endothelin-1 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

We assessed the ability of mid-regional proadrenomedullin (MR-proADM) and C-terminal proendothelin-1 (CT-proET-1) to predict 28-day mortality in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia.. Biomarkers were collected during the first seven days in this prospective observational cohort study. We investigated the relationship between biomarkers and mortality in a multivariable Cox regression model adjusted for age and SOFA score.. In 105 critically ill patients with confirmed SARS-CoV-2 pneumonia 28-day mortality was 28.6%. MR-proADM and CT-proET-1 were significantly higher in 28-day non-survivors at baseline and over time. ROC curves revealed high accuracy to identify non-survivors for baseline MR-proADM and CT-proET-1, AUC 0.84, (95% CI 0.76-0.92), p < 0.001 and 0.79, (95% CI 0.69-0.89), p < 0.001, respectively. The AUC for prediction of 28-day mortality for MR-proADM and CT-proET-1 remained high over time. MR-proADM ≥1.57 nmol/L and CT-proET-1 ≥ 111 pmol/L at baseline were significant predictors for 28-day mortality (HR 6.80, 95% CI 3.12-14.84, p < 0.001 and HR 3.72, 95% CI 1.71-8.08, p 0.01).. Baseline and serial MR-proADM and CT-proET-1 had good ability to predict 28-day mortality in critically ill patients with SARS-CoV-2 pneumonia.. NEDERLANDS TRIAL REGISTER, NL8460.

Topics: Adrenomedullin; Biomarkers; COVID-19; Critical Illness; Endothelin-1; Endothelium; Humans; Peptide Fragments; Pneumonia; Prognosis; Prospective Studies; Protein Precursors; SARS-CoV-2

We tested the hypothesis that higher mid-regional pro-adrenomedullin (MR-proADM), carboxy-terminal pro-endothelin-1 (CT-proET-1), procalcitonin (PCT) and C-reactive protein (CRP) plasma concentrations would be associated with increased prediction of mortality risk scores.. Prospective observational study set in two pediatric intensive care units (PICUs). Two-hundred-thirty-eight patients were included. MR-proADM, CT-proET-1, PCT and CRP levels were compared between children with PRISM III and PIM 2 > p75 (Group A; n = 33) and the rest (Group B; n = 205).. Median (range) MR-proADM levels were 1.39 nmol/L (0.52-12.67) in group A versus 0.54 (0.15-3.85) in group B (P < 0.001). CT-proET-1 levels were 172 pmol/L (27-500) versus 58 (4-447) (P < 0.001). PCT levels were 7.77 ng/mL (0.34-552.00) versus 0.28 (0.02-107.00) (P < 0.001). CRP levels were 6.23 mg/dL (0.08-28.25) versus 1.30 mg/dL (0.00-42.09) (P = 0.210). The area under the ROC curve (AUC) for the differentiation of group A and B was 0.87 (95% CI:0.81-0.821) for MR-proADM, 0.86 (95% CI:0.79-0.92) for CT-proET-1 and 0.84 (95% CI:0.74-0.94) for PCT. A MR-proADM > 0.79 nmol/L had 93% sensitivity and 76% specificity to differentiate groups, whereas a CT-proET-1 > 123 pmol/L had 77% sensitivity and 84% specificity, and a PCT concentration > 2.05 ng/mL had 80% sensitivity and specificity.. In critically ill children, high levels of MR-proADM, CT-proET-1 and PCT were associated with increased prediction of mortality risk scores. MR-proADM, CT-proET-1 and PCT concentrations higher than 0.80 nmol/L, 123 pmol/L and 2 ng/mL, respectively, could be used by clinicians to identify critically ill children at higher prediction of risk death scores.

Topics: Adrenomedullin; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Child; Child, Preschool; Critical Illness; Endothelin-1; Female; Humans; Male; Prospective Studies; Protein Precursors; Risk; Sensitivity and Specificity; Spain

Most patients with critical leg ischaemia (CLI) have co-existing coronary heart disease, which is the main cause of their increased mortality rate. The aim of this study was to investigate whether any markers of endothelial function could predict death in these patients.. In a cohort of 39 patients with CLI who were scheduled for lower-limb amputation, blood levels of vascular endothelial growth factor, homocysteine, endothelin (ET) 1, von Willebrand factor and vascular cell adhesion molecule 1 were measured, as well as forearm vascular responses to the endothelium-dependent vasodilator acetylcholine.. Levels of ET-1 were significantly higher in patients who subsequently died within 3 years than in those who were still alive (P = 0.002) and Cox proportional hazards regression analysis demonstrated that ET-1 was an independent predictor of all-cause mortality:hazard ratio 3.53 (95 per cent confidence interval (c.i.) 1.29 to 9.70; P = 0.007) and cardiovascular mortality:hazard ratio 4.15 (95 per cent c.i. 1.30 to 13.23); P = 0.014.. ET-1 was an independent predictor of death in these patients with CLI.

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Biomarkers; Cohort Studies; Critical Illness; Endothelin-1; Female; Humans; Ischemia; Leg; Male; Middle Aged; Survival Analysis

In patients with acute respiratory distress syndrome (ARDS), the prone position may enhance oxygenation by changing ventilation/perfusion ratio. In this study, we investigated whether the prone position affects the net balance between pulmonary endothelin (ET-1) and angiotensin II (Ang II) production and clearance, two metabolic functions of lung endothelial cells.. Anaesthesiological intensive care unit of a university hospital.. Ten ARDS patients (Murray score > 2.5) were studied in both the supine position (SP) and the prone position (PP). MEASUREMENTS AND DESIGN: Blood samples were taken simultaneously from the patient in SP for assessment of mixed venous and arterial ET-1 and Ang II concentrations, and plasma renin concentration (PRC). This was repeated after 60 min in SP, immediately after turning the patient into PP, and 60 min thereafter. Net arterial/mixed venous ET-1 clearances and net Ang II formations were calculated.. arterial oxygen tension increased from SP to PP by an average of 60 mmHg, about 20%. Arterial ET-1 concentrations of ARDS patients were 1.57 +/- 1.1 pg/ml (mean +/- SD) and within the range of healthy persons. Net ET-1 clearances were negative in SP, indicating pulmonary release of ET-1, and did not change in PP. Arterial Ang II concentrations (73 +/- 56 pg/ml) as well as PRC (126 +/- 85 pg/ml) were markedly elevated. Net transpulmonary Ang II formation did not change.. Acute changes of oxygenation in ARDS patients by positioning do not induce any short-term effects on pulmonary ET-1 net clearance or Ang II net formation.

Topics: Adult; Analysis of Variance; Angiotensin II; Critical Illness; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Hemodynamics; Humans; Male; Middle Aged; Prone Position; Renin; Respiratory Distress Syndrome; Severity of Illness Index; Supine Position

To determine the predictive value of early determination of tumor necrosis factor (TNF)-alpha, TNF-alpha 1 and 2 soluble receptors (sTNFR1 and sTNFR2) and endothelin-1 (ET-1) for mortality in patients with septic shock.. Prospective study.. Intensive care unit of a university hospital.. Twenty-one patients with septic shock.. None.. Patients with septic shock had a pulmonary artery catheter inserted and blood samples drawn at time zero, 6, 12 and 24 h, simultaneously with hemodynamic assessments. Plasma levels of all markers were measured by ELISA. All patients were followed up to hospital discharge or death. Age and APACHE II scores were significantly higher in nonsurvivors (n = 11) than in survivors (n = 10). Hemodynamic assessments did not aid in the discrimination between the two groups of patients (P > 0.05). Levels of TNF-alpha were higher in nonsurvivors than in survivors at all time-points. sTNFR1 and sTNFR2 were also significantly elevated in nonsurvivors, but not in all measurements. Endothelin-1, however, was significantly higher in nonsurvivors than in survivors only at 6 h (P = 0.02). When both TNF-alpha and ET-1 were increased at early time-points, the best predictive values for mortality were obtained [positive and negative predictive values of 72 and 100% at 6 h, odds ratio 3.0, 95% CI (1.2-7.6)].. Increased levels of TNF-alpha were consistently higher at all time-points in nonsurvivors with septic shock. ET-1 levels, however, appeared also to be an early and sensitive predictor of mortality. Very early determination of TNF-alpha and ET-1 in septic shock may help to identify patients at higher risk for adverse outcome.

Topics: Adult; Aged; Aged, 80 and over; Antigens, CD; APACHE; Critical Illness; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Hemodynamics; Humans; Male; Middle Aged; Predictive Value of Tests; Prognosis; Prospective Studies; Receptors, Tumor Necrosis Factor; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Shock, Septic; Tumor Necrosis Factor-alpha

To examine the effect of a single episode of continuous venovenous haemofiltration (CVVH) on indicators of endothelial injury and the protein C/S system in critically ill patients.. Observational study.. University teaching hospital intensive care unit.. 12 critically ill patients with acute renal failure receiving their first episode of CVVH.. Blood samples were collected prior to starting CVVH and at 15 min and 1, 3-4, 8-12, and 24 h, and at 24-h intervals thereafter until the filter clotted.. Soluble tissue factor, soluble thrombomodulin, E-selectin and endothelin-1 were measured as indicators of endothelial injury. Changes in the protein C/S system were assessed by measurement of protein C (PC) and both free and total protein S (PS). Levels of PC and both free and total PS were subnormal in 6 and 11 patients, respectively, prior to CVVH, but there were no further changes during CVVH. Levels of tissue factor, thrombomodulin, E-selectin, and endothelin-1 were raised prior to haemofiltration in 9, 10, 9 and 9 patients, respectively. There were further increases during CVVH in at least one, but not all, of the markers of endothelial injury in most patients. There was no consistency between the changes in different markers of endothelial injury during haemofiltration in individual patients.. The PC/PS system and endothelial integrity is compromised in critically ill patients prior to haemofiltration, but a single episode of CVVH has little effect on the PC/PS system. The increase in markers of endothelial dysfunction seen during CVVH is more likely to be related to the underlying condition of the patient rather than any specific consequence arising from the technique itself.

Topics: Acute Kidney Injury; Adult; Aged; Blood Coagulation Factors; Critical Illness; E-Selectin; Endothelin-1; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Female; Hemofiltration; Humans; Intensive Care Units; Male; Middle Aged; Respiratory Distress Syndrome; Treatment Outcome

Gastric microcirculatory disturbances are involved in the pathogenesis of stress ulcers; however, vasomodulators causing this process are not fully understood. This study was conducted to investigate the role of endothelin 1 (ET-1), a potent vasoconstrictive peptide, in stress ulcers in critically ill patients.. Using sandwich enzyme immunoassay, we measured ET-1 content in plasma and the gastric mucosa of 16 critically ill patients with traumatic head injury on admission and of 11 healthy subjects. Gastric mucosal samples were obtained endoscopically. When gastric drainage contained occult blood, endoscopic examination was performed again, and ET-1 concentrations in injured and adjacent normal mucosa were compared.. Plasma and mucosal ET-1 concentrations were significantly higher in critically ill patients on admission (6.1 +/- 0.6 pg/ml and 13.8 +/- 1.6 ng/g, respectively) compared with values in control subjects (2.7 +/- 0.4 pg/ml and 8.2 +/- 0.5 ng/g, respectively) (p < 0.01). The mucosal ET-1 concentration tended to be elevated in patients who had experienced hypoxia compared with those who had not (p = 0.07). In five patients who were again examined endoscopically, the ET-1 concentration in the injured mucosa was significantly higher than that in adjacent mucosa (19.2 +/- 3.2 and 10.1 +/- 1.6 ng/g, respectively; p < 0.05).. These results suggest that endogenous ET-1 plays an important role in the local pathogenesis of stress ulcers, especially those caused by hypoxia.

Topics: Adult; Critical Illness; Endothelin-1; Female; Gastric Mucosa; Humans; Hypoxia; Male; Middle Aged; Prospective Studies; Stomach Ulcer; Time Factors