Patent Publication Number: US-2023140163-A1

Title: Systems and methods for synthesis of nitric oxide

Description:
CROSS-REFERENCES TO RELATED APPLICATIONS 
     The present application is based on, claims priority to, and incorporates herein by reference in their entirety, U.S. Provisional Patent Application No. 62/065,825, filed Oct. 20, 2014, and entitled “Producing Nitric Oxide for Inhalation by Electric Discharge in Air,” and U.S. Provisional Patent Application No. 62/077,806, filed Nov. 10, 2014, and entitled “Synthesis of Nitric Oxide.” 
     STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH 
     Not Applicable. 
    
    
     BACKGROUND 
     The disclosure relates generally to the electrical plasma synthesis of nitric oxide (NO) from gases and, more specifically, to systems and methods for producing safe NO to be used in medical applications. 
     NO is a crucial mediator of many biological systems, and is known to control the level of systemic and pulmonary artery blood pressure, help the immune system kill invading parasites that enter cells, inhibit the division of cancer calls, transmit signals between brain cells, and contribute to the death of brain cells that debilitates people with strokes or heart attacks, among other things. NO mediates the relaxation of smooth muscle present, for example, in the walls of blood vessels, bronchi, the gastrointestinal tract, and urogenital tract. Administration of NO gas to the lung by inhalation has been shown to produce localized smooth muscle relaxation within the lung&#39;s blood vessels and is widely used to treat pulmonary hypertension, pneumonia, hypoxemic respiratory failure of a newborn, etc. without producing systemic side effects. 
     Inhaling NO can immediately produce potent and selective pulmonary vasodilation that improves the matching of ventilation with perfusion, thereby increasing an injured lung&#39;s oxygen transport efficiency, and breathing NO can raise the arterial oxygen tension. Breathing NO produces the rapid onset of pulmonary vasodilator action occurring within seconds of commencing breathing with the absence of systemic vasodilatation, once inhaled, NO diffuses through the pulmonary vasculature into the bloodstream, where it is rapidly inactivated by combination with hemoglobin (the NO dioxygenation reaction). Therefore, the vasodilatory effects of inhaled NO are limited to these pulmonary therapeutic advantages in the treatment of acute and chronic pulmonary hypertension. Inhaled NO can also be used to prevent ischemia reperfusion injury after percutaneous coronary intervention in adults with heart attacks. Furthermore, inhaled NO can produce systemic anti-inflammatory and anti-platelet effects by increasing the levels of circulating NO biometabolites and by other mechanisms, such as the oxidation of circulating ferrous hemoglobin in the plasma. Finally, NO has known anti-microbial activity. 
     BRIEF SUMMARY 
     The present disclosure provides systems and methods for producing nitric oxide (NO) to be used in medical applications. Specifically, systems and methods are provided for a NO generator that is capable of generating a desired concentration of pure and safe NO to be provided to a respiratory system for inhalation by a patient. 
     In one aspect, the present disclosure provides an apparatus for generating nitric oxide including one or more pairs of electrodes, a filter arranged downstream of the electrodes, and a scavenger arranged downstream of the electrodes. The apparatus further includes one or more sensors configured to measure at least one of a flowrate of gas, an oxygen concentration upstream of the electrodes, a nitric oxide concentration downstream of the scavenger, and a nitrogen dioxide concentration downstream of the scavenger, and a controller in communication with the electrodes and the one or more sensors and configured to supply an electrical signal to the electrodes that controls timing and sparking characteristics of the electrodes. The sparking characteristics of the electrodes determine a concentration of nitric oxide generated by the electrodes. 
     In some embodiments, the electrodes comprise at least one of tungsten carbide, carbon, nickel, iridium, titanium, rhenium, and platinum 
     In some embodiments, the electrodes comprise iridium. 
     In some embodiments, the scavenger is fabricated from calcium hydroxide. 
     In some embodiments, the one or more sensors include an airway flowmeter arranged downstream of the electrodes, an oxygen sensor arranged upstream of the electrodes, a nitric oxide sensor arranged downstream of the scavenger, and a nitrogen dioxide sensor arranged downstream of the scavenger. 
     In some embodiments, an ignition coil is in communication with the controller and the electrodes. 
     In some embodiments, the controller is further configured to instruct the ignition coil to supply stored electrical energy to the electrodes. 
     In some embodiments, the electrical signal supplied to the electrodes controls at least one of a number of electrode spark groups per second, a number of individual electrode sparks per spark group, a time between individual electrode sparks, and a pulse duration. 
     In some embodiments, the controller is further configured to vary at least one of the number of electrode spark groups per second, the number of individual electrode sparks per spark group, the time between individual electrode sparks, and the pulse duration in response to feedback from the one or more sensors. 
     In some embodiments, the apparatus further comprises a gas pump arranged upstream of the electrodes. 
     In some embodiments, the one or more sensors provide an indication of inspiration. 
     In some embodiments, the controller is further configured to supply the electrical signal to the electrodes in response to detecting inspiration. 
     In some embodiments, the filter is configured to filter particles flowing downstream of the electrodes with a diameter greater than approximately 0.22 micrometers. 
     In another aspect, present disclosure provides an apparatus for generating nitric oxide to be integrated into a respiratory system having a breathing apparatus, an inspiratory line, and an airway flowmeter arranged on the inspiratory line. The apparatus includes one or more pairs of electrodes in gaseous communication with the inspiratory line, a filter arranged downstream of the electrodes, and a scavenger arranged downstream of the electrodes. The apparatus further includes one or more sensors configured to measure at least one of an oxygen concentration upstream of the electrodes, a barometric pressure, a nitric oxide concentration downstream of the scavenger; and a nitrogen dioxide concentration downstream of the scavenger, and a controller in communication with the electrodes, the one or more sensors, and the airway flowmeter; and configured to supply an electrical signal to the electrodes that controls timing and sparking characteristics of the electrodes. The sparking characteristics of the electrodes determine a concentration of nitric oxide generated by the electrodes. 
     In some embodiments, the electrodes are arranged between an inlet and an outlet, the outlet is coupled to the inspiratory line. 
     In some embodiments, the electrodes are at least partially integrated into the inspiratory line. 
     In some embodiments, the filter is arranged on the inspiratory line. 
     In some embodiments, the scavenger is arranged on the inspiratory line. 
     In some embodiments, the electrodes comprise at least one of tungsten carbide, carbon, nickel, iridium, titanium, rhenium, and platinum. 
     In some embodiments, the electrodes comprise iridium. 
     In some embodiments, the scavenger is fabricated from calcium hydroxide. 
     In some embodiments, the one or more sensors include an oxygen sensor arranged upstream of the electrodes, a nitric oxide sensor arranged downstream of the scavenger, and a nitrogen dioxide sensor arranged downstream of the scavenger. 
     In some embodiments, an ignition coil is in communication with the controller and the electrodes. 
     In some embodiments, the controller is further configured to instruct the ignition coil to supply stored electrical energy to the electrodes. 
     In some embodiments, the electrical signal supplied to the electrodes controls at least one of a number of electrode spark groups per second, a number of individual electrode sparks per spark group, a time between individual electrode sparks, and a pulse duration. 
     In some embodiments, the controller is further configured to vary at least one of the number of electrode spark groups per second, the number of individual electrode sparks per spark group, the time between individual electrode sparks, and the pulse duration in response to feedback from the one or more sensors. 
     In some embodiments, the apparatus further comprises a gas pump arranged upstream of the electrodes. 
     In some embodiments, the airway flowmeter provides an indication of inspiration. 
     In some embodiments, the controller is further configured to supply the electrical signal to the electrodes in response to detecting inspiration. 
     In some embodiments, the filter is configured to filter particles flowing downstream of the electrodes with a diameter greater than approximately 0.22 micrometers. 
     In some embodiments, the breathing apparatus comprises one of a ventilator system, a continuous positive airway pressure (CPAP) system, a high frequency oscillatory ventilator (HFOV), a face mask, a nasal cannula, or an inhaler. 
     In still another aspect, the present disclosure provides an apparatus for generating nitric oxide to be integrated into a respiratory system having a breathing apparatus and an inspiratory line. The apparatus includes a chamber having a chamber inlet and at least one or more pairs of electrodes arranged within the chamber, a main chamber configured to provide a fluid path to an airway of a patient. The apparatus further includes a filter arranged downstream of the electrodes, a scavenger arranged downstream of the electrodes, and one or more sensors configured to measure at least one of an oxygen concentration upstream of the electrodes, a barometric pressure, a nitric oxide concentration downstream of the scavenger, and a nitrogen dioxide concentration downstream of the scavenger. The apparatus further includes a controller in communication with the electrodes and the one or more sensors. The controller is configured to supply an electrical signal to the electrodes that controls timing and sparking characteristics of the electrodes. The chamber is in communication with the main chamber and gas in the chamber is non-mechanically introduced into the main chamber. 
     In some embodiments, the main chamber includes a venturi. 
     In some embodiments, the apparatus further comprises a passage connecting the chamber to the venturi of the main chamber. 
     In some embodiments, a flow of gas through the venturi is configured to draw a vacuum on the chamber. 
     In some embodiments, the apparatus further comprises a pre-scavenger arranged upstream of the chamber inlet. 
     In some embodiments, the apparatus further comprises a pre-filter arranged upstream of the chamber inlet. 
     In some embodiments, the main chamber and the chamber define a parallel path. 
     In yet another aspect, the present disclosure provides a method of generating nitric oxide in a respiratory system having a breathing apparatus in communication with an airway of a patient. The method includes coupling a nitric oxide generator having a pair of electrodes to the airway of the patient, triggering the nitric oxide generator to produce a desired concentration of nitric oxide gas, and determining desired sparking characteristics of the electrodes to produce the desired concentration of nitric oxide gas. The method further includes once the sparking characteristics have determined, supplying an electrical signal to the electrodes that initiates the desired sparking characteristics between the electrodes to generate the desired concentration of nitric oxide gas in a flow of gas provided to the airway of the patient. 
     In some embodiments, triggering the nitric oxide generator to produce a desired concentration of nitric oxide gas comprises monitoring at least one of a gas flowrate provided to the patient, a temperature of gas provided to the patient, and a pressure of gas provided to the patient, detecting a change in at least one of the gas flowrate provided to the patient, the temperature of gas provided to the patient, and the pressure of gas provided to the patient, and determining that the change detected is indicative of an inspiratory event. 
     In some embodiments, the method further comprises filtering particulates in the flow of gas provided to the patient. 
     In some embodiments, the method further comprises scavenging at least one of nitrogen dioxide and ozone in the flow of gas provided to the patient. 
     In some embodiments, determining desired sparking characteristics of the electrodes comprises measuring an atmospheric pressure, and determining a number of electrode spark groups per second, a number of individual electrode sparks per spark group, a time between individual electrode sparks, and a pulse duration. 
     In some embodiments, the method further comprises monitoring a nitric oxide concentration downstream of the electrodes, determining that the nitric oxide concentration is not equal to the desired concentration of nitric oxide, and in response to determining that the nitric oxide concentration downstream of the electrodes is not equal to the desired nitric oxide concentration, varying via the electrical signal, at least one of a number of electrode spark groups per second, a number of individual electrode sparks per spark group, a time between individual electrode sparks, and a pulse duration. 
     In some embodiments, the method further comprises monitoring a nitrogen dioxide concentration downstream of the electrodes, determining that the nitrogen dioxide concentration is greater than a pre-defined maximum concentration, and upon determining that the nitrogen dioxide concentration downstream of the electrodes is greater than the pre-defined maximum concentration, ceasing the supplying of the electrical signal to the electrodes. 
     The foregoing and other aspects and advantages of the invention will appear from the following description. In the description, reference is made to the accompanying drawings which form a part hereof, and in which there is shown by way of illustration a preferred embodiment of the invention. Such embodiment does not necessarily represent the full scope of the invention, however, and reference is made therefore to the claims and herein for interpreting the scope of the invention. 
    
    
     
       BRIEF DESCRIPTION OF DRAWINGS 
       The invention will be better understood and features, aspects and advantages other than those set forth above will become apparent when consideration is given to the following detailed description thereof. Such detailed description makes reference to the following drawings. 
         FIG.  1    shows a schematic illustration of a respiratory system according to one embodiment of the present invention. 
         FIG.  2    shows a detailed schematic of a nitric oxide generator in the respiratory system of  FIG.  1    according to one embodiment of the present disclosure. 
         FIG.  3    shows an electrical signal applied to electrodes of the nitric oxide generator of  FIG.  2    according to one embodiment of the present disclosure. 
         FIG.  4    shows a schematic illustration of a respiratory system according to another embodiment of the present invention. 
         FIG.  5    shows a detailed schematic of a nitric oxide generator in the respiratory system of  FIG.  4    according to another embodiment of the present disclosure. 
         FIG.  6    shows one implementation of the nitric oxide generator of  FIG.  5    according to one embodiment of the present disclosure. 
         FIG.  7    shows a respiratory system according to yet another embodiment of the present disclosure. 
         FIG.  8    shows a respiratory system according to still another embodiment of the present disclosure. 
         FIG.  9    is a flowchart illustrating steps for operating a respiratory system according to the present disclosure. 
         FIG.  1 . 0    shows a schematic used for testing a nitric oxide generator according to one embodiment of the present disclosure. 
         FIG.  11    shows a graph illustrating concentrations of NO and NO2 generated while testing the nitric oxide generator of  FIG.  2   . 
         FIG.  1 . 2    shows a graph illustrating NO and NO2 concentrations generated by the nitric oxide generator of  FIG.  2    over the 10 day test. 
         FIG.  13 A  shows a graph illustrating the effect of varying number of spark groups per second on NO and NO2 concentration for the nitric oxide generator of  FIG.  2   . 
         FIG.  13 B  shows a graph illustrating the effect of varying number of spark discharges per group on NO and NO2 concentration for the nitric oxide generator of  FIG.  2   . 
         FIG.  13 C  shows a graph illustrating the effect of varying time between spark discharges on NO and NO2 concentration for the nitric oxide generator of  FIG.  2   . 
         FIG.  1 . 3 D  shows a graph illustrating the effect of pulse duration on NO and NO2 concentration for the nitric oxide generator of  FIG.  2   . 
         FIG.  1 . 4    shows a graph illustrating NO and NO2 concentrations generated by the nitric oxide generator of  FIG.  2    at varying atmospheric pressures. 
         FIG.  15    shows a graph illustrating the NO and NO2 concentrations entering and exiting a scavenger following and in series with the nitric oxide generator of  FIG.  2   . 
         FIG.  16    shows a graph illustrating the NO and NO2 concentrations entering and exiting a scavenger of the nitric oxide generator of  FIG.  5   . 
         FIG.  17    shows a graph illustrating the ozone (O3) concentrations entering and exiting a scavenger of the nitric oxide generator of  FIG.  2   . 
         FIG.  18 A  shows a magnified view of an unused electrode tip. 
         FIG.  18 B  shows a magnified view of the electrode tip of  FIG.  18 A  after continuous sparking for 10 days. 
         FIG.  19 A  shows a magnified view of an unused filter. 
         FIG.  19 B  shows a magnified view of the filter of  FIG.  19 A  after being arranged downstream of electrodes continuously sparking for 10 days. 
         FIG.  20 A  shows a graph illustrating the energy-dispersive X-ray (EDX) spectroscopy results of the filter of  FIG.  19 A   
         FIG.  20 B  shows a graph illustrating the energy-dispersive X-ray (EDX) spectroscopy results of the filter of  FIG.  19 B . 
         FIG.  21    shows a graph illustrating the NO2/NO ratio generated by electrodes fabricated from various metals. 
         FIG.  22    shows a graph illustrating the NO and NO2 concentrations generated with and without a macroporous membrane covering the nitric oxide generator of  FIG.  5   . 
         FIG.  23 A  shows a graph illustrating the mean pulmonary artery pressure (PAP) of an anesthetized lamb with acute pulmonary hypertension due to U46619 infusion following inhalation of nitric oxide generated using the respiratory system of  FIG.  1    and compared with nitric oxide delivered from a compressed NO/N2 gas cylinder. 
         FIG.  23 B  shows a graph illustrating the pulmonary vascular resistance index (PAP) of an anesthetized lamb with acute pulmonary hypertension following inhalation of nitric oxide generated using the respiratory system of  FIG.  1    and compared with nitric oxide delivered from a compressed. NO/N2 gas cylinder. 
         FIG.  24 A  shows a graph illustrating the mean pulmonary artery pressure (PAP) of an anesthetized lamb with acute pulmonary hypertension following inhalation of nitric oxide generated using the respiratory system of  FIG.  4    with the nitric oxide generator continuously sparking and compared with nitric oxide delivered from a compressed gas cylinder. 
         FIG.  24 B  shows a graph illustrating the pulmonary vascular resistance index (PVRI) of an anesthetized lamb with acute pulmonary hypertension following inhalation of nitric oxide generated using the respiratory system of  FIG.  4    with the nitric oxide generator continuously sparking and compared with nitric oxide delivered from a compressed gas cylinder, 
         FIG.  25 A  shows a graph illustrating the mean pulmonary artery pressure (PAP) of an anesthetized lamb with acute pulmonary hypertension following inhalation of nitric oxide generated using the respiratory system of  FIG.  4    with the nitric oxide generator intermittently sparking and compared with nitric oxide delivered from a compressed gas cylinder. 
         FIG.  25 B  shows a graph illustrating the pulmonary vascular resistance index (PVRI) of an anesthetized lamb with acute pulmonary hypertension following inhalation of nitric oxide generated using the respiratory system of  FIG.  2    with the nitric oxide generator intermittently sparking and compared with nitric oxide delivered from a compressed gas cylinder. 
     
    
    
     DETAILED DESCRIPTION 
     The use of the terms “downstream” and “upstream” herein are terms that indicate direction relative to the flow of a gas. The term “downstream” corresponds to the direction of gas flow, while the term “upstream” refers to the direction opposite or against the direction of gas flow. 
     Currently, administration of inhaled nitric oxide (NO) therapy requires the use of heavy compressed gas cylinders, a gas cylinder distribution network, a complex delivery device, gas monitoring and calibration devices, and trained respiratory therapy staff. These requirements for administering NO therapy present a significant cost to the institution (e.g., a hospital) administering the NO therapy and, therefore, to the patient receiving the NO therapy. For many institutions, inhaled NO therapy can be one of the most expensive drugs used in neonatal medicine. The use of bulky gas cylinders and the expense of inhaled NO therapy result in inhaled NO therapy not being available in most of the world and it is not available for outpatient use. 
     Several methods have been attempted to produce NO for biomedical purposes, such as, chemically preparing NO from N2O4 requiring extensive scavenging with antioxidants. Various electrical systems have also been attempted, such as, pulsed arc, gliding arc, dielectric barrier, microwave, corona, radio frequency induced coupled discharge, and non-thermal atmospheric pressure high-frequency plasma discharge. However, these systems and methods produce large amounts of harmful byproducts (e.g., nitrogen dioxide (NO2) and ozone (O3)) and require complex purification systems. 
     Due to the current difficulties in administering and generating NO for inhalation therapy, it would be desirable to have a lightweight and economical. NO generator that can be used for NO inhalation therapy at the bedside of a patient or in portable applications. It would also be desirable to have the NO generator be easily coupled to or integrated into current ventilator systems. It is advantageous from a safety perspective to have the NO that is generated be as clean as possible, so that even in the event that a scavenger fails or is exhausted, the NO that is delivered to a patient is not contaminated with NO2 or O3 
       FIG.  1    shows a respiratory system  10  for administering NO to a patient  11  according to one non-limiting example of the present disclosure. The respiratory system  10  includes a breathing apparatus  12  and a NO generator  14 . In some non-limiting examples, the breathing apparatus  12  can be a ventilator system, a continuous positive airway pressure (CPAP) system, a High Frequency Oscillatory Ventilator (HFOV), a face mask, a nasal cannula or an inhaler. The breathing apparatus  12  is configured to enable the passage of gas to and from an airway of the patient  11 . In some non-limiting examples, the breathing system  12  can provide mechanical ventilation (i.e., positive pressure to inflate the patient&#39;s  11  lungs) to the patient. In other non-limiting examples, the patient  11  may be breathing on their own and the breathing system  12  can provide a flow path to the airway of the patient  11 . The illustrated breathing system  12  includes an inspiratory line  18 , an expiratory line  20 , and an airway flowmeter  22  coupled to the inspiratory line  18 . The ventilator  16  can be a commercially available mechanical ventilator used in biomedical applications (e.g., inhalation therapy). As is known in the art, the mechanical ventilator  16  is configured to provide a flow of gas (e.g., air or a nitrogen/oxygen gas mixture) via the inspiratory line  18  to the respiratory tract of the patient  11 . Subsequently, the ventilator  16  is configured to remove a flow of gas (e.g., exhaled gas) via the expiratory line  20  from the respiratory tract of the patient  11 . In this way, the ventilator  16  can simulate the breathing process for the patient  11 . The airway flowmeter  22  measures the flowrate of gas in the inspiratory line  18 . In one non-limiting example, the airway flowmeter  22  may control a timing and amount of NO that is synthesized from spark plasma discharge in the NO generator  14 . 
     The NO generator  14  is arranged between an inlet  24  and an outlet  26 . Gas (e.g., air or a nitrogen/oxygen gas mixture) is drawn into the NO generator  14  at the inlet  24 . The NO generator  14  is configured to generate a predetermined concentration of NO to be inhaled by the patient  11 , as will be described in detail below. The NO containing gas is furnished from the NO generator  14  to the outlet  26 . The outlet  26  communicates with the inspiratory line  18  of the breathing apparatus  12  upstream of the airway flowmeter  22 . 
     The respiratory system  10  includes a pre-filter  28 , a gas pump  30 , a gas flow sensor  32  all arranged upstream of the NO generator  14 . The pre-filter  28  is arranged downstream of the inlet  24  and upstream of the gas pump  30 . The gas flow sensor  32  is arranged downstream of the gas pump  30  and upstream of the NO generator  14 . In one non-limiting example, the pre-filter  28  can be configured to filter particles, water droplets and bacteria with a diameter larger than approximately 0.22 micrometers (μm). It should be known that the particle size filtered by the pre-filter  28  is not meant to be limiting in any way, and alternative pre-filters that filter different particle sizes are within the scope of the present disclosure. In other non-limiting examples, the pre-filter  28  may be removed if the fluid provided at the inlet  24  is be pre-treated (i.e., filtered and dried). In some embodiments, a pre-scavenger (not shown) can be arranged upstream of the pre-filter  28  to remove, for example, CO2 from the inlet gas. Removing CO2 from the inlet gas negates the need for the scavenging CO2 in the gas output from the NO generator  14 . 
     The gas pump  30  is configured to draw gas from inlet  24  and furnish the gas under an increased pressure towards NO generator  14  and through the outlet  26 . It should be known that, in other non-limiting examples, the gas pump  30  can be replaced by a fan or a bellows type device. The gas flow sensor  32  is configured to measure a flowrate of gas flowing from the gas pump  30  to the NO generator  14 . A controller  33  is in communication with the NO generator  14 , the gas pump  30 , the gas flow sensor  32  and the airway flowmeter  22 . The controller  33  is configured to control the operation of the NO generator  14  and the gas pump  30 , as will be described in detail below. 
     As shown in  FIG.  2   , the NO generator  14  includes an oxygen sensor  34  arranged upstream of electrodes  36 . The oxygen sensor  34  measures an oxygen concentration in the gas being supplied, via the gas pump  30 , to the electrodes  36 . In some non-limiting examples, the electrodes  36  can include one or more pairs of individual electrodes that can be fabricated from or plated with tungsten carbide, carbon, nickel, iridium, titanium, platinum, rhenium, or an alloy of the aforementioned materials. In one exemplary non-limiting example, the electrodes  36  are fabricated from or plated with iridium because, as described below, iridium can produce a lower concentration of NO2 relative to the concentration of NO generated which is an important safety factor of the NO generator  14 . 
     An ignition coil  38  is in communication with the electrodes  36  and is configured to store and release electrical energy. The energy stored by the ignition coil  38  is delivered to the electrodes  36  to create a plasma in a gap between the electrodes  36 . The plasma generated between the electrodes  36  generates NO, as long as nitrogen and oxygen are present in the gas being supplied to the electrodes  36 . The controller  33  is in communication with the ignition coil.  38  and is configured to control when the ignition coil  38  delivers the stored energy and, therefore, control when the electrodes  36  spark (i.e., form a plasma and generate NO). It should be known that, in some non-limiting examples, the controller  33  can be combined with the NO generator  14  into a single, portable unit. 
     Downstream of the electrodes  36 , the NO generator  14  includes a scavenger  42 , a post-filter  44 , a NO sensor  46 , and a NO2 sensor  48 . The post-filter  44  is arranged upstream of the NO and NO2 sensors  46  and  48 , and downstream of the scavenger  42 . The scavenger  42  is configured to remove harmful byproducts (e.g., NO2 and 03) produced in the plasma created by sparking the electrodes  36 . In one non-limiting example, the scavenger  42  can be fabricated from calcium hydroxide (Ca(OH)2). The post-filter  44  is configured to filter particles (e.g., fragments from the scavenger  42  and/or particles that break off from the electrodes  36  during sparking) in the fluid flowing from the electrodes  36  to the outlet  26 . This can prevent the patient  11  from inhaling particle-laden gas and from inhaling electrode particles that boil off due to high temperatures during sparking. In one non-limiting example, the post-filter  44  can be configured to filter particles with a diameter larger or smaller than approximately 0.22 μm. It should be known that the particle size filtered by the post-filter  44  is not meant to be limiting in any way, and alternative post-filters that filter different particle sizes are within the scope of the present disclosure. However, the particle size filtered by the post-filter  44  should be sufficiently small to maintain the safety and health of the patient  11 . 
     The NO sensor  46  measures a concentration of NO in the gas flowing from the electrodes  36  to the outlet  26 , and the NO2 sensor  48  measures a concentration of NO2 in the fluid flowing from the electrodes  36  to the outlet  26 . 
     With continued reference to  FIG.  2   , the controller  33  receives input power from a power supply  50 , In one non-limiting example, the power supply  50  can be external to the NO generator  14  (e.g., wall power). In another non-limiting example, the power supply  50  can be integrated into the NO generator  14 . In this non-limiting example, the power supply  50  can be in the form of a battery or a rechargeable battery. The controller  33  includes a transceiver  52  and a communication port  54 . The controller  33  can be configured to communicate wirelessly, via the transceiver  52 , with an external processor (not shown) and/or a display (not shown) using Bluetooth®, WiFi, or any wireless communication protocol known in the art or developed in the future. Alternatively or additionally, the controller  33  can be configured to communicate, via the communication port  54 , with the external processor (not shown) and/or the display (not shown) using a universal serial bus (USB) connection, an Ethernet connection, or any wired communication protocol known in the art or developed in the future. 
     The controller  33  is in communication with the gas pump  30 , the gas flow sensor  32 , the oxygen sensor  34 , the NO sensor  46  and the NO2 sensor  48 . In operation, the controller  33  is configured to control a displacement (i.e., a flowrate of gas from the inlet  24  to the outlet  26 ) of the gas pump  30 . For example, a desired flowrate of 5 liters/minute (L/min) can be input to the controller  33  by the external processor. In this non-limiting example, the controller  33  can adjust the displacement of the gas pump  30  in response to the flowrate measured by the gas flow sensor  32  to attempt to maintain the flowrate within a predefined margin of approximately 5 L/min. 
     The concentrations measured by the oxygen sensor  34 , the NO sensor  46 , and the NO2 sensor  48  are communicated to the controller  33 . In operation, the controller  33  is configured to vary the timing and the sparking characteristics of the electrodes  36  in response to the measurements of the oxygen sensor  34 , the NO sensor  46  and the NO2 sensor  48  and the airway flowmeter  22 . In one non-limiting example, the timing of the electrodes  36  can be with respect to inspiration of the patient  11 . As shown in  FIG.  3   , the controller  33  is configured supply an electrical signal to the ignition coil  38  and thereby to the electrodes  36  that comprises a plurality of square waves. In the non-limiting example shown in  FIG.  3   , the electrical signal supplied to the electrodes  36  by the controller  33  can include groups of square waves where each individual square wave in the respective group represents a spark of the electrodes  36 . In this non-limiting example, the controller  33  can be configured to control a number spark groups per second (B), a number of individual sparks per group (N), a time between individual sparks (P), and a pulse duration of each individual square wave in the group (H). 
     Varying the values of B, N, P, and H can alter concentrations of NO and NO2 generated by the NO generator  14 , as will be described in detail below. The data gathered from varying B, N, P, and H can be used to develop a theoretical model for generating a given concentration of NO. The theoretical model can be further refined by testing the NO generator  14  at different oxygen concentrations, pressures, humidities, and temperatures. Then, knowing the oxygen concentration, pressure, temperature, and/or humidity of the fluid flowing to the electrodes  36 , the controller  33  can calculate an ideal B, N, P, and H to generate a desired concentration of NO. The NO sensor  46  monitors the concentration of NO produced and provides feedback to the controller  33  which, in response to the concentration of NO produced deviating from a desired concentration, can alter the values of B, N, P, and/or H accordingly. 
     In one non-limiting example, the oxygen concentration of the gas provided to the electrodes  36  may be a constant, known value (e.g., air with 21% O2) which is input to the controller  33 . In this non-limiting example, the oxygen sensor  34  may be omitted from the NO generator  14 . Alternatively or additionally, a pressure sensor (not shown) can be arranged upstream of the electrodes  36  to measure ambient pressure. As described below, the amount of NO produced by the NO generator  14  can be a function of atmospheric pressure. In one non-limiting example, the controller  33  can be configured to adjust the sparking characteristics of the electrodes  36  in response to the pressure measured by the pressure sensor. Alternatively or additionally, the controller  33  can be configured to monitor a condition, or health, of the scavenger  42  by determining if the concentration of NO2, measured by the NO2 sensor  48 , exceeds a pre-determined value. If the NO2 concentration exceeds the pre-determined value, the scavenger  42  may be exhausted and the controller  33  can cease the sparking of the electrodes  36  and instruct a user of the NO generator  14  to replace the scavenger  42 . Alternatively or additionally, a colorimetric pH sensor can estimate exhaustion of the scavenger  42 . 
     In operation, the NO generator  14  is configured to produce therapeutic concentrations of NO, for example, between approximately 5 and 80 parts per million (ppm) by pulsed sparking of the electrodes  36 . The therapeutic concentrations of NO produced by the NO generator  14  can be supplied to the inspiratory line  18  and thereby to the patient  11 . Thus, the NO generator  14  does not require the use of valves to enable the flow of NO laden gas to the patient  11 . In one non-limiting example, the electrodes  36  of the NO generator  14  can be triggered, by the controller  33 , to spark continuously. In another non-limiting example, the electrodes  36  of the NO generator  14  can be triggered, by the controller  33 , to spark during or prior to inspiration of the patient  11 . Triggering the electrodes  36  during or prior to inspiration can avoid waste NO generated during exhalation, and can enable the NO generator  14  to demand less power when compared with continuous operation. 
     The controller  33  can be configured to detect inspiration of the patient  11  based on the flowrate measured by the airway flowmeter  22 , a temperature in the inspiratory line  18 , a temperature in the expiration line  20 , a pressure in the inspiratory line  18 , and/or a pressure in the expiration line  20 . The theoretical model executed by the controller  33  for determining the values of B, N, P, and H for a desired NO concentration can be adjusted whether the electrodes  36  are being sparked continuously or intermittently (i.e., triggered during or prior to inspiration). 
       FIG.  4    shows a schematic illustration of a respiratory system  100  according to another non-limiting example of the present disclosure. The respiratory system  100  of  FIG.  4    is similar to the respiratory system  10  of  FIG.  1    except as described below or is apparent from  FIG.  4   . As shown in  FIG.  4   , the respiratory system  100  includes a NO generator  102  integrated into the inspiratory line  18  of the breathing apparatus  12 . With the NO generator  102  integrated into the inspiratory line  18 , the respiratory system  100  may not include the pre-filter  28 , the gas pump  30 , and the gas flow sensor  32 , as the ventilator  16  provides the flow of gas to the NO generator  102 . 
     The NO generator  102  of  FIG.  5    is similar to the NO generator  14  of  FIG.  1    except as described below or is apparent from  FIG.  5   . As shown in  FIG.  5   , the scavenger  42 , the post-filter  44 , the NO sensor  46  and the NO2 sensor are integrated into the inspiratory line  18 , and the NO generator  102  includes a membrane  104  surrounding or covering the electrodes  36 . The membrane  104  protects the electrodes  36  from any water droplets or mucous in the inspiratory line  18  while allowing the gas flowing through the inspiratory line  18  (e.g., air or a nitrogen/oxygen gas mixture) to freely pass through the membrane  104 . In one non-limiting example, the membrane  104  can be a microporous polytetrafluoroethylene (PTFE) membrane. It should be known that the electrodes  36  do not need be completely integrated into the inspiratory line  18 , and that only the tips of the electrodes  36  need to be in the gas path defined by the inspiratory line  18 . 
     In operation, placing the NO generator  102  inline with the inspiratory line  18  reduces the transit time of the generated NO gas to the lung of the patient  11 . This reduces the probability of the generated. NO oxidizing to NO2 prior to reaching the patient  11 . Also, placing the NO generator  102  inline with the inspiratory line  18  negates the need for valves to enable the flow of NO laden gas to the patient  11 , In one non-limiting example, the controller  33  is configured to intermittently spark the electrodes  36  of the NO generator  102  prior to or during inspiration of the patient  11 . Generating NO only during or upon inspiration, compared to continuous sparking of the electrodes  36 , enables the NO generator  102  to generate NO during approximately one quarter to one eighth of the total respiratory cycle time of the patient  11 . This can reduce the power demanded of the NO generator  102 , favor portable applications, avoid generating waste NO, and reduce a necessary size of the scavenger  42 . 
       FIG.  6    shows one non-limiting implementation of the NO generator  102  where the controller  33  and the ignition coil  38  are enclosed in a base  110 . The base  110  is coupled to a tube  112  configured to be placed inline with an inspiratory line of a respiratory system, or breathing apparatus. The electrodes  36  are arranged partially within the base  110  such that the tips of the electrodes  36  are in a fluid path defined by the tube  112 . The illustrated NO generator  102  includes a power cord  114  attached to the base  102  to supply power to the controller  33  and the power supply  50 . The power cord  114  is detachable from the base  110  to aid in the portability of the NO generator  102 . 
     A first end  116  of the tube  112  is configured to receive a cartridge assembly  118  and a second end  117  of the tube  112  is configured to couple to the inspiratory line  18 . The cartridge assembly  118  includes a cartridge inlet  119  configured to couple to the first end  116  of the tube  112 , a cartridge  120  arranged upstream of and coupled to the post-filter  44 , and a cartridge outlet  122  configured to couple to the inspiratory line  18 . In one non-limiting example, the cartridge  120  can be filled with a microporous material (e.g., foam). The scavenger  42  is arranged between the cartridge  120  and the post-filter  44 . 
       FIG.  7    shows a respiratory system  200  having an NO generator  201  according to another non-limiting example of the present disclosure. As shown in  FIG.  7   , the NO generator  201  includes a chamber  202  having a chamber inlet  204  arranged upstream of electrodes  206 . Similar to the electrodes  36 , described above, the electrodes  206  can be powered by a controller  207  which is configured to control when energy is delivered to the electrodes  206  and, therefore, control when the electrodes  206  spark (i.e., form a plasma and generate NO). The chamber  202  is coupled to a main chamber  208  via passage  210 . The main chamber  208  includes a main inlet  212 , a main outlet  214  and a venturi  216  arranged therebetween. The main outlet  214  is in gas communication with the respiratory tract of a patient. The passage  210  is coupled to the venturi  216  of the main chamber  208  and includes a post-filter  218  and a post-scavenger  220 . The post-filter  218  is configured to filter particles (e.g., particles that break off or are vaporized from the electrodes  36  during sparking) in the gas flowing through the passage  210  from the chamber  202  to the main chamber  208 . The post-scavenger  220  is configured to remove harmful byproducts (e.g., NO2 and O3) produced in the plasma created by sparking the electrodes  206 . In other non-limiting examples, the post-filter  218  and/or the post-scavenger  220  may be arranged in the main chamber  208  downstream of the venturi  216 . 
     In one non-limiting example, a pre-filter  222  may be arranged upstream of the chamber inlet  202  to remove particles and/or water droplets in the fluid being supplied to the chamber inlet  202 . Alternatively or additionally, a pre-scavenger  224  may be arranged upstream of the chamber inlet  202  to remove compounds which are potentially harmful to the post-scavenger  220  (e.g., carbon dioxide (CO2)). Pre-scavenging the gas flowing to the electrodes  206  can enable a size of the post-scavenger (not the post-filter)  220  to be reduced. Reducing the size of the post-scavenger  220  by pre-scavenging can, in one non-limiting example, enable the post-scavenger  220  to be placed over a spark gap between the electrodes  206  within a tracheostomy tube or an endotracheal tube to produce NO within the airway, even close to the carina. 
     One or more sensors  226  are arranged downstream of the venturi  216 , The sensors  226  are configured to measure an oxygen concentration, a NO concentration, and/or an NO2 concentration in the gas flowing from the venturi  216  to the main outlet  214 . Alternatively or additionally, the chamber  202  may include one or more additional sensors (not shown) to measure at least one of a pressure, a temperature, and a humidity in the chamber  202 . 
     In some non-limiting examples, the main chamber  208 , the chamber  202 , and/or the passage  210  may include one or more other passages or modules, such as a ventilator gas stream or breathing apparatus. 
     In operation, the main inlet  212  and the chamber inlet.  204  receive a flow of gas (e.g., air or a nitrogen/oxygen gas mixture). The flowrate of gas provided to the main inlet  212  can be sufficiently greater than the flowrate of gas provided to the chamber inlet  204  which causes the flow through the venturi  216  to draw a vacuum on the chamber  202 . The vacuum drawn on the chamber  202  can draw fluid from the chamber  202  into the main chamber  208 . This operation of the NO generator  201  can obviate the need to control the total amount of NO rich gas injected into the main chamber  208  with one or more valves. Also, the NO generator  201  non-mechanically, (i.e., without the use of a pump or valves) provides the flow of NO laden gas to the patient. 
     The operation of the controller  207  is similar to the controller  33 , described above, and is configured to control the concentration of NO generated by sparking the electrodes  206  by varying B, N, P, and H. The controller  207  can adjust B N, P, and/or H in response to the measurements by the one or more sensors  226 . In one non-limiting example, the desired concentration of NO generated for a particular application can be calculated by the controller  207  based on the mass flowrate of gas through the main chamber  208  and the amount of vacuum drawn on the chamber  202 . In some non-limiting examples, the NO generator  201  can include a flow sensor (not shown) in communication with the controller  207  to enable timed inspiratory generation of NO. In this non-limiting example, the controller  207  can be configured to trigger the electrodes  206  to generate NO during or prior to inspiration of the patient which can reduce wear of the electrodes  206 , oxidation of NO into NO2, and the power requirements of the NO generator  201 . 
       FIG.  8    shows a respiratory system  300  having a NO generator  301  according to another non-limiting example of the present disclosure. The NO generator  301  of  FIG.  8    is similar to the NO generator  201  of  FIG.  7    except as described below or is apparent from  FIG.  8   . As shown in  FIG.  8   , the NO generator  301  can employ a proportional parallel delivery. Rather than mixing the gas before it is delivered to the patient, an inspiration can pull NO rich gas from the chamber  202  and fluid from the main chamber  208  from a parallel passage  302 . That is, the patient can draw output gas directly from the parallel passage  302  without requiring the use of valves or a pump to furnish the produced NO laden gas to the patient. 
     As described above, the NO generators  14 ,  102 ,  201 , and  301  may operate similarly to provide safe and pure NO to a patient&#39;s airway. The operation of the respective controller (i.e., controllers  33  and  207 ) in the respiratory systems  10 ,  100 ,  200 , and  300  can control the operation of the NO generators  14 ,  102 ,  201 , and  301 .  FIG.  9    shows one non-limiting example of the operation of any of the above-described respiratory systems  10 ,  100 ,  200 , and  300 . As shown in  FIG.  9   , a NO generator (e.g., NO generator  14 ,  102 ,  201 , and/or  301 ) is coupled to an airway of a patient at step  304 . As described above, the NO generator can be coupled to the airway of the patient, for example via a connection to an inspiration line, a venturi, a parallel path, or the NO generator can be placed inline with an airway of the patient. With the NO generator coupled to the airway of the patient, the controller (e.g., controller  33  or controller  207 ) monitors sensor inputs to the patient at step  306 . In some non-limiting examples, the controller can monitor an oxygen concentration downstream of the NO generator, an ambient pressure, a gas flowrate being provided (mechanically or non-mechanically) to the patient, a NO concentration downstream of the NO generator, and a NO2 concentration downstream of the NO generator. 
     The controller (e.g., controller  33  or controller  207 ) then determines at step  308  if the NO generator should be triggered to produce NO to be inhaled by the patient. In some non-limiting examples, the controller can be configured to trigger at or just before an inspiratory event (e.g., by monitoring the gas flow provided to the patient, a pressure in an inspiratory line, a temperatures in an inspiratory line, etc.). In other non-limiting examples, the controller can be manually triggered by a user of the NO generator. Once the NO generator has been triggered by the controller at step  308 , the controller can determine the desired sparking characteristics, provided by a pulsed electrical signal, to be sent to electrodes (e.g., electrodes  36  or electrodes  208 ) at step  310 . The controller can be pre-configured to produce a desired concentration of pure and safe NO gas to be inhaled by the patient. In one non-limiting example, the pre-configured concentration of NO gas is determined at step  310  by the controller as a function of the atmospheric pressure and/or the B, N, P, and H electrode spark characteristics, described above. That is, the controller can, based on the measured atmospheric pressure, determine the desired. B, N, P, and H of the electrical signal to produce the pre-configured concentration of NO. 
     With the desired sparking characteristics determined at step  310 , the controller sends the corresponding electrical signal to the electrodes and the NO generator produces, at step  312 , the pre-configured concentration on pure and safe NO gas by spark plasma discharge to be provided to the airway of the patient. While the NO generator is producing NO gas at step  312 , the controller monitors the inputs from the sensors (e.g., an oxygen concentration upstream of the NO generator, an ambient pressure, a gas flowrate being provided (mechanically or non-mechanically) to the patient, a NO concentration downstream of the NO generator, and a NO2 concentration downstream of the NO generator. Based on the inputs from the sensors, the controller determines at step  314  whether or not to adjust the NO production. For example, if controller detects that the output NO gas concentration is not substantially equal to the desired. NO gas concentration, the controller can alter the sparking characteristics of the electrodes, at step  316 , by varying at least one of B, N, P, and H to bring the produced NO gas concentration in line with the desired NO gas concentration. Alternatively or additionally, if the controller detects an increase in gas flow being provided to the airway of the patient, the controller can alter the sparking characteristics of the electrodes, at step  316  by varying at least one off, N, P, and H accordingly. Thus, the controller (e.g., controller  33  or controller  207 ) is configured to alter the sparking characteristics (i.e., a concentration of synthesized NO gas produced by spark plasma discharge between the electrodes) based on the feedback from one or more sensors. 
     Examples 
     The following examples set forth, in detail, ways in which the respiratory systems  100  and  200  and/or the NO generators  14 ,  102 ,  201  and  301  may be used or implemented, and will enable one of skill in the art to more readily understand the principle thereof. The following examples are presented by way of illustration and are not meant to be limiting in any way. 
     Example 1: Measuring NO and NO2 Generation at Varying Oxygen and Nitrogen Concentrations 
     The NO generator  14  was tested with varying nitrogen and oxygen concentrations being provided to the electrodes  36 . The test was performed using the test setup shown in  FIG.  1 . 0    and at atmospheric pressure. The controller  33  was configured to spark the electrodes  36  using the following settings: B=25; N=35; P=240 μs; and H=100 μs. The NO and NO2 concentrations generated by the NO generator  14  were measured at a constant gas flow of 5 L/min and with oxygen levels of 10%, 21%, 50%, 80%, and 90% and a balanced amount of nitrogen.  FIG.  11    shows the concentrations of NO and NO2 generated during the test. As shown in  FIG.  11   , maximum NO (68±4 ppm) and NO2 (6±2 ppm) concentrations were generated at 50% oxygen. Lower concentrations of NO and NO2 were generated as the oxygen concentration deviated from 50% (i.e., either increasing the oxygen concentration above 50% or decreasing the oxygen concentration below 50%). 
     Example 2: Measuring the NO and NO2 Concentrations During Continuous 
     Operation for 10 Days 
     The NO generator  14  was tested at an oxygen concentration of 21% (i.e., in air) and a constant gas flow rate of 5 L/min. The electrodes  36  were fabricated from iridium-platinum. The test was performed using the test setup shown in  FIG.  10    and at atmospheric pressure. The controller  33  was configured to spark the electrodes  36  using the following settings to produce approximately 50 ppm of NO: B=20, N=20, P=240 μs; and H=70 μs.  FIG.  12    shows the NO and NO2 concentrations generated by the NO generator over the 10 day test. As shown in  FIG.  12   , the NO and NO2 concentrations remained substantially constant over the 10 days. 
     Example 3: Measuring NO and NO2 Generation at Varying B, N, P, and H 
     As described above, a theoretical model of the NO and NO2 generation at varying B, N, P, and H, can be input to the controller of the respective respiratory system. The NO generator  14  was tested at an oxygen concentration of 21% (i.e., in air) and a constant gas flow rate of 5 L/min. The electrodes were fabricated from iridium-platinum. The test was performed using the test setup shown in  FIG.  10    and at atmospheric pressure.  FIG.  13 A  shows the effect of varying B with N=25, P=240 μs, and H=100 μs. As shown in  FIG.  13 A , the NO and NO2 concentrations generated increased substantially and linearly with increasing values of B.  FIG.  13 B  shows the effect of varying N with B=35, P=240 μs, and H=1.00 μs. As shown in  FIG.  13 B , the NO and NO2 concentrations generated increased substantially and linearly with increasing values of N.  FIG.  13 C  shows the effect of varying P with B=35, N=25, and H=100 μs. As shown in  FIG.  13 C , the NO and NO2 concentrations generated increased substantially and linearly with increasing values of P.  FIG.  13 D  shows the effect of varying H with B=35, N=25, and P=240 μs. As shown in  FIG.  13 D , the NO and NO2 concentration generated increased substantially and linearly with increasing values of H. The data shown in  FIGS.  12 A- 1   ) indicate that NO production can be precisely controlled (using B, N, P, and H), and that NO production can increase with pulse repetition (B and N) and energy storage capacitance (P and H). 
     Example 4: Measuring NO and NO2 Generation at Varying Atmospheric Pressure 
     The NO generator  14  was tested at an oxygen concentration of 21% (i.e., in air) in a 500 milliliter chamber. The controller  33  was configured to spark the electrodes  36  using the following settings: B=100, N=10, P=140 μs; and H=10 μs. The NO generator was run for 1 minute and the NO and NO2 concentrations were measured at one-third atmospheres absolute pressure (ATA), one-half ATA, one ATA, and two ATA.  FIG.  14    shows the NO and NO2 concentrations at the varying atmospheric pressures. As shown in  FIG.  14   , compared to NO and NO2 concentrations generated at one ATA, the NO and NO2 production decreased with decreasing ATA and increased with increasing ATA. However, the ration of NO2/1\10 remained substantially constant for each of the atmospheric pressures tested. 
     Example 5: Measuring NO and NO2 Concentrations Entering and Exiting the Scavenger  42  of the NO Generator  14  at Varying Oxygen and Nitrogen Concentrations 
     The NO generator  14  was tested at a constant gas flow rate of 5 L/min. The electrodes  36  were fabricated from iridium-platinum. The test was performed using the test setup shown in  FIG.  10    at atmospheric pressure. The scavenger  42  comprised 72 grams (g) of Ca(OH)2 and the post-filter  44  was placed downstream of the scavenger  42 . The controller  33  was configured to spark the electrodes  36  using the following settings: B=25, N=35, P=240 μs; and H=100 μs. The NO and NO2 concentrations generated by the NO generator  14  were measured entering (i.e., upstream) and exiting (i.e., downstream) of the scavenger  42  at oxygen levels of 21% (i.e., air), 50%, and 80%, and a balanced amount of nitrogen.  FIG.  15    shows the concentrations of NO and NO2 measured during the test. As shown in  FIG.  15   , at 21% oxygen (i.e., in air), the NO generator  14  produced 48±5 ppm NO and 44±5 ppm exited the scavenger  42 . The NO generator  14  produced 4.1±0.4 ppm NO2 and 0.5±0.03 ppm exited the scavenger  42 . At 50% oxygen, the NO generator  14  produced 68±11 ppm NO and 62±11 ppm exited the scavenger  42 . The NO generator  14  produced 6.2±0.4 ppm NO2 and 0.7±0.02 ppm exited the scavenger  42 . At 80% oxygen, the NO generator  14  produced 41±1 ppm NO and 37±2 ppm exited the scavenger  42 . The NO generator  14  produced. 3.9±0.5 ppm NO2 and 0.9±0.04 ppm exited the scavenger  42 . Thus, the scavenger  42  removed between approximately 87% and 95% of the NO2 produced by the NO generator  14 . These results demonstrate that the scavenger  42  is highly efficient at removing NO2 (to below the Environmental Protection Agency (EPA) limit after scavenging) without reducing the NO concentrations. 
     Example 6: Measuring NO and NO2 Concentrations Entering and Exiting the Scavenger  42  of the NO Generator  102   
     As described above, the NO generator  102  is similar to the NO generator  14  but is arranged inline on the inspiratory line  18 , upstream of exhaled CO2, which enables the scavenger  42  to be of a reduced size. The NO generator  102  was tested at a constant gas flow rate of 5 L/min. The test was performed using the test setup shown in  FIG.  10    at atmospheric pressure. The electrodes  36  were fabricated from iridium-platinum. The scavenger  42  comprised 15 g of Ca(OH)2 and the post-filter  44  was placed downstream of the scavenger  42 . The controller  33  was configured to spark the electrodes  36  using the following settings: B=35, N=25, P=240 μs; and H=70 μs. The NO and NO2 concentrations generated by the NO generator  102  were measured entering (i.e., upstream) and exiting (i.e., downstream) the scavenger  42  at oxygen levels of 21% (i.e., air), 50%, and 80%, and a balanced amount of nitrogen.  FIG.  16    shows the concentrations of NO and NO2 measured during the test. As shown in  FIG.  16   , the scavenger  42  removed approximately over 95% of the NO2 produced by the NO generator  102 . These results are similar to the larger (75 g) scavenger  42 . Thus, the smaller scavenger  42  with less gas flow resistance (e.g., 0.2 cmH20*min*L−1), used in the NO generator  102 , efficiently removes NO2 without reducing the NO concentrations. 
     Example 7: Measuring and Scavenging O3 Concentrations Produced by the NO Generator  14   
     The NO generator  14  was tested at a constant gas flow rate of 5 L/min. The electrodes  36  were fabricated from iridium-platinum. The test was performed using the test setup shown in  FIG.  10    and at atmospheric pressure. The scavenger  42  comprised 72 grams (g) of Ca(OH)2 and the post-filter  44  was placed downstream of the scavenger  42 . The controller  33  was configured to spark the electrodes  36  using the following settings: B=25, N=35, P=240 μs; and H=100 μs. The O3 concentrations generated by the NO generator  14  were measured entering (i.e., upstream) and exiting (i.e., downstream) of the scavenger  42  at oxygen levels of 21% (i.e., air), 50%, and 80%, and a balanced amount of nitrogen.  FIG.  17    shows the concentrations of O3 measured during the test. As shown in  FIG.  17   , at 21% oxygen (i.e., in air), the NO generator  14  produced 17±2 parts per billion (ppb) O3 and &lt;0.1 ppb exited the scavenger  42 . At 50% oxygen, the NO generator  14  produced 18±10 ppb O3 and &lt;0.1 ppb exited the scavenger  42 . At 80% oxygen, the NO generator  14  produced 20±1 ppb O3 and &lt;0.1 ppb exited the scavenger  42 . These results demonstrate that the scavenger  42  is highly efficient at removing O3 to negligible levels well below the EPA O3 limits. Similar results were achieved when testing of the smaller scavenger  42  of the NO generator  102 . 
     Example 8: Electrode Erosion 
     As described above, the electrodes can break down and vaporize over time due to the sparking.  FIG.  18 A  shows a new iridium electrode tip and  FIG.  18 B  shows a used iridium electrode tip after ten days of operation producing 50 ppm NO at 5 L/min gas flowrate. As shown in  FIG.  18 B , the electrode tip has degraded and lost material due to the sparking events. Thus, the requirement for the post-filter  44  in the NO generator  14  and  102 , and the post-filter  218  in the NO generator  201  and  301 . As the electrodes erode and vaporize, the electrode fragments are deposited on the post-filter  44 ,  218 . To verify that the post-filter  44 ,  218  catches the electrode fragments, a post-filter with a 0.22 μm particle size cutoff was imaged after the ten days of sparking.  FIG.  19 A  shows a new 0.22 μm post-filter and  FIG.  19 B  shows the 0.22 μm post-filter after the ten days of operation. As shown in  FIG.  19 B , the used 0.22 μm post-filter contains iridium fragments. This was verified by energy-dispersive X-ray (EDX) spectroscopy as shown in the plots of  FIG.  20 A  and  FIGS.  20 B .  FIG.  20 A  shows the EDX spectroscopy of the new 0.22 μm post-filter and  FIG.  20 B  shows the EDX spectroscopy of the used 0.22 μm post-filter. As shown in  FIGS.  20 A and  20 B , the used 0.22 μm post-filter contains iridium while the new 0.22 μm post-filter does not contain iridium. Thus, a single 0.22 μm post-filter was sufficient and necessary to catch electrode fragments produced by electrode erosion. 
     Example 9: Minimizing NO2 Generation by Varying Electrode Composition 
     The NO generator  14  was tested at a constant gas flow rate of 5 L/min with electrodes  36  fabricated from tungsten carbide, carbon, nickel, and iridium. The test was performed using the test setup shown in  FIG.  10    and at atmospheric pressure. The controller  33  was configured to spark the electrodes  36  using the following settings: B=25, N=35, P=240μs; and H=50 μs.  FIG.  21    shows the ratio of NO2/NO generated for the different electrode compositions. As shown in  FIG.  21   , the iridium electrode produced 4.5±0.1% of NO2/NO, the nickel electrode produced 6.5±0.1% of NO2/NO, the carbon electrode produced 7.8±0.5% of NO2/NO, and the tungsten carbide electrode generated 12.9±1.9% of NO2/NO. Obviously, the lower the ratio of NO2/NO the better and, thus, the iridium electrode is an ideal candidate for the composition of the electrodes  36 . 
     Example 10: Measuring NO and NO2 Diffusion Rates Through the Membrane  104  of the NO Generator  102   
     As described above, since the NO generator  102  is placed inline with the inspiratory line  18 , the microporous membrane  104  can be placed around the electrodes  36  to protect them from droplets of water or airway secretions. The NO generator  102  was tested at a constant gas flow rate of 0.5 L/min for 5 minutes while producing NO. The NO and NO2 produced was averaged over the 5 minutes and the concentrations with (+) and without (−) the membrane  104  were measured. The controller  33  was configured to spark the electrodes  36  using the following two sets of settings. Setting #1: B=25, N=35, P=240 μs; and H=30 μs. Setting #2: B=25, N=35, P=240 μs; and H=60μs.  FIG.  22    shows the NO and NO2 concentrations produced during the 5 minutes with (+) and without (−) the membrane  104  at the two different spark settings. As shown in  FIG.  22 ,  95   ±2% of the NO generated without (−) the membrane  104  was generated with (+) the membrane  104 , and 95±1% of the NO2 generated without (−) the membrane  104  was generated with (±) the membrane  104 . Thus, the addition of the membrane  104  does not significantly alter the NO production characteristics of the NO generator  102 . 
     Animal Studies 
     Animal studies were approved by the Institutional. Animal Care and Use Committee of Massachusetts General Hospital (Boston, Mass.). Eight lambs (New England  Ovis , Dover, N.H.) weighing 32±2 kg were studied. General anesthesia was induced with 5% inhaled isoflurane (1-chloro-2,2,2-trifluoroethyldifluromethyl ether, Baxter, Deerfield, Ill.) in oxygen delivered via a mask and then maintained with 1-4% isoflurane in 50% oxygen during surgery. After tracheal intubation, the lambs were instrumented with indwelling carotid artery pulmonary artery catheters. All hemodynamic measurements were performed in anesthetized lambs ventilated with a mechanical ventilator (model 7200, Puritan Bennett, Pleasanton, Calif.) at a tidal volume of 400 ml/min and rate of 12-15 breaths/min. 
     To induce pulmonary hypertension, a potent pulmonary vasoconstrictor U46619 (Cayman Chemical, Ann Arbor, Mich.), the analog of the endoperoxide prostaglandin H2, was infused intravenously at a rate of 0.8-0.9 μg/kg/min to increase pulmonary arterial pressure (PAP) to 30 mmHg. The mean arterial pressure and PAP were continuously monitored using a Gould 6600 amplifier system (Gould Electronics, Inc., Eastlake, Ohio). Pulmonary capillary wedge pressure, heart rate, and cardiac output were intermittently measured at baseline, during U46619 infusion, and before and after inhalation of NO generated using either the respiratory system  10 , the respiratory system  100 , or NO delivered and diluted at the same level from a compressed gas cylinder. Cardiac output was assessed by thermal dilution as the average of three measurements after an intravenous bolus injection of 10 mL of ice-cold saline solution. Pulmonary vascular resistance index (PVRI), as well as cardiac index (CI), were calculated using standard formulae. The gas cylinder contained 500 ppm NO diluted in nitrogen. 
     Example 1.1: Continuous NO Generation from Air Using the Respiratory System  10  on Anesthetized Lambs 
     The respiratory system  10  was tested with an anesthetized lamb as the patient  11 . A baseline (BL) was generated then the NO generator  14  of the respiratory system  10  was triggered to continuously spark (i.e., generate NO) after 1746619 was administered for 30 minutes. The NO was pumped at 5 L/min. into the inspiratory line  18 . The electrodes  36  were fabricated from iridium-platinum. Once triggered, the controller  33  was configured to spark the electrodes  36  for 4 minutes using the following settings: B=35, N=25, P=240 μs; and H=100 μs, which produced approximately 40 ppm of NO, and then the controller  33  stopped the NO generator  14 . The test was performed when 21% oxygen was supplied to the inlet  24  of the NO generator  14 , when 50% oxygen was supplied to the inlet  24  of the NO generator  14 , and compared with NO supplied at the same concentration to the anesthetized lamb from a gas cylinder, 
       FIG.  23 A  shows the mean pulmonary artery pressure (PAP) of the anesthetized lamb for the duration of the tests, and  FIG.  23 B  shows the pulmonary vascular resistance index (PVRI) of the anesthetized lamb for the duration of the tests. As shown in  FIGS.  23 A and  23 B , during the 4 minute window  400  when. NO was continuously produced by the NO generator  14 , PAP and PVRI were rapidly reduced while breathing both 21% and 50% oxygen. Also, the reduction in PAP and PVRI for the NO produced by the NO generator  14  was similar to the reduction in PAP and PVRI for the NO supplied at the same level by dilution from the gas cylinder. Therefore, the respiratory system  10  can be a viable and equivalent replacement for gas cylinders when administering NO inhalation therapy. 
     Example 12: Continuous NO Generation from Air Using the Respiratory System  100  on Anesthetized Lambs 
     The respiratory system  100  was tested with an anesthetized lamb as the patient  11 . A baseline (BL) was generated then the NO generator  102  of the respiratory system  100  was triggered to continuously spark (i.e., generate NO) after U46619 was administered for 30 minutes. The electrodes  36  were fabricated from iridium-platinum. Once triggered, the controller  33  was configured to spark the electrodes  36  for 4 minutes using the following settings: B=35, N=25, P=240 μs; and H=100 μs, which produced approximately 40 ppm of NO, and then the controller  33  stopped the NO generator  102 . The test was performed when 21% oxygen was supplied in the inspiratory line  18 , when 50% oxygen was supplied in the inspiratory line  18 , and when NO was supplied to the anesthetized lamb diluted from a compressed gas cylinder. 
       FIG.  24 A  shows the mean pulmonary artery pressure (PAP) of the anesthetized lamb for the duration of the tests, and  FIG.  24 B  shows the pulmonary vascular resistance index (MU) of the anesthetized lamb for the duration of the tests. As shown in  FIGS.  24 A and  24 B , during the 4 minute window  402  when NO was continuously produced by the NO generator  102 , PAP and PVRI were rapidly reduced while breathing both 21% and 50% oxygen. Also, the reduction in PAP and PVRI for the NO produced by the NO generator  102  was similar to the reduction in PAP and PVRI for the NO supplied by the gas cylinder. Also, the performance of the respiratory system  100  was similar to the respiratory system  10 . Therefore, the respiratory system  100  can provide a viable and equivalent replacement for compressed gas cylinders when administering NO inhalation therapy. 
     Example 13: Intermittent NO Generation from Air Using the Respiratory System  100  on Anesthetized Lambs 
     The respiratory system  100  was tested with an anesthetized lamb as the patient  11 . A baseline (BL) was generated then the NO generator  102  of the respiratory system  100  was triggered to intermittently spark (i.e., generate NO) after U46619 was administered for 30 minutes. The electrodes  36  were fabricated from iridium-platinum. The controller  33  was configured to spark the electrodes  36  only during the first 0.8 seconds of inspiration for 4 minutes using the following settings: B=35, N=25, P=240 μs; and H=100 μs and then the controller  33  stopped the NO generator  102 , The test was performed when 21% oxygen was supplied in the inspiratory line  18 , when 50% oxygen was supplied in the inspiratory line  18 , and when. NO was supplied to the anesthetized Iamb from a gas cylinder. 
       FIG.  25 A  shows the PAP of the anesthetized lamb for the duration of the tests, and  FIG.  25 B  shows the PVRI of the anesthetized lamb for the duration of the tests. As shown in  FIGS.  24 A and  24 B , during the 4 minute window  404  when NO was produced during the first 0.8 seconds of inspiration by the NO generator  102 , mean pulmonary artery pressure (PAP) and the pulmonary vascular resistance index (PVRI) were rapidly reduced breathing either 21% and 50% oxygen. Also, the reduction in PAP and PVRI for the NO produced by the NO generator  102  was similar to the reduction in PAP and PVRI for NO supplied and diluted from the compressed gas cylinder. Also, the performance of the respiratory system  100  when intermittently sparking the electrodes  36  was similar to the respiratory system  100  and the respiratory system  10  when continuously sparking the electrodes  36 . Therefore, intermittently generating NO with the respiratory system  100  can be a viable replacement for gas cylinders when administering NO inhalation therapy. 
     Whilst the invention has been described above, it extends to any inventive combination of features set out above or in the following description. Although illustrative embodiments of the invention are described in detail herein with reference to the accompanying drawings, it is to be understood that the invention is not limited to these precise embodiments. Furthermore, it is contemplated that a particular feature described either individually or as part of an embodiment can be combined with other individually described features, or parts of other embodiments, even if the other features and embodiments make no mention of the particular feature. Thus, the invention extends to such specific combinations not already described. 
     While the invention has been described above in connection with particular embodiments and examples, the invention is not necessarily so limited, and that numerous other embodiments, examples, uses, modifications and departures from the embodiments, examples and uses are intended to be encompassed by the claims attached hereto. The entire disclosure of each patent and publication cited herein is incorporated by reference, as if each such patent or publication were individually incorporated by reference herein.