Toward a digital decision- and workflow-support system for initiation and control of long-term non-invasive ventilation in stable hypercapnic COPD patients.

Introduction: Due to an increasing demand for the initiation and control of non-invasive ventilation (NIV), digital algorithms are suggested to support therapeutic decisions and workflows in an ambulatory setting. The DIGIVENT project established and implemented such algorithms for patients with chronic hypercapnic respiratory failure due to chronic obstructive pulmonary disease (COPD) by a predefined process. Methods: Based on long-term clinical experience and guideline recommendations as provided by the German Respiratory Society, detailed graphical descriptions of how to perform NIV in stable COPD patients were created. Subsequently, these clinical workflows were implemented in the Business Process Model and Notation (BPMN) as one tool to formalize these workflows serving as input for an executable digital implementation. Results: We succeeded in creating an executable digital implementation that reflects clinical decision-making and workflows in digital algorithms. Furthermore, we built a user-friendly graphical interface that allows easy interaction with the DIGIVENT support algorithms. Conclusion: The DIGIVENT project established digital treatment algorithms and implemented a decision- and workflow-support system for NIV whose validation in a clinical cohort is planned.

Establishment of a Pre-vascularized 3D Lung Cancer Model in Fibrin Gel-Influence of Hypoxia and Cancer-Specific Therapeutics.

Lung cancer is the most frequently diagnosed cancer worldwide and the one that causes the highest mortality. In order to understand the disease and to develop new treatments, in vitro human lung cancer model systems which imitate the physiological conditions is of high significance. In this study, a human 3D lung cancer model was established that features the organization of a tumor with focus on tumor angiogenesis. Vascular networks were formed by co-culture of human umbilical vein endothelial cells and adipose tissue-derived mesenchymal stem cells (ASC) for 14 days in fibrin. A part of the pre-vascularized fibrin gel was replaced by fibrin gel containing lung cancer cells (A549) to form tri-cultures. This 3D cancer model system was cultured under different culture conditions and its behaviour after treatment with different concentrations of tumor-specific therapeutics was evaluated. The evaluation was performed by measurement of metabolic activity, viability, quantification of two-photon laser scanning microscopy and measurement of the proangiogenic factor vascular endothelial growth factor in the supernatant. Hypoxic conditions promoted vascularization compared to normoxic cultured controls in co- and tri-cultures as shown by significantly increased vascular structures, longer structures with a higher area and volume, and secretion of vascular endothelial growth factor. Cancer cells also promoted vascularization. Treatment with 50 µM gefitinib or 50 nM paclitaxel decreased the vascularization significantly. VEGF secretion was only reduced after treatment with gefitinib, while in contrast secretion remained constant during medication with paclitaxel. The findings suggest that the herein described 3D lung cancer model provides a novel platform to investigate the angiogenic potential of cancer cells and its responses to therapeutics. Thus, it can serve as a promising approach for the development and patient-specific pre-selection of anticancer treatment.

Towards a Biohybrid Lung: Endothelial Cells Promote Oxygen Transfer through Gas Permeable Membranes.

In patients with respiratory failure, extracorporeal lung support can ensure the vital gas exchange via gas permeable membranes but its application is restricted by limited long-term stability and hemocompatibility of the gas permeable membranes, which are in contact with the blood. Endothelial cells lining these membranes promise physiological hemocompatibility and should enable prolonged application. However, the endothelial cells increase the diffusion barrier of the blood-gas interface and thus affect gas transfer. In this study, we evaluated how the endothelial cells affect the gas exchange to optimize performance while maintaining an integral cell layer. Human umbilical vein endothelial cells were seeded on gas permeable cell culture membranes and cultivated in a custom-made bioreactor. Oxygen transfer rates of blank and endothelialized membranes in endothelial culture medium were determined. Cell morphology was assessed by microscopy and immunohistochemistry. Both setups provided oxygenation of the test fluid featuring small standard deviations of the measurements. Throughout the measuring range, the endothelial cells seem to promote gas transfer to a certain extent exceeding the blank membranes gas transfer performance by up to 120%. Although the underlying principles hereof still need to be clarified, the results represent a significant step towards the development of a biohybrid lung.

Optimizing inhalation technique using web-based videos in obstructive lung diseases.

BACKGROUND: Inhaled agents are widely used in the treatment of chronic airway diseases. Correct technique is required to ensure appropriate drug deposition, but poor technique is common. This study investigated whether inhalation technique could be improved by patient training using short videos from the German Airway League. METHODS: Outpatients from a university hospital respiratory clinic who had incorrect inhalation technique were asked to demonstrate this again immediately after viewing the training videos, and after 4-8 weeks' follow-up. Inhalation technique was rated by a study nurse using specific checklists. RESULTS: One hundred and twelve patients with obstructive lung disease treated with inhaled bronchodilators or corticosteroids were included. More than half (51.8%) had at least one mistake in inhalation technique at baseline. Of these, most (88%) understood the training videos, 76% demonstrated correct device use immediately after training, and 72% were still able to demonstrate correct inhalation technique at follow-up (p = 0.0008 for trend). In addition, the number of mistakes decreased significantly after video training (by 1.82 [95% confidence interval 1.39-2.25]; p < 0.0001 vs. baseline). CONCLUSIONS: German Airway League inhalation technique training videos were easy to understand and effectively improved inhalation technique in patients with airway diseases.

Nebulized versus Standard Local Application of Lidocaine during Flexible Bronchoscopy: A Randomized Controlled Trial.

BACKGROUND: Endobronchial administration of local anesthetics such as lidocaine is often used for cough suppression during bronchoscopy. To achieve a better distribution of lidocaine in the tracheobronchial tree, spray catheters have been developed, allowing nebulization of the local anesthetic solution. However, there are little data on the efficacy and safety of this approach, or on the consumption of sedative drugs and lidocaine during nebulized administration. OBJECTIVES: To investigate the tolerability of nebulized lidocaine compared to conventional lidocaine administration via syringe through the working channel of the bronchoscope in patients undergoing bronchoscopy. Consumption of sedative drugs and lidocaine was also compared between the two lidocaine administration approaches. METHODS: Patients requiring bronchoscopy with endobronchial or transbronchial biopsy were randomly assigned to receive topical lidocaine either via syringe or via nebulizer. Endpoints were consumption of lidocaine and sedative drugs, as well as patient tolerance and safety. RESULTS: Thirty patients were included, 15 in each group. Patients in the nebulizer group required lower doses of endobronchial lidocaine (184.7 ± 67.98 vs. 250.7 ± 21.65 mg, p = 0.0045) and intravenous fentanyl (0.033 ± 0.041 vs. 0.067 ± 0.045 mg, p = 0.0236) than those in the syringe group; midazolam or propofol dosages did not differ between the two groups. In addition, there were no between-group differences in patient tolerance or safety (all p > 0.05). CONCLUSION: Endobronchial administration of lidocaine during bronchoscopy via nebulizer was found to be well tolerated and safe and was associated with reduced lidocaine and fentanyl dosages compared to administration via syringe.

Flexible Endoscopic Spray Application of Respiratory Epithelial Cells as Platform Technology to Apply Cells in Tubular Organs.

INTRODUCTION: Inoperable airway stenoses are currently treated by placing stents. A major problem of covered stents is missing mucociliary clearance, which is caused by covering the native respiratory epithelium. By coating a stent with respiratory epithelium, this problem can be overcome. However, no methods are available for efficient endoscopic cell seeding. METHODS: We designed a flexible endoscopic spraying device based on a bronchoscope and tested it with respiratory epithelial cells. With this device cells can also be applied in a thin layer of fibrin glue. We evaluated the survival rate directly after spray application with a live-dead staining and the long-term differentiation capacity with histology and electron microscopy. Furthermore, the random distribution of cells when applied in a tube was analyzed and the macroscopic and microscopic characteristics of the endoscopic spray were investigated using high-speed visualization. RESULTS: Spray visualization revealed a polydisperse character of the spray with the majority of droplets larger than epithelial cells. Spray application does not influence the survival rate and differentiation of respiratory epithelial cells. After 4 weeks, cells built up a pseudostratified epithelial layer with cilia and goblet cells. When cells are applied in a thin layer of fibrin gel into a tube, a nearest neighbor index of 1.2 is obtained, which suggests a random distribution of the cells. CONCLUSIONS: This spraying device is a promising tool for application of various cell types onto stents or implants with high survival rates and homogeneous distribution as shown in this study for ovine respiratory epithelial cells. The system could also be used for cell therapy to locally apply cells to the diseased parts of hollow organs. For the first time, the fluid dynamics of a spray device for cells were examined to validate in vitro results.