Die chronisch thromboembolische pulmonale Hypertonie (CTEPH) tritt als Spätkomplikation von akuten Lungenembolien (LE) auf. Narbige Verengungen der Lungenstrombahn infolge insuffizienter Thrombolyse und eine variable Mikrovaskulopathie erhöhen den pulmonalen Gefäßwiderstand. Eine frühestmögliche Erkennung ist von besonderer Bedeutung, da effektive potenziell kurative Therapieoptionen bestehen. Zur Diagnose und Therapieplanung wird eine hochwertige Bildgebung in Kombination mit hämodynamischer Evaluation durch Rechtsherzkatheter benötigt, die an spezialisierten Zentren mit multidisziplinären Teams erfolgen sollten. Wenn möglich sollten Patient*innen mittels chirurgischer pulmonaler Endarteriektomie behandelt werden. Ist diese nicht möglich, werden bei geeigneten Zielläsionen wiederholte Ballonangioplastien angewandt und beide mechanischen Verfahren bei konkomitierender distaler Komponente mit medikamentöser Therapie ergänzt. Mit multimodalen Therapiekonzepten lassen sich exzellente Ergebnisse mit einer 3-Jahres-Überlebensrate von über 90 % erreichen.

Extracorporeal membrane oxygenation (ECMO) is an important rescue therapy method for the treatment of severe hypoxic lung injury. In some cases, oxygen saturation and oxygen partial pressure in the arterial blood are low despite ECMO therapy. There are case reports in which patients with such instances of refractory hypoxemia received a second membrane lung, either in series or in parallel, to overcome the hypoxemia. It remains unclear whether the parallel or serial connection is more effective. Therefore, we used an improved version of our full-flow ECMO mock circuit to test this. The measurements were performed under conditions in which the membrane lungs were unable to completely oxygenate the blood. As a result, only the photometric pre- and post-oxygenator saturations, blood flow and hemoglobin concentration were required for the calculation of oxygen transfer rates. The results showed that for a pre-oxygenator saturation of 45% and a total blood flow of 10 L/min, the serial connection of two identical 5 L rated oxygenators is 17% more effective in terms of oxygen transfer than the parallel connection. Although the idea of using a second membrane lung if refractory hypoxia occurs is intriguing from a physiological point of view, due to the invasiveness of the solution, further investigations are needed before this should be used in a wider clinical setting.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease, but an important late sequela after acute pulmonary embolism. Therefore, follow-up after at least three months of sufficient anticoagulation is recommended. Patients with suspected CTEPH should be referred to specialized CTEPH centers for further evaluation and treatment.Three treatment modalities are available: pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and pulmonary hypertension-targeted drugs. The indication for surgery depends mainly on the localization of the pulmonary arterial obstructions. Severe comorbidities as well as advanced age need individual evaluation, but do not present strict exclusion criteria. Multimodal treatments are common practice in inoperable CTEPH. However, treatment decision making in an experienced multidisciplinary team is mandatory.

Chronic thromboembolic pulmonary disease (CTEPD) is an important late complication of acute pulmonary embolism, in which the thrombi transform into fibrous tissue, become integrated into the vessel wall, and lead to chronic obstructions. CTEPD is differentiated into cases without pulmonary hypertension (PH), characterized by a mean pulmonary arterial pressure up to 20 mmHg and a form with PH. Then, it is still referred to as chronic thromboembolic pulmonary hypertension (CTEPH).When there is suspicion of CTEPH, initial diagnostic tests should include echocardiography and ventilation/perfusion scan to detect perfusion defects. Subsequently, referral to a CTEPH center is recommended, where further imaging diagnostics and right heart catheterization are performed to determine the appropriate treatment.Currently, three treatment modalities are available. The treatment of choice is pulmonary endarterectomy (PEA). For non-operable patients or patients with residual PH after PEA, PH-targeted medical therapy, and the interventional procedure of balloon pulmonary angioplasty (BPA) are available. Increasingly, PEA, BPA, and pharmacological therapy are combined in multimodal concepts.Patients require post-treatment follow-up, preferably at (CTE)PH centers. These centers are required to perform a minimum number of PEA surgeries (50/year) and BPA interventions (100/year).

Abstract Background: A number of prognostic markers of mortality are known in chronic obstructive pulmonary disease (COPD) but less so for early and mild stages of the disease. We thus analyzed several biomarkers as potential predictors of mortality in early COPD. Methods: The blood biomarkers considered were copeptin (COPAVP), midregional adrenomedullin (MRproADM), midregional pro atrial naturetic peptide (MRproANP), and fibrinogen. Analyses were performed in patients with stable “early COPD” defined by GOLD grades 0-2 and diagnosis of COPD ≤5 years prior to inclusion into the COSYCONET cohort (COPD and Systemic Consequences - Comorbidities Network), using Cox regression analysis with stepwise adjustment for multiple COPD characteristics, comorbidities, troponin and NT-proBNP. Results: 655 patients with early COPD were included. In the initial regression model, 43 of 655 patients died during the 6-year follow-up, in the final model 27 of 487. Regression analyses with adjustment for confounders identified COPAVP and MRproANP as statistically robust biomarkers (p<0.05 each) of all-cause mortality, while MRproADM and fibrinogen were not. The fourth quartile of MRproANP (97 pmol/L) was associated with a hazard ratio of 4.5 (95%CI: 1.6; 12.8), and the fourth quartile of COPAVP (9.2 pmol/L) with 3.0 (1.1; 8.0). The results for MRproANP were confirmed in the total cohort of grade 0-4 (n=1470 finally). Conclusion: In patients with early COPD, elevated values of COPVP and in particular MRproANP were robust, independent biomarkers for all-cause mortality risk after adjustment for multiple other factors. This suggests that these markers might be considered in the risk assessment of early COPD.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease, but an important late sequela after acute pulmonary embolism. Therefore, follow-up after at least three months of sufficient anticoagulation is recommended. Patients with suspected CTEPH should be referred to specialized CTEPH centers for further evaluation and treatment.Three treatment modalities are available: pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and pulmonary hypertension-targeted drugs. The indication for surgery depends mainly on the localization of the pulmonary arterial obstructions. Severe comorbidities as well as advanced age need individual evaluation, but do not present strict exclusion criteria. Multimodal treatments are common practice in inoperable CTEPH. However, treatment decision making in an experienced multidisciplinary team is mandatory.

To the Editor: We thank Wieruszewski et al.1 for their critical evaluation of our manuscript2 demonstrating increased extracorporeal membrane oxygenator (ECMO) half-life through administration of recombinant tissue plasminogen activator (rtPA) and would like to address several points made by the authors: In their letter,1 they advise against a systemic bolus application of rtPA for oxygenator thrombolysis since its application through a local catheter directed to the site of the thrombus will provide a superior risk-benefit ratio. In contrast to localized deep vein thrombosis or occlusive pulmonary embolism (PE), thrombi in an ECMO oxygenator will be concentrated to the basal sites of the inflow part,3 making it difficult to place a catheter in proximity. To our knowledge, no ECMO consumable provider currently offers such a system. If an integrated ECMO thrombolysis catheter were to be engineered, attention to avoid air embolism when the catheter is advanced in the draining circuit will be crucial. A thrombolysis catheter launched from the arterial site to the oxygenator may not reach most thrombi,3 plus it will be useless if clots are sucked into the oxygenator from the patient’s central veins. Therefore, a step-back to an intravenous or intracircuitry injection of thrombolytic agents will be inevitable. Despite thorough literature research, we were not able to identify sufficient data to assess whether a bolus injection or continuous application of rtPA into the ECMO circuit should be chosen for oxygenator lysis. We suggest investigating the optimal administration route for rtPA or different thrombolytic agents through controlled trials. Wieruszewski et al. advice against bolus administrations of rtPA, potentially causing ‘devastating’ bleeding complications. It is recommended for hemodynamically unstable patients with pulmonary embolism to inject similar doses of rtPA intravenously, followed by a continuous perfusion.4 In contrast to acute PE with hemodynamic compromise; we chose not to administer rtPA by continuous infusion to avoid excess bleeding risk. The expectable mortality of complete ECMO oxygenator thrombosis in case of full ECMO dependence is presumably close to 100% with no reserve oxygenator available. Another of Wieruszewski et al.1 concerns is that lowering ECMO blood flow in between multiple rtPA injections might have obscured pressure drops in one particular patient. We chose to define pump head efficiency ƞ (ml of conveyed blood per pump head revolution) exactly to avoid such clouding. Thrombolysis increased ƞ in that patient (0.88 ± 0.04 ml/revolution vs. 0.93 ± 0.03 ml/revolution, p = 0.04), before and after rates per minute were lowered. Optimal target activated thromboplastin time (aPTT) to prevent ECMO circuitry component thrombosis is under debate. While they criticize our selected aPTT target of 45–55 s as being too low, no suggestions as to what the ideal range should be are made. They cite Extracorporeal Life Support Organization 2020 interim guidelines5 to support their claim, however, said guidelines merely acknowledge weak evidence that aPTT should be titrated to the ‘higher end of normal’4 for coronavirus disease 2019. A recent report revealed no correlation between aPTT of heparin-treated patients on ECMO and clot load or distribution in their explanted ECMO oxygenator.3 Due to complex alterations of hemostasis and diffuse intravascular coagulation, COVID-19 Acute respiratory distress syndrome patients are prone to both thromboembolism and bleeding complications. The work referenced by Wieruszewski et al. suggesting higher targets of anticoagulation is based on a publication that included eight patients treated in a single ECMO center.6 This can hardly be regarded as satisfactory evidence to support such a suggestion—especially since Guihaire et al.6 report that 4 of 24 patients suffered life-threatening lung bleeding, in one case requiring bronchial artery embolization and one patient suffered hemorrhagic stroke under stricter anticoagulation.

Chronic thromboembolic pulmonary disease (CTEPD) is an important late complication of acute pulmonary embolism, in which the thrombi transform into fibrous tissue, become integrated into the vessel wall, and lead to chronic obstructions. CTEPD is differentiated into cases without pulmonary hypertension (PH), characterized by a mean pulmonary arterial pressure up to 20 mmHg and a form with PH. Then, it is still referred to as chronic thromboembolic pulmonary hypertension (CTEPH).When there is suspicion of CTEPH, initial diagnostic tests should include echocardiography and ventilation/perfusion scan to detect perfusion defects. Subsequently, referral to a CTEPH center is recommended, where further imaging diagnostics and right heart catheterization are performed to determine the appropriate treatment.Currently, three treatment modalities are available. The treatment of choice is pulmonary endarterectomy (PEA). For non-operable patients or patients with residual PH after PEA, PH-targeted medical therapy, and the interventional procedure of balloon pulmonary angioplasty (BPA) are available. Increasingly, PEA, BPA, and pharmacological therapy are combined in multimodal concepts.Patients require post-treatment follow-up, preferably at (CTE)PH centers. These centers are required to perform a minimum number of PEA surgeries (50/year) and BPA interventions (100/year).

In late 2020, during the second wave of COVID-19 in Germany, we started using the MobyBox, which is a novel fully pneumatically driven ECMO device, on a regular basis to meet the increasing demand for ECMO therapy. In this case series, we performed a retrospective chart review of seven patients with severe COVID-19-related acute respiratory distress syndrome (ARDS) requiring veno-venous (vv)-ECMO support with the MobyBox. During ECMO treatments we have observed no disadvantages in comparison to conventional ECMO systems. There were no system failures or adverse events directly attributable to the MobyBox system. Our data support that providing vv-ECMO with the MobyBox device is safe and feasible. Furthermore, our findings suggest that the MobyBox device might represent an advantage in terms of biocompatibility. Therefore, more data on this issue is needed to better understand how the pneumatically driven pump affects cellular blood components.

As a consequence of the continued Covid-19 lockdown in Germany, in-hospital teaching for medical students was impossible. While lectures and other theoretical training were relatively easily converted into online sessions using platforms such as Moodle, Zoom and Microsoft Teams, this was not the case for practical skills and clinical interventions, such as bronchoscopy or colonoscopy. This study describes a workaround that was implemented at the Saarland University Hospital utilizing virtual reality equipment to convey the impressions of shadowing clinical procedures to the students without physical presence. To achieve this, 3D 180° videos of key clinical interventions of various internal medicine specialities were recorded, cut, and censored. The videos were uploaded to the e-learning YouTube channel of our institution and shared with the students via the private share function. The students could choose whether to use a VR-viewer to watch the videos immersively or to watch them without a viewer on a screen non-immersively. At the end of the course after 1 week, the students completed a questionnaire anonymously focusing on learning-success regarding the presented topics, a self-assessment, and an evaluation of the course. A total of 27 students watched the videos with a VR-Viewer and 74 watched non-immersively. Although the VR-viewer group self-assessed their expertise higher, there was no significant difference between the two groups in the learning-success test score. However, students in the VR-viewer group rated the learning atmosphere, comprehensibility, and overall recommendation of the course significantly higher. They also agreed significantly more to the statement, that they gained a better conception of the presented procedures, and that virtual reality might be an appropriate tool for online teaching. Video-assisted teaching facilitates learning and might be a valuable add-on to conventional teaching.Abbreviations: Covid-19: severe acute respiratory syndrome coronavirus 2; 3D: three-dimensional; 2D: Two-dimensional; VR: virtual reality.

Coronavirus disease 2019 (COVID-19) has drastically increased the number of patients requiring extracorporeal life support. We investigate the efficacy and safety of low-dose recombinant tissue-type plasminogen activator (rtPA) injection into exhausted oxygenators to delay exchange in critically ill COVID-19 patients on veno-venous extracorporeal membrane oxygenation (V-V ECMO). Small doses of rtPA were injected directly into the draining section of a V-V ECMO circuit. We compared transmembrane pressure gradient, pump head efficiency, membrane arterial partial oxygen pressure, and membrane arterial partial carbon dioxide pressure before and after the procedure. Bleeding was compared with a matched control group of 20 COVID-19 patients on V-V ECMO receiving standard anticoagulation. Four patients received 16 oxygenator instillations with rtPA at 5, 10, or 20 mg per dose. Administration of rtPA significantly reduced transmembrane pressure gradient (Δp m = 54.8 ± 18.1 mmHg before vs. 38.3 ± 13.3 mmHg after, p < 0.001) in a dose-dependent manner (Pearson’s R −0.63, p = 0.023), allowing to delay oxygenator exchange, thus reducing the overall number of consumed oxygenators. rtPA increased blood flow efficiency η (1.20 ± 0.28 ml/revolution before vs. 1.24 ± 0.27 ml/r, p = 0.002). Lysis did not affect membrane blood gases or systemic coagulation. Minor bleeding occurred in 2 of 4 patients (50%) receiving oxygenator lysis as well as 19 of 20 control patients (95%). Lysis of ECMO oxygenators effectively delays oxygenator exchange, if exchange is indicated by an increase in transmembrane pressure gradient. Application of lysis did not result in higher bleeding incidences compared with anticoagulated patients on V-V ECMO for COVID-19.

Extracorporeal membrane oxygenation (ECMO) has become an important therapeutic approach in the COVID-19 pandemic. The development and research in this field strongly relies on animal models; however, efforts are being made to find alternatives. In this work, we present a new mock circuit for ECMO that allows measurements of the oxygen transfer rate of a membrane lung at full ECMO blood flow. The mock utilizes a large reservoir of heparinized porcine blood to measure the oxygen transfer rate of the membrane lung in a single passage. The oxygen transfer rate is calculated from blood flow, hemoglobin value, venous saturation, and post-membrane arterial oxygen pressure. Before the next measuring sequence, the blood is regenerated to a venous condition with a sweep gas of nitrogen and carbon dioxide. The presented mock was applied to investigate the effect of a recirculation loop on the oxygen transfer rate of an ECMO setup. The recirculation loop caused a significant increase in post-membrane arterial oxygen pressure (paO2). The effect was strongest for the highest recirculation flow. This was attributed to a smaller boundary layer on gas fibers due to the increased blood velocity. However, the increase in paO2 did not translate to significant increases in the oxygen transfer rate because of the minor significance of physically dissolved oxygen for gas transfer. In conclusion, our results regarding a new ECMO mock setup demonstrate that recirculation loops can improve ECMO performance, but not enough to be clinically relevant.

Low flow extracorporeal carbon dioxide removal (ECCO2R) is a promising approach to correct hypercapnic lung failure, facilitate lung protective ventilation in acute respiratory distress syndrome and to possibly prevent the application of invasive ventilation. However, the predominant availability of adult membrane lungs (MLs) at most intensive care units are burdens for low flow ECCO2R that intends to reduce cannula size and promote the mobility of the patients. Herein, in a mock setup, we combine the idea of a low flow ECCO2R and the use of adult MLs by installing a recirculation channel into the circuit and comparing the new setup to an already clinically established setup, “the Homburg lung.” Furthermore, to make stronger reference to hypercapnic respiratory failure, we investigate the influence of CO2 partial pressure in blood on CO2 removal of both setups. A linear association between CO2 partial pressure in blood and CO2 removal of the ML in the physiologically relevant range was observed. To understand this linear dependence, a simplified mathematical model was proposed. Our new ECCO2R mock setup combines the idea of a low flow ECCO2R and an adult size ML. It shows a reasonable alternative to the current available low flow setups based on pediatric MLs.

Extracorporeal carbon dioxide removal (ECCO2R) is an important technique to treat critical lung diseases such as exacerbated chronic obstructive pulmonary disease (COPD) and mild or moderate acute respiratory distress syndrome (ARDS). This study applies our previously presented ECCO2R mock circuit to compare the CO2 removal capacity of circular versus parallel-plated membrane lungs at different sweep gas flow rates (0.5, 2, 4, 6 L/min) and blood flow rates (0.3 L/min, 0.9 L/min). For both designs, two low-flow polypropylene membrane lungs (Medos Hilte 1000, Quadrox-i Neonatal) and two mid-flow polymethylpentene membrane lungs (Novalung Minilung, Quadrox-iD Pediatric) were compared. While the parallel-plated Quadrox-iD Pediatric achieved the overall highest CO2 removal rates under medium and high sweep gas flow rates, the two circular membrane lungs performed relatively better at the lowest gas flow rate of 0.5 L/min. The low-flow Hilite 1000, although overall better than the Quadrox i-Neonatal, had the most significant advantage at a gas flow of 0.5 L/min. Moreover, the circular Minilung, despite being significantly less efficient than the Quadrox-iD Pediatric at medium and high sweep gas flow rates, did not show a significantly worse CO2 removal rate at a gas flow of 0.5 L/min but rather a slight advantage. We suggest that circular membrane lungs have an advantage at low sweep gas flow rates due to reduced shunting as a result of their fiber orientation. Efficiency for such low gas flow scenarios might be relevant for possible future portable ECCO2R devices.

Background Titanium dioxide nanoparticles (TiO 2 NPs) have a wide range of applications in several industrial and biomedical domains. Based on the evidence, the workers exposed to inhaled nanosized TiO 2 powder are more susceptible to the risks of developing respiratory diseases. Accordingly, this issue has increasingly attracted the researchers’ interest in understanding the consequences of TiO 2 NPs exposure. Regarding this, the present study was conducted to analyze the local effects of TiO 2 NPs on allergic airway inflammation and their uptake in a mouse model of ovalbumin (OVA)-induced allergic airway inflammation. Methods For the purpose of the study, female BALB/c mice with or without asthma were intranasally administered with TiO 2 NPs. The mice were subjected to histological assessment, lung function testing, scanning electron microscopy (SEM), inductively coupled plasma mass spectrometry (ICP-MS), and NP uptake measurement. In addition, T helper (Th) 1/Th2 cytokines were evaluated in the lung homogenate using the enzyme-linked immunosorbent assay. Results According to the results, the mice receiving OVA alone or OVA plus TiO 2 NPs showed eosinophilic infiltrates and mucus overproduction in the lung tissues, compared to the controls. Furthermore, a significant elevation was observed in the circulating Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13 after NP exposure. The TiO 2 NPs were taken up by alveolar macrophages at different time points. As the results of the SEM and ICP-MS indicated, TiO 2 NPs were present in most of the organs in both asthmatic and non-asthmatic mice. Conclusion Based on the findings of the current study, intranasally or inhalation exposure to high-dose nanosized TiO 2 particles appears to exacerbate the allergic airway inflammation and lead to systemic uptake in extrapulmonary organs. These results indicate the very important need to investigate the upper limit of intranasally or inhalation exposure to nanosized TiO 2 particles in occupational and environmental health policy.

Rationale: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by multiple subtypes and variable disease progression. While FEV1 is an insufficient candidate for the prediction of disease progression, we investigated, whether copeptin correlates with clinical endpoints and mortality. Methods: We measured copeptin in plasma samples of 1 patients with stable COPD (GOLD 0-4, GOLD A-D) from the German COPD cohort study COSYCONET. Results: In the cross sectional analysis of a linear regression model that considers age, BMI, Gender, cardiovascular index, and packyears of smoking as confounders, copeptin correlated with the impairment of: airway obstruction (FEV1, sRawTot) (p<0.001), exacerbation frequency (p<00.1), 6-MWT (p<00.1), BODE index (p<00.1), SGRQ (p<00.1), and EQ5D-Score (p<0.01). In Cox regression analyses including adjustments for COPD assessments, cardiovascular risk factors and cardiovascular diseases copeptin was a significant predictor for all-cause mortality (hazard ratio for log Copeptin, 2.23 (1.12‒4.43), p=0.022) Discussion/Conclusion: While previous groups studied copeptin in patients with COPD exacerbations, we provide evidence that copeptin is a suitable biomarker for all-cause mortality in stable COPD taking into account many covariates.

Introduction: Chronic obstructive pulmonary disease (COPD) is based on chronic inflammation of the lung and a systemic disease with different phenotypes and comorbidities. Conventional markers including lung function parameters only partially correlate with severity, progression and mortality, thus novel, additional biomarkers would be valuable. As a candidate marker, our study examined pro-adrenomedullin, a peptide with vasodilatory and immunomodulatory effects. Methods: The concentration of pro-adrenomedullin was measured in plasma samples from 1805 patients with stable COPD (GOLD 0-4, GOLD A-D) of the German multicenter COPD cohort COSYCONET. Data analysis was carried out using linear regression models that took into account age, sex, cardiovascular index and pack years of cigarette smoking as covariates. Results: pro-adrenomedullin correlated in cross-sectional analyses (each p<0.001) with impairments of the following parameters: airway obstruction (FEV1, sRawtot), exacerbation frequency, emphysema (TLC, ITGV), restriction of physical activity (6-minute walking test, timed-up-and-go test), BODE index, health-related quality of life (SGRQ: activity score, impact score, overall score), and cognitive performance (DemTect score). In a Cox regression model, pelevated pro-adrenomedullin levels were associated with increased mortality (p<0.001). Conclusions: pro-adrenomedullin is suitable as a biomarker in stable COPD. Even taking into account important confounders, this biomarker turned out to be robust.