Angiopoietin-2 is associated with capillary leak and predicts complications after cardiac surgery.

BACKGROUND: Patients undergoing cardiac surgery are prone to numerous complications. Increased vascular permeability may be associated with morbidity and mortality due to hemodynamic instability, fluid overload, and edema formation. We hypothesized that markers of endothelial injury and inflammation are associated with capillary leak, ultimately increasing the risk of postoperative complications. METHODS: In this prospective, observational, multidisciplinary cohort study at our tertiary academic medical center, we recruited 405 cardiac surgery patients. Patients were assessed daily using body impedance electrical analysis, ultrasound, sublingual intravital microscopy, and analysis of serum biomarkers. Multivariable models, as well as machine learning, were used to study the association of angiopoietin-2 with extracellular water as well as common complications after cardiac surgery. RESULTS: The majority of patients underwent coronary artery bypass grafting, valvular, or aortic surgeries. Across the groups, extracellular water increased postoperatively (20 ± 6 preoperatively to 29 ± 7L on postoperative day 2; P < 0.001). Concomitantly, the levels of the biomarker angiopoietin-2 rose, showing a strong correlation based on the time points of measurements (r = 0.959, P = 0.041). Inflammatory (IL-6, IL-8, CRP) and endothelial biomarkers (VE-Cadherin, syndecan-1, ICAM-1) suggestive of capillary leak were increased. After controlling for common risk factors of edema formation, we found that an increase of 1 ng/mL in angiopoietin-2 was associated with a 0.24L increase in extracellular water (P < 0.001). Angiopoietin-2 showed increased odds for the development of acute kidney injury (OR 1.095 [95% CI 1.032, 1.169]; P = 0.004) and was furthermore associated with delayed extubation, longer time in the ICU, and a higher chance of prolonged dependence on vasoactive medication. Machine learning predicted postoperative complications when capillary leak was added to standard risk factors. CONCLUSIONS: Capillary leak and subsequent edema formation are relevant problems after cardiac surgery. Levels of angiopoietin-2 in combination with extracellular water show promising potential to predict postoperative complications after cardiac surgery. TRIAL REGISTRATION NUMBER: German Clinical Trials Registry (DRKS No. 00017057), Date of registration 05/04/2019, www.drks.de.

Clinical Impact of ACE-I/ARB for Conservatively Treated Patients with Moderate to Severe Mitral Regurgitation: A Single Center Observational Study.

(1) Background: Mitral regurgitation (MR) is associated with increased mortality and frequent hospital admissions. Although mitral valve intervention offers improved clinical outcomes for MR, it is not feasible in many cases. Moreover, conservative therapeutic opportunities remain limited. The aim of this study was to evaluate the impact of ACE inhibitors and angiotensin receptor blockers (ACE-I/ARB) on elderly patients with moderate-to-severe MR and mildly reduced to preserved ejection fraction. (2) Methods: In total, 176 patients were included in our hypothesis-generating, single-center observational study. Hospitalization for heart failure and all-cause death have been defined as the combined 1-year primary endpoint. (3) Results: Patients treated with ACE-I/ARB showed a lower risk for the combined endpoint of death and heart failure-related readmission (HR 0.52 95%CI 0.27-0.99; p = 0.046), even after adjustment for EUROScoreII and frailty (HR 0.52 95%CI 0.27-0.99; p = 0.049) (4) Conclusions: The use of an ACE-I/ARB in patients with moderate-to-severe MR and preserved to mildly reduced left-ventricular ejection fraction (LVEF) significantly associates with improved clinical outcome and might be indicated as a valuable therapeutic option in conservatively treated patients.

[Pharmaceutical therapy of infarct-related cardiogenic shock]. / Medikamentöse Therapie des infarktbedingten kardiogenen Schocks.

Acute myocardial infarction complicated by cardiogenic shock (AMI-CS) is a comparably seldom but fatal entity. The definition of cardiogenic shock - unlike e. g. septic shock - is not uniform. Immediate revascularization is central to the patient's prognosis in AMI-CS. Patients who continue to meet the criteria of shock despite revascularization should be hemodynamically phenotyped to allow guidance of personalized subsequent therapy. Antiplatelet medication is the cornerstone for maintaining myocardial (re)perfusion. In hypotension, norepinephrine should be used as the first-line vasopressor, depending on afterload and after compensation for possible hypovolemia. Dobutamine is recommended to increase inotropy, possibly augmented or substituted by calcium sensitizers such as levosimendan. PDE-III (phosphodiesterase enzyme type III)-inhibitors should be used with restraint in myocardial infarction. Dopamine is no longer recommended in Europe. A sasodilator may be an option in highly selected patients with AMI-CS. This review will provide a detailed updated overview on pharmacological treatment modalities and indications in individual patients.

Variations in end-of-life care practices in older critically ill patients with COVID-19 in Europe.

BACKGROUND: Previous studies reported regional differences in end-of-life care (EoLC) for critically ill patients in Europe. OBJECTIVES: The purpose of this post-hoc analysis of the prospective multicentre COVIP study was to investigate variations in EoLC practices among older patients in intensive care units during the coronavirus disease 2019 pandemic. METHODS: A total of 3105 critically ill patients aged 70 years and older were enrolled in this study (Central Europe: n = 1573; Northern Europe: n = 821; Southern Europe: n = 711). Generalised estimation equations were used to calculate adjusted odds ratios (aORs) to population averages. Data were adjusted for patient-specific variables (demographic, disease-specific) and health economic data (gross domestic product, health expenditure per capita). The primary outcome was any treatment limitation, and 90-day mortality was a secondary outcome. RESULTS: The frequency of the primary endpoint (treatment limitation) was highest in Northern Europe (48%), intermediate in Central Europe (39%) and lowest in Southern Europe (24%). The likelihood for treatment limitations was lower in Southern than in Central Europe (aOR 0.39; 95% confidence interval [CI] 0.21-0.73; p = 0.004), even after multivariable adjustment, whereas no statistically significant differences were observed between Northern and Central Europe (aOR 0.57; 95%CI 0.27-1.22; p = 0.15). After multivariable adjustment, no statistically relevant mortality differences were found between Northern and Central Europe (aOR 1.29; 95%CI 0.80-2.09; p = 0.30) or between Southern and Central Europe (aOR 1.07; 95%CI 0.66-1.73; p = 0.78). CONCLUSION: This study shows a north-to-south gradient in rates of treatment limitation in Europe, highlighting the heterogeneity of EoLC practices across countries. However, mortality rates were not affected by these results.

Health-related quality of life in older patients surviving ICU treatment for COVID-19: results from an international observational study of patients older than 70 years.

BACKGROUND: health-related quality of life (HRQoL) is an important patient-centred outcome in patients surviving ICU admission for COVID-19. It is currently not clear which domains of the HRQoL are most affected. OBJECTIVE: to quantify HRQoL in order to identify areas of interventions. DESIGN: prospective observation study. SETTING: admissions to European ICUs between March 2020 and February 2021. SUBJECTS: patients aged 70 years or older admitted with COVID-19 disease. METHODS: collected determinants include SOFA-score, Clinical Frailty Scale (CFS), number and timing of ICU procedures and limitation of care, Katz Activities of Daily Living (ADL) dependence score. HRQoL was assessed at 3 months after ICU admission with the Euro-QoL-5D-5L questionnaire. An outcome of ≥4 on any of Euro-QoL-5D-5L domains was considered unfavourable. RESULTS: in total 3,140 patients from 14 European countries were included in this study. Three months after inclusion, 1,224 patients (39.0%) were alive and the EQ-5D-5L from was obtained. The CFS was associated with an increased odds ratio for an unfavourable HRQoL outcome after 3 months; OR 1.15 (95% confidence interval (CI): 0.71-1.87) for CFS 2 to OR 4.33 (95% CI: 1.57-11.9) for CFS ≧ 7. The Katz ADL was not statistically significantly associated with HRQoL after 3 months. CONCLUSIONS: in critically ill old intensive care patients suffering from COVID-19, the CFS is associated with the subjectively perceived quality of life. The CFS on admission can be used to inform patients and relatives on the risk of an unfavourable qualitative outcome if such patients survive.

The Interdisciplinary Management of Acute Chest Pain.

BACKGROUND: Acute chest pain of non-traumatic origin is a common reason for presentation to physician's offices and emergency rooms. Coronary heart disease is the cause in up to 25% of cases. Because acute chest pain, depending on its etiology, may be associated with a high risk of death, rapid, goal-oriented management is mandatory. METHODS: This review is based on pertinent articles and guidelines retrieved by a selective search in PubMed. RESULTS: History-taking, physical examination, and a 12-lead electrocardiogram (ECG) are the first steps in the differential diagnostic process and generally allow the identification of features signifying a high risk of lifethreatening illness. If the ECG reveals ST-segment elevation, cardiac catheterization is indicated. The timedependent measurement of highly sensitive troponin values is a reliable test for the diagnosis or exclusion of acute myocardial infarction. A wide variety of other potential causes (e.g., vascular, musculoskeletal, gastroenterologic, or psychosomatic) must be identified from the history if they are to be treated appropriately. Elderly patients need special attention. CONCLUSION: Acute chest pain is a major diagnostic challenge for the physician. Common errors are traceable to non-recognition of important causes and to an inadequate diagnostic work-up. Future studies should be designed to help optimize the interdisciplinary management of patients with chest pain.

Molecular size and origin do not influence the harmful side effects of hydroxyethyl starch on human proximal tubule cells (HK-2) in vitro.

BACKGROUND: Recently, clinical trials revealed renal impairment induced by hydroxyethyl starch (HES) in septic patients. In prior studies, we managed to demonstrate that HES accumulated in renal proximal tubule cells (PTCs). The related pathomechanism has not yet been discovered. To validate our hypothesis that the HES molecule itself is harmful, regardless of its molecule size or origin, we conducted a comprehensive study to elucidate the influences of different HES preparations on PTC viability in vitro. METHODS: Cell viability of human PTC was measured with a cytotoxicity assay, quantifying the reduction of tetrazolium salt to colored formazan. Experiments were performed by assessing the influence of different carrier solutions of HES (balanced, nonbalanced, culture medium), different average molecular weights (70, 130, 200 kDa), different origins (potato or corn derived), and various durations of incubation (2-21 hours). Furthermore, HES 130/0.4 was fractionated by ultrafiltration, and the impact on cell viability of average single-size fractions with <3, 3 to 10, 10 to 30, 30 to 50, 50 to 100, and >100 kDa was investigated. We also tested the possible synergistic effects of inflammation induced by tumor necrosis factor-α. RESULTS: All tested HES solutions, regardless of origin or carrier matrix, decreased cell viability in an equivalent, dose-dependent manner. Coincubation with tumor necrosis factor-α did not reduce HES-induced reduction of cell viability. Minor differences were detected comparing 70, 130, and 200 kDa preparations. Analysis of fractionated HES revealed that each fraction decreased cell viability. Even small HES molecules (10-30 kDa) were significantly deleterious. CONCLUSIONS: For the first time, we were able to show that only the total mass of HES molecules applied is responsible for the harmful impact on renal PTC in vitro. Neither molecular size nor their origin showed any relevance.

The effects of colloid solutions on renal proximal tubular cells in vitro.

Renal failure is a common complication of critically ill patients. Colloids such as hydroxyethyl starch (HES), gelatin, or albumin are regularly used for intravascular volume resuscitation, but there are increasing reports about the nephrotoxic side effects of synthetic colloids in septic patients. Therefore, we investigated the influence of colloids (HES130/0.4 (Voluven®), gelatin (Gelafundin®), human albumin, and the crystalloid Sterofundin® ISO on cell viability of human proximal tubular (HK-2) cells. HK-2 cells were incubated with colloids (0.1%-4%) and with equivalent volumes of the crystalloid solution Sterofundin ISO. After 21 hours, cell viability of HK-2 cells was measured by EZ4U assay (dye XTT). Application of HES130/0.4 decreased cell viability significantly in a concentration-dependent manner (86.80% ± 10.79% by 0.5% HES down to 24.02% ± 4.27% by 4% HES). Human albumin (>1.25%) as well as gelatin (>1%) also showed deleterious effects on HK-2 cells. Interestingly, in lower concentrations, human albumin and the crystalloid solution Sterofundin ISO were cytoprotective in comparison with the NaCl control. In conclusion, synthetic and natural colloids showed a harmful impact on HK-2 cells in higher concentrations without any prior proinflammatory stimulus. HES130/0.4 exhibited the most distinctive harmful impact, whereas the application of crystalloid Sterofundin ISO revealed cytoprotective effects.