Adjuvante Therapien für Beatmungsassoziierten Lungenschaden und akutes Lungenversagen

Die Mortalität des akuten Lungenversagens ist auch nach vielen Dekaden experimenteller und klinischer Forschung weiterhin hoch. Die Beatmungsassoziierte Lungenschädigung (VILI; ventilator-induced lung injury) ist ein integraler Bestandteil des ARDS mit relevanten Einfluss auf Morbidität und Mortalität. Sowohl die Mechanismen des ARDS als auch des VILI sind mittlerweile sehr gut charakterisiert und die bekannten molekularen Mechanismen legen nahe, dass pharmakologische adjuvante Therapien im ARDS/VILI wirksam sein können. In dieser Arbeit wurden exemplarisch drei pharmakologische Therapiestrategien für das akute Lungenversagen untersucht in komplexen Tiermodellen vorgestellt von denen zwei in diesem Kontext effektiv waren: Adrenomedullin und die Neutralisation von C5a. Sowohl Adrenomedullin, als auch die C5a Neutralisation werden derzeit in klinischen Studien bei ARDS und Sepsis untersucht. Neben adjuvanten pharmakologischen Interventionen könnten auch subtile Veränderungen von Beatmungsparametern Einfluss auf den Krankheitsverlauf von ARDS Patient:innen haben. Hier wurde diesbezüglich eine Arbeit vorgestellt, in der die Verlängerung der Inspirationszeit bei gleicher Atemfrequenz, Plateaudrücken, PEEP und Tidalvolumen zur Aggravierung von VILI führt. In der Zukunft könnten sowohl adjuvante pharmakologische Therapien als auch ein besseres Verständnis der Mechanismen von VILI dazu beitragen, das Überleben von Patienten im ARDS zu verbessern

Assessing uncertainties in flood forecasts for decision making: prototype of an operational flood management system integrating ensemble predictions

Ensemble forecasts aim at framing the uncertainties of the potential future development of the hydro-meteorological situation. A probabilistic evaluation can be used to communicate forecast uncertainty to decision makers. Here an operational system for ensemble based flood forecasting is presented, which combines forecasts from the European COSMO-LEPS, SRNWP-PEPS and COSMO-DE prediction systems. A multi-model lagged average super-ensemble is generated by recombining members from different runs of these meteorological forecast systems. A subset of the super-ensemble is selected based on a priori model weights, which are obtained from ensemble calibration. Flood forecasts are simulated by the conceptual rainfall-runoff-model ArcEGMO. Parameter uncertainty of the model is represented by a parameter ensemble, which is a priori generated from a comprehensive uncertainty analysis during model calibration. The use of a computationally efficient hydrological model within a flood management system allows us to compute the hydro-meteorological model chain for all members of the sub-ensemble. The model chain is not re-computed before new ensemble forecasts are available, but the probabilistic assessment of the output is updated when new information from deterministic short range forecasts or from assimilation of measured data becomes available. For hydraulic modelling, with the desired result of a probabilistic inundation map with high spatial resolution, a replacement model can help to overcome computational limitations. A prototype of the developed framework has been applied for a case study in the Mulde river basin. However these techniques, in particular the probabilistic assessment and the derivation of decision rules are still in their infancy. Further research is necessary and promising

Intermedin Stabilized Endothelial Barrier Function and Attenuated Ventilator-induced Lung Injury in Mice

Background: Even protective ventilation may aggravate or induce lung failure, particularly in preinjured lungs. Thus, new adjuvant pharmacologic strategies are needed to minimize ventilator-induced lung injury (VILI). Intermedin/Adrenomedullin-2 (IMD) stabilized pulmonary endothelial barrier function in vitro. We hypothesized that IMD may attenuate VILIassociated lung permeability in vivo. Methodology/Principal Findings: Human pulmonary microvascular endothelial cell (HPMVEC) monolayers were incubated with IMD, and transcellular electrical resistance was measured to quantify endothelial barrier function. Expression and localization of endogenous pulmonary IMD, and its receptor complexes composed of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs) 1–3 were analyzed by qRT-PCR and immunofluorescence in non ventilated mouse lungs and in lungs ventilated for 6 h. In untreated and IMD treated mice, lung permeability, pulmonary leukocyte recruitment and cytokine levels were assessed after mechanical ventilation. Further, the impact of IMD on pulmonary vasoconstriction was investigated in precision cut lung slices (PCLS) and in isolated perfused and ventilated mouse lungs. IMD stabilized endothelial barrier function in HPMVECs. Mechanical ventilation reduced the expression of RAMP3, but not of IMD, CRLR, and RAMP1 and 2. Mechanical ventilation induced lung hyperpermeability, which was ameliorated by IMD treatment. Oxygenation was not improved by IMD, which may be attributed to impaired hypoxi

Adjunctive therapy with the Tie2 agonist Vasculotide reduces pulmonary permeability in Streptococcus pneumoniae infected and mechanically ventilated mice

Community acquired pneumonia, mainly caused by Streptococcus pneumoniae (S.pn.), is a common cause of death worldwide. Despite adequate antibiotic therapy, pneumococcal pneumonia can induce pulmonary endothelial hyperpermeability leading to acute lung injury, which often requires mechanical ventilation (MV) causing ventilator-induced lung injury (VILI). Endothelial stabilization is mediated by angiopoietin-1 induced Tie2 activation. PEGylated (polyethylene glycol) Tie2-agonist Vasculotide (VT) mimics Angiopietin-1 effects. Recently, VT has been shown to reduce pulmonary hyperpermeability in murine pneumococcal pneumonia. The aim of this study was to determine whether VT reduces lung damage in S.pn. infected and mechanically ventilated mice. Pulmonary hyperpermeability, immune response and bacterial load were quantified in S.pn. infected mice treated with Ampicillin + /-VT and undergoing six hours of MV 24 h post infection. Histopathological lung changes, Tie2-expression and -phosphorylation were evaluated. VT did not alter immune response or bacterial burden, but interestingly combination treatment with ampicillin significantly reduced pulmonary hyperpermeability, histological lung damage and edema formation. Tie2-mRNA expression was reduced by S.pn. infection and/or MV but not restored by VT. Moreover, Tie2 phosphorylation was not affected by VT. These findings indicate that VT may be a promising adjunctive treatment option for prevention of VILI in severe pneumococcal pneumonia

protection by adrenomedullin

Ventilator-induced lung injury (VILI) contributes to morbidity and mortality in acute respiratory distress syndrome (ARDS). Particularly pre-injured lungs are susceptible to VILI despite protective ventilation. In a previous study, the endogenous peptide adrenomedullin (AM) protected murine lungs from VILI. We hypothesized that mechanical ventilation (MV) contributes to lung injury and sepsis in pneumonia, and that AM may reduce lung injury and multiple organ failure in ventilated mice with pneumococcal pneumonia. We analyzed in mice the impact of MV in established pneumonia on lung injury, inflammation, bacterial burden, hemodynamics and extrapulmonary organ injury, and assessed the therapeutic potential of AM by starting treatment at intubation. In pneumococcal pneumonia, MV increased lung permeability, and worsened lung mechanics and oxygenation failure. MV dramatically increased lung and blood cytokines but not lung leukocyte counts in pneumonia. MV induced systemic leukocytopenia and liver, gut and kidney injury in mice with pneumonia. Lung and blood bacterial burden was not affected by MV pneumonia and MV increased lung AM expression, whereas receptor activity modifying protein (RAMP) 1-3 expression was increased in pneumonia and reduced by MV. Infusion of AM protected against MV-induced lung injury (66% reduction of pulmonary permeability p<0.01; prevention of pulmonary restriction) and against VILI- induced liver and gut injury in pneumonia (91% reduction of AST levels p<0.05, 96% reduction of alanine aminotransaminase (ALT) levels p<0.05, abrogation of histopathological changes and parenchymal apoptosis in liver and gut). MV paved the way for the progression of pneumonia towards ARDS and sepsis by aggravating lung injury and systemic hyperinflammation leading to liver, kidney and gut injury. AM may be a promising therapeutic option to protect against development of lung injury, sepsis and extrapulmonary organ injury in mechanically ventilated individuals with severe pneumonia

Characterization of antimicrobial use and co-infections among hospitalized patients with COVID-19: a prospective observational cohort study

Purpose: To investigate antimicrobial use and primary and nosocomial infections in hospitalized COVID-19 patients to provide data for guidance of antimicrobial therapy. Methods: Prospective observational cohort study conducted at Charite-Universitatsmedizin Berlin, including patients hospitalized with SARS-CoV-2-infection between March and November 2020. Results: 309 patients were included, 231 directly admitted and 78 transferred from other centres. Antimicrobial therapy was initiated in 62/231 (26.8%) of directly admitted and in 44/78 (56.4%) of transferred patients. The rate of microbiologically confirmed primary co-infections was 4.8% (11/231). Although elevated in most COVID-19 patients, C-reactive protein and procalcitonin levels were higher in patients with primary co-infections than in those without (median CRP 110 mg/l, IQR 51-222 vs. 36, IQR 11-101, respectively; p < 0.0001). Nosocomial bloodstream and respiratory infections occurred in 47/309 (15.2%) and 91/309 (29.4%) of patients, respectively, and were associated with need for invasive mechanical ventilation (OR 45.6 95%CI 13.7-151.8 and 104.6 95%CI 41.5-263.5, respectively), extracorporeal membrane oxygenation (OR 14.3 95%CI 6.5-31.5 and 16.5 95%CI 6.5-41.6, respectively), and haemodialysis (OR 31.4 95%CI 13.9-71.2 and OR 22.3 95%CI 11.2-44.2, respectively). The event of any nosocomial infection was significantly associated with in-hospital death (33/99 (33.3%) with nosocomial infection vs. 23/210 (10.9%) without, OR 4.1 95%CI 2.2-7.3). Conclusions: Primary co-infections are rare, yet antimicrobial use was frequent, mostly based on clinical worsening and elevated inflammation markers without clear evidence for co-infection. More reliable diagnostic prospects may help to reduce overtreatment. Rates of nosocomial infections are substantial in severely ill patients on organ support and associated with worse patient outcome

CD169/SIGLEC1 is expressed on circulating monocytes in COVID-19 and expression levels are associated with disease severity

Coronavirus disease 2019 (COVID-19) is caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Type I interferons are important in the defense of viral infections. Recently, neutralizing IgG auto-antibodies against type I interferons were found in patients with severe COVID-19 infection. Here, we analyzed expression of CD169/SIGLEC1, a well described downstream molecule in interferon signaling, and found increased monocytic CD169/SIGLEC1 expression levels in patients with mild, acute COVID-19, compared to patients with severe disease. We recommend further clinical studies to evaluate the value of CD169/SIGLEC1 expression in patients with COVID-19 with or without auto-antibodies against type I interferons