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Advanced pulmonary vascular monitoring for optimum Nitric Oxide delivery in acute respiratory distress syndrome. Expanding Nitric Oxide applications

Periodic Reporting for period 1 - OPVANOX-ARDS (Advanced pulmonary vascular monitoring for optimum Nitric Oxide delivery in acute respiratory distress syndrome. Expanding Nitric Oxide applications)

Reporting period: 2018-05-01 to 2020-04-30

This project is framed within the therapies for acute respiratory distress syndrome (ARDS), particularly, the efficacy of the use of inhaled nitric oxide (iNO). This syndrome has a high mortality and most of the disease management are based on mechanical ventilation. In patients with ARDS, iNO improves gas exchange and pulmonary hemodynamic but has not proven to decrease mortality nor relevant clinical outcomes. A better description of the effects of iNO on pulmonary vascular function and how this can be used for a better characterization of the response to this therapy is needed. This can also lead to a better discrimination of those patients that could benefit from the iNO treatment but the improvement in the patient monitoring during the iNO therapy is a key factor.
The impact on society of this study is based on the fact the ARDS has a high mortality and that this syndrome is very frequent in intensive care units and results as a complication of several pulmonary and non-pulmonary diseases. Complementary therapies as iNO could decrease not only mortality but also the number of days patient is under mechanical ventilation and consequently the complications related with ARDS. The high impact of this study is not only from the clinical point of view but also from an economical one because the cost for hospitals and healthcare systems. Furthermore, a better selection of patients in which iNO is used can lead to resources optimisation, decreasing the expenditures in patients with low probability of good response to this therapy.
The development of tools to improve iNo therapy and patient selection can be strategically relevant for companies working in this field and is beneficial for the entrepreneurship.
The main objective of this study was to define bedside parameters to guide and monitor pulmonary vascular function during iNO delivery in ARDS. Specific objectives are:
- To explore bedside physiologically driven parameters and monitoring tools to control iNO delivery for treating pulmonary vascular dysfunction in ARDS,
- To evaluate the pulmonary vascular effect of NO in ARDS by means of advanced imaging tools,
- To propose new algorithms based in physiologic variables for selecting patient for NO application,
- To set the most extended clinical application of iNO as a treatment for pulmonary vascular dysfunction and prevention of right ventricle failure in ARDS patients,
- To describe the dose response of iNO for the components developed to evaluate pulmonary vascular function,
- To explore new therapeutic applications of NO.
The conclusion of the study indicates it is possible to monitor parameters of the patient that represent the effect of the iNO on the patient efficiently. The results will conduct to an important improvement in patient safety for a potential use of iNO in hospital and more importantly in domiciliary condition. The results permit to optimise the use of iNO in those patients that respond properly to the treatment. Additionally, understanding better the pulmonary physiology is also key for the next set of experiments. In summary, these results are key for the design of more secure devices for also extending the application of iNO in other segment of patients.
The work started by a critical review of the literature. More than 50 papers were evaluated, and the conclusions were used for planning the strategy to evaluate new ways for improving the monitoring of patient receiving iNO therapy. It was also used for optimizing the animal studies protocols and the number of subjects. Additionally, the re-analysis of a previous animal model study (swine model) performed was conducted. A model of ARDS by means of lung saline lavage and injurious mechanical ventilation was used to compare iNO with other standard therapies. Pulmonary hemodynamic was evaluated by means of Swan-Ganz catheter, arterial gases were analyzed, and a complete systemic hemodynamic evaluation was performed by means of trans-pulmonary thermodilution and arterial pulse contour analysis. A trend to pulmonary hemodynamic and gas exchange was observed in pigs subjected to iNO therapy. Several protocols were designed and discussed for the evaluation of the effects of iNO in different animal models and the efficacy of some different monitoring tools.
A long-term swine model of mild ARDS with severe pulmonary hemodynamic deterioration was conducted in pigs. This model consists of high dose of intravenous endotoxin infusion. The hypothesis is based on the early use of iNO in patients with ARDS could improve the survival of the subjects by protecting right ventricle even before they develop severe gas exchange and respiratory mechanics affection. This protocol has remarkably high translational potential as well as relationship with the main objectives of this project. A very completed hemodynamic and pulmonary monitoring was used which was complemented with thoracic electric impedance tomography. Six animals were randomized to either iNO or to conventional therapy. The results of this set of experiments indicates the pigs treated with iNO showed a longer survival (approximately 16h vs 10h) and rapid improvement on pulmonary hemodynamic. The results are promising but it is recommended to increase the number of animals for confirmation what was not possible due to the unexpected early termination of the project due to experienced fellowship was called back to clinical practice due to Covid-19 pandemic.
A small animal study protocol was designed to evaluate in detail the effect of iNO in the pulmonary perfusion, ventilation and inflammation by positron emission tomography (PET). This study was not completed during the project due to the unexpected early termination, it will be completed soon, and the preliminary results are promising.
The results of the work permitted to stablish the effect of iNO therapy by mean of some monitoring parameter that will conduct to an important improvement in patient safety for a potential use of iNO in hospital and more importantly in domiciliary condition. The results permit to optimize the use of iNO in those patients that respond properly to the treatment. Additionally, understanding better the pulmonary physiology is also key for the next set of experiments. In summary, these results are key for the design of more secure devices for also extending the application of iNO in other segment of patients.
The major progress beyond the state of the art of this project relates with the possibility of expanding the application iNO at earlier stages of ARDS looking for protection of the right ventricle. Currently iNo is indicated in ARDS patients as a rescue therapy usually in very sick patients and a advanced stages of the disease. However the preliminary results of the animal studies of this project show a positive effect on relevant outcomes even when the damage on the lung function not fully developed. This could have a relevant impact opening a fully new translational research line involving not only clinical studies but also the possibility of technological developments directed to improve patient monitoring during iNo therapy.
The project has not a web. But the beneficiary web page has information about the current iNO system that is the base for a new generation including the results of this project for using iNO in domiciliary environment and for a more safety and optimized way in hospital and during transportation.
Graph with representative results