Novel diagnostics and treatment of acute lung injury and transplantation - Preclinical and clinical implementation

Acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome (ARDS) limit the utilization of donor lungs for transplantation but is also a common cause of death in the intensive care unit. There is a general lack of diagnostic tools by which to assess lung function in ARDS but, in addition, the treatments offered are limited. In the present thesis, the aim was to explored particles in exhaled air as a diagnostic tool for ALI, but also the use of cytokines as a treatment target for such injury. A porcine model was used where ALI and ARDS were induced, using either lipopolysaccharide (LPS), repeated lavage or gastric content aspiration. The lungs were evaluated in vivo during non-transplant and transplant conditions and with or without extra corporal membrane oxygenation (ECMO) support. The lungs were also evaluated by machine perfusion using ex vivo lung perfusion (EVLP). Measurements of exhaled breath particles (EBP), expressed as particle flow rate (PFR), from the airways preceded early signs of ARDS, not only in an LPS-induced ARDS porcine model but could also be used for monitoring lung injury during ECMO treatment both in pigs but also in patients with COVID-19-induced ARDS. Increased PFR also preceded clinical signs of ALI in the gastric aspiration model, whereas only a trend could be seen in the repeated lavage model. The LPS models showed a similar pattern of massive cytokine release as also seen in the COVID-19 patients. The cytokines were detected both in plasma and in bronchoalveolar lavage fluid (BALF). The cytokine release was not as prominent in the repeated lavage model and in the gastric aspiration model. In the collected samples of EBPs, specific proteins connected to ALI were detected in all animal models. Given the role of cytokines in lung injury, cytokines are interesting targets for lung repair and regeneration. EVLP has lately gained acceptance as an evaluation platform for marginal lungs initially declined for transplantation. A new aspect is using the platform to repair or restore lung function of donor lungs with ALI that are declined both for EVLP and for transplantation. A cytokine filter was connected to the EVLP during perfusion of LPS-damaged donor lungs. The cytokine filter restored lung function after 4 hours of EVLP, shown by improved oxygenation and confirmation by histology. For optimal treatment, the restored lungs were transplanted into a healthy recipient and received another 12 hours of cytokine filtration post-transplantation. The lungs were evaluated regarding the development of primary graft dysfunction (PGD) where cytokines seem to be an important target given the outcome of significantly less PGD in the group receiving cytokine filtration. In conclusion, PFR may be used as a diagnostic tool in mechanical ventilation and to detect ALI, but also to monitor lung injury over time. Cytokines as a treatment target have their role in restoring lung function in damaged donor lungs

Pulsatile flow does not improve efficacy in ex vivo lung perfusion.

Introduction Ex vivo lung perfusion (EVLP) has the potential to increase the donor pool for lung transplantation by facilitating extended evaluation of marginal organs. Current methodology employs continuous flow pumps for perfusion. In vivo, continuous flow has been shown to increase pulmonary vascular resistance (PVR). Thus, pulsatile flow EVLP may reduce PVR and improve organ preservation by providing physiologic flow morphology. Methods Lung blocks harvested from male, Yorkshire pigs were allocated into continuous (CF, n=3) and pulsatile flow (PF, n=4) groups. Lungs were ventilated at 4-5 mL/kg, 30% FiO2 and perfused with an acellular, albumin-based solution corrected for osmolarity, acid/base balance, and CO2 concentration (=19 hours at 30°C). Prostaglandin E2 and 30% albumin were infused continuously at 250 ?g/hr and 100 mL/hr, respectively. Hemodynamic, respiratory, and blood gas parameters were recorded hourly. Parenchymal biopsies were used for quantification of wet: dry ratio and IL-6, IL-8, and TNF-a using ELISA. Results ?PO2/FoO2 in mmHg was 261±47 and 313±37 at baseline and 174±36 and 152±36 at hour 12 for CF and PF, respectively. Wet: dry ratio was 5.53±0.56 and 6.06±0.09 at baseline and 5.27±0.48 and 5.12±0.40 at hour 12 for CF and PF, respectively. Average PVR in Woods Units was 15.17±1.33 and 13.60±1.91 over the 12 hour test period for CF and PF groups, respectively. Peak airway pressure (PAWP) in cm H2O was 17±1.15 and 16±0.75 at baseline and 21±1.67 and 21±0.41 at hour 12 for CF and PF, respectively. There were no discernable differences in TNF-a, IL-6, and IL-8 concentrations, PVR, ?PO2/FiO2, wet: dry ratio, and PAWP between CF and PF. Conclusion EVLP system successfully maintained lungs up to 19 hours using a modified perfusate. These data suggest PF does not offer benefits over CF for prolonged ex vivo lung preservation

Advances in Extracorporeal Membrane Oxygenation in the Setting of Lung Transplantation

Lung transplantation has become an increasingly important modality for the treatment of severe lung disease. From its inception, the procedure has been refined so that it now represents the standard of care for end stage respiratory failure. The widespread adoption of this treatment option, however, has brought into sharp relief the current organ donor shortage. In tandem with the explosion in lung transplant procedures, a number of support modalities have seen an expanded role. Perhaps one of the most versatile tools in the armamentarium of the pulmonary transplant surgeon is extracorporeal membrane oxygenation (ECMO). This powerful tool is being increasingly implemented in all stages of lung transplantation—from supporting the failing native organ as a bridging tool to transplantation, to stabilizing the patient intra-operatively during the transplant procedure, to rescuing the patient with severe primary graft dysfunction immediately post-transplant. A number of advanced techniques for the application of ECMO in order to optimize the pulmonary transplant procedure are gaining traction—and with ECMO’s expanded role in lung transplantation, so also has come a new set of technical and ethical challenges that must also be overcome