Inhaled nitric oxide (INO) is widely used within hospitals to treat lung failure, ranging from acute respiratory distress syndrome (ARDS) in adults and persistent pulmonary hypertension in newborns (PPHN), to postoperative pulmonary hypertension in patients with congenital heart disease and patients with pneumonia or other lung infections. INO may also have great benefit to ambulatory patients deficient in NO production, including those with cystic fibrosis and chronic rhinosinusitis, in which inadequate levels of NO are linked to high risks of chronic infection/biofilm formation on epithelial cells tht line the upper airways. Further, addition of gas phase NO to the sweep gas used in oxygenators that are employed in extracorporeal circulation (EC) procedures (including cardio-pulomonary bypass (CPB) and extracorporeal membrane oxygenation (ECMO)) can also potentially be useful in preventing activation of platelets (leading to thrombus) and leukocytes (leading to systemic inflammatory response syndrome (SIRS)). Current methods to generate therapeutic levels of gas phase NO for biomedical applications are very expensive, owing to the high cost of compressed gas cylinders typically containing 100 - 400 ppmv of NO (in nitrogen). Indeed, with time, NO at such levels can undergo disproportionation reactions to generate low levels of toxic NO2. Hence, constant monitoring of the gas phase concentrations of these species is required, and use of relatively new compressed tanks of NO are mandatory, making INO and EC applications of gas phase NO extremely expensive. To greatly reduce the cost, and potentially increase the broader use of therapeutic gas phase NO (possibly also for home use), we now propose a simple electrochemical NO generator that makes pure NO gas on demand from a small reservoir solution of dissolved inorganic nitrite (NO2-) salt. The NO gas will be generated by a one electron electrochemical reduction of NO2- at large area mesh electrodes using novel copper(II)-ligand complexes that serve as electron transfer mediators. The NO gas levels produced in this manner will diffuse through gas exchanger hollow fibers to create the desired NO levels within a flowing nitrogen stream that will then be appropriately diluted downstream with oxygen/air for potential INO as well as EC sweep gas applications. Via this R21 grant, we will optimize the chemistry/electrochemistry for this approach, examine the purity of NO produced in the gas phase via IR spectroscopy and demonstrate the ability to control the precise NO levels in the source and recipient gas streams merely by varying the applied voltage/current for the electrochemical reduction reaction. We will also examine the feasibility of incorporating a highly sensitive NO gas phase sensor to continuously monitor NO levels within the gas phases produced by this new technology to servo-regulate the electrochemical NO generation process in the nitrite/Cu(II)-ligand complex reservoir solution.
The very high cost associated with using gas phase NO has been an obstacle to its wider use. We propose to investigate a new, safe, inexpensive and highly portable electrochemical method to create gas phase NO from inorganic nitrite solutions for potential applications in gas phase INO therapy as well as to generate NO within the sweep gas for EC procedures. This advance could dramatically reduce the cost and increase the wider clinical application of gas phase NO for a variety of patients who could benefit from such treatment.