline solution as placebo (control group, n = 15) were continuously given. Infusion was started on the day of admission to the intensive care unit (ICU) and continued for the next 5 days. From arterial blood samples, plasma levels of endothelin-1 (ET), atrial natriuretic peptide (ANP), renin, vasopressin, angiotensin-II, and catecholamines (epinephrine, norepinephrine) were measured. All measurements were carried out before infusion (= baseline values) and during the next 5 days. In both enalaprilat groups, mean arterial blood pressure (MAP) decreased similarly; heart rate (HR) and central venous pressure (CVP) did not change, and were without differences in comparison to the untreated control. Except for ET, plasma levels of all vasoactive substances exceeded normal range at baseline. Angiotensin-II plasma concentrations significantly decreased during enalaprilat infusion (0.25 mg/h: from 53.1 +/- 11.3 to 22.1 +/- 9.3 pg/ml; 0.50 mg/h: 62.1 +/- 14.4 to 17.9 +/- 7.9 pg/ml), but they remained significantly elevated in the untreated control patients. Vasopressin plasma level increased only in the control group (p < 0.01) and decreased in the patients in whom 0.50 mg/h of enalaprilat was infused.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Angiotensin-Converting Enzyme Inhibitors; Blood Pressure; Central Venous Pressure; Critical Illness; Enalaprilat; Female; Heart Rate; Homeostasis; Hormones; Humans; Infusions, Intravenous; Male; Middle Aged; Prospective Studies