Systems and methods for delivery of nitric oxide gas

Abstract

Disclosed herein are systems and methods for delivering nitric oxide gas. According to an embodiment, a nitric oxide gas delivery system can include: a first nitric oxide (NO) gas generator, wherein the first NO gas generator includes a plasma chamber enclosing two electrodes separated by a gap; a plurality of port lights surrounding a plurality of corresponding gas outlet ports, wherein each of the port lights are configured to display a color; and an electronic control circuit, wherein the electronic control circuit is configured to enable the plurality of port lights to display the color based on a status of a plasma current across the two electrodes.

Description

[0001] Inventors: Craig R. Tolmie, Robert Lepage, Chad Schweitzer

[0002] SYSTEMS AND METHODS FOR DELIVERY OF NITRIC OXIDE GAS

[0003] RELATED APPLICATION

[0004] This application claims the benefit of U.S. Provisional Application No. 63 / 722.537 filed November 19, 2024. The entire contents of the above-referenced application are incorporated by reference herein.

[0005] FIELD OF THE INVENTION

[0006] The present invention relates to systems and methods for del i x ery of nitric oxide gas.

[0007] BACKGROUND OF THE INVENTION

[0008] Nitric oxide (NO) delivery systems can deliver NO to mechanical ventilator breathing circuits in controlled concentrations. Such systems generally require a gas monitoring system (with alarms) for measuring the gas concentrations of NO, nitrogen dioxide (NO2) and oxy gen (O2) in the ventilator breathing circuit just prior to inhalation by the patient, via a gas sample line. However, current deliver}’ systems do not provide feedback or confirmation that the set concentration or flow rate of NO is actually being delivered.

[0009] As such, there is a need for systems and methods of delivering NO gas that address the above deficiencies.

[0010] SUMMARY OF THE INVENTION

[0011] This Summary introduces a selection of concepts in simplified form that are described further below in the Detailed Description. This Summary neither identifies key or essential features, nor limits the scope, of the claimed subject matter.

[0012] Disclosed herein are systems and methods for delivering nitric oxide gas.

[0013] According to an embodiment, a nitric oxide gas deliver}' system can include: a first nitric oxide (NO) gas generator, wherein the first NO gas generator includes a plasma chamber enclosing two electrodes separated by a gap; a plurality of port lights surrounding a plurality of corresponding gas outlet ports, wherein each of the port lights are configured to display a color; and an electronic control circuit, wherein the electronic control circuit is configured to enable the plurality of port lights to display the color based on a status of a plasma current across the two electrodes. According to an embodiment, the plurality of port lights are illuminated upon activation of the corresponding gas ports.

[0014] According to an embodiment, the color displayed by the port lights indicates whether a set concentration of NO gas is being delivered through the corresponding gas port.

[0015] According to an embodiment, the plurality of port lights are configured to: (i) display a first color if the NO gas is being delivered through the corresponding gas port at the set concentration, (li) display a second color if the NO gas is being delivered through the corresponding gas port at a concentration different from the set concentration, and (iii) display a third color if the NO gas is not being delivered through the corresponding gas port at all.

[0016] According to an embodiment, the gas outlet is selected from a NO delivery outlet or a manual resuscitation bagging outlet.

[0017] According to an embodiment, the gas outlet is the manual resuscitation bagging outlet.

[0018] According to an embodiment, the status of the plasma current is determined by a current sensor.

[0019] According to an embodiment, the status of the plasma current indicates a concentration of the NO gas being delivered through the corresponding gas port.

[0020] According to an embodiment, the concentration of the NO gas is determined based on an electric charge associated with the plasma current.

[0021] According to an embodiment, the system further comprises a second NO gas generator.

[0022] According to an embodiment, the first and second NO gas generators are operated simultaneously.

[0023] According to an embodiment, only one of the first and second NO gas generators is operated at a time.

[0024] According to an embodiment, one of the plurality of port lights displays a first color during the operation of the first NO gas generator and displays a second color during the operation of the second NO gas generator.

[0025] According to an embodiment, an apparatus for generating nitric oxide can include: a plasma chamber enclosing two electrodes separated by a gap; a gas inlet port for introducing a flow of reactant gas comprising oxygen and nitrogen into the plasma chamber; an electronic control circuit configured to: (i) generate one or more electrical pulses across the two electrodes to produce a product gas comprising a desired concentration of nitric oxide, wherein the one or more electrical pulses form a plasma current, (ii) sense at least one peak of the one or more electrical pulses in the formed plasma current, and (iii) upon determining that the sensed at least one peak exceeds or falls below one or more predefined limits, generate one or more further electrical pulses that differ with the generated one or more electrical pulses in at least one of: (a) duty cycle, (b) pulse duration, and c) generated electric charge; and a gas outlet port for delivering the product gas comprising nitric oxide for use thereof.

[0026] According to an embodiment, the apparatus can further comprise a voltage controller in communication with the electronic control circuit to generate the one or more electrical pulses and the one or more further electrical pulses.

[0027] According to an embodiment, the voltage controller is any suitable voltage controller know in the art including but not limited to a metal-oxide-semiconductor field-effect transistor (MOSFET) or a triode for alternating current (TRIAC).

[0028] According to an embodiment, the apparatus can further comprise a current sensor in communication with the electronic control circuit to sense the at least one peak of the one or more electrical pulses in the formed plasma current.

[0029] According to an embodiment, the current sensor comprises a differential amplifier and an analog-to-digital converter (ADC).

[0030] According to an embodiment, the differential amplifier is connected in series with the plasma chamber.

[0031] According to an embodiment, the electronic control circuit includes first and second timers, wherein the first timer controls the timing for the voltage controller and the second timer controls the timing for the current sensor.

[0032] According to an embodiment, the first and second timers run at the same frequency.

[0033] According to an embodiment, the duty cycle of the second timing signal is of a shorter width than the duty' cycle of the first timing signal.

[0034] According to an embodiment, wherein modifications to the first timing signal results in proportional modifications to the second timing signal.

[0035] According to an embodiment, a method for generating nitric oxide gas can include: (i) receiving a flow of reactant gas comprising oxygen and nitrogen into a reaction chamber enclosing two electrodes separated by a gap; (ii) generating one or more electrical pulses across the two electrodes to produce a product gas comprising a desired concentration of nitric oxide, wherein the one or more electrical pulses form a plasma current; (iii) sensing at least one peak of the one or more electrical pulses in the formed plasma current; and (iv) upon determining that the sensed at least one peak exceeds or falls below' one or more predefined limits, generating one or more further electrical pulses that differ with the generated one or more electrical pulses in at least one of: (a) duty cycle, (b) pulse duration, and (c) generated electric charge.

[0036] According to an embodiment, the one or more electrical pulses and the one or more further electrical pulses are generated based on a first timing signal.

[0037] According to an embodiment, the at least one peak of the one or more electrical pulses are sensed based on a second timing signal.

[0038] According to an embodiment, the first timing signal is at the same frequency as the second timing signal.

[0039] According to an embodiment, a nitric oxide gas delivery system can include: at least one nitric oxide (NO) gas generator, wherein the NO gas generator includes a plasma chamber enclosing two electrodes separated by a gap; at least one gas outlet port for delivering the NO gas generated by the at least one NO gas generator; an NO delivery module in fluid communication with the at least gas outlet port, wherein the NO delivery module comprises a breathing gas flow sensor configured to detect a breathing gas flow rate; an electronic control circuit configured to modify a spark frequency between the two electrodes based on the detected breathing gas flow rate.

[0040] According to an embodiment, the electronic control circuit is configured to: (i) increase the spark frequency if the detected breathing gas flow rate exceeds a predefined value and (ii) decrease the spark frequency if the detected breathing gas flow rate falls below the predefined value.

[0041] According to an embodiment, the electronic control circuit is configured to: (i) increase the spark frequency if a detected breathing gas flow rate of change exceeds a positive predefined threshold and (ii) decrease the spark frequency if a detected breathing gas flow rate of change exceeds a negative predefined threshold.

[0042] According to an embodiment, the system can further comprise a pressure sensor configured to detect a pressure at the plasma chamber.

[0043] According to an embodiment, upon determining that (i) an average breathing gas flow rate over a period of time is less than a predefined flow rate amount and (ii) the detected pressure at the plasma chamber exceeds a predefined pressure amount, the electronic control circuit is further configured to control the flow rate of the generated NO such that it is maintained at an average of the flow rate over the period of time. According to an embodiment, the electronic control circuit is further configured to determine a flow state of the generated NO based on a detected breathing gas flow rate of change.

[0044] BRIEF DESCRIPTION OF THE FIGURES

[0045] Some embodiments of the invention are herein described, by way of example only, with reference to the accompanying drawings. With specific reference now to the drawings in detail, it is stressed that the particulars show n are by w ay of example and for purposes of illustrative discussion of embodiments of the invention. In this regard, the description taken with the drawings makes apparent to those skilled in the art how embodiments of the invention may be practiced.

[0046] In the drawings:

[0047] FIG. 1 A is an illustration of the front of a nitric oxide delivery system, showing, inter alia, the gas ports.

[0048] FIG. IB is a perspective view of the system, according to an embodiment of the invention.

[0049] FIG. 2 is an illustration of the graphical user interface display, according to an embodiment of the invention.

[0050] FIG. 3 is a cross-sectional view of the plasma chamber showing the main components of the plasma chamber design, according to an embodiment of the invention.

[0051] FIG. 4 is a schematic diagram of the nitric oxide generator showing the components of the system and their electrical and pneumatic connections, according to an embodiment of the invention.

[0052] FIG. 5 is an electronic schematic of the pulsed electric discharge drive circuit, according to an embodiment of the invention.

[0053] FIG. 6A is a schematic diagram of the nitric oxide generator, showing the components of the system and their electrical and pneumatic connections, according to another embodiment of this invention.

[0054] FIG. 6B is a schematic diagram depicting the interaction betw een the electronic control circuit and the plasma chamber, according to an embodiment of this invention.

[0055] FIG. 6C is a schematic diagram depicting the interaction between the electronic control circuit, the voltage controller, the current sensor, and the plasma chamber, according to an embodiment of this invention. FIG. 6D depicts the timing diagrams for the voltage controller and the current sensor, according to an embodiment of this invention.

[0056] FIG. 6E depicts portions of the timing diagrams for the voltage controller and the current sensor in relation to the generated plasma current, according to an embodiment of this invention.

[0057] FIG. 7A is a schematic diagram of a nitric oxide generation system, including two nitric oxide generators, according to an embodiment of this invention.

[0058] FIG. 7B is a schematic diagram of the nitric oxide delivery module depicted in FIG. 7 A, according to an embodiment of this invention.

[0059] DETAILED DESCRIPTION OF THE INVENTION

[0060] The following Detailed Description references the accompanying drawings which form a part this application, and which show, by way of illustration, specific example implementations. Other implementations may be made without departing from the scope of the disclosure.

[0061] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein.

[0062] As used herein, the singular forms “a”, “an”, and “the” include both singular and plural referents unless the context clearly dictates otherwise.

[0063] Throughout this disclosure, various aspects of the invention can be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50, as well as all intervening decimal values between the aforementioned integers such as, for example, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, and 1.9. With respect to sub-ranges, “nested sub-ranges” that extend from either end point of the range are specifically contemplated. For example, a nested sub-range of an exemplary range of 1 to 50 may comprise 1 to 10, 1 to 20, 1 to 30, and 1 to 40 in one direction, or 50 to 40, 50 to 30, 50 to 20, and 50 to 10 in the other direction.

[0064] FIG. lA is an illustration of the front of a NO delivery system, showing, inter alia, the gas ports, and FIG. IB is a perspective drawing of the system. As depicted in the figures, NO deliver}' system 1 includes: a plurality of gas ports 2, 3, and 4, with corresponding port lights 2a, 3a, and 4a; a nitric oxide delivery module (NDM) cable port 5; a gas sample line port 6; a user interface display 7; knob 7a; light bar 7b; speakers 7c; and filter latch 8.

[0065] According to an embodiment, the gas port 2 corresponds to the main NO deliver}' outlet, the gas port 3 corresponds to the manual resuscitation bagging outlet, and the gas port 4 corresponds to the manual resuscitation bagging inlet. In this regard, gas ports 3 and 4 are part of the bagging system, where the gas port 4 is used to connect to an air / oxygen source through oxygen tubing or equivalent to provide an external flow, and the gas port 3 is used to connect to a manual resuscitator for manually ventilating a patient.

[0066] According to an embodiment, port lights 2a, 3 a, and 4a can be controlled by an electronic control circuit programmed to operate a corresponding light engine to display a visible light of a color. The light engine can be enabled, for example, if a gas delivery mass flow controller is providing the appropriate amount of NO-containing gas in liters per minute. The displayed colors can represent different conditions. For example, a first color can be used to indicate a first condition, i.e., proper operation and deliver ’ of NO gas, a second color can be used to indicate a second condition, i.e., improper operation or delivery of NO gas, and a third color can be used to indicate a third condition, i.e., a state between the first and second conditions. According to another embodiment, instead of displaying a certain color, the port lights can flash at different frequencies to indicate the different conditions. In this regard, the flashing can correspond to the urgency of the condition. For example, with the first condition, there could be no flashing since the device is operating properly. For the second condition, there can be a higher frequency flashing since the device is not operating properly. Lastly, for the third condition, there can be a lower frequency.

[0067] According to an embodiment, the NDM cable port 5 can be used to receive a cable from the NDM, which is used to measure gas flow in the breathing circuit and proportionally deliver the NO gas mixture into the inspiratory' limb of the breathing circuit.

[0068] According to an embodiment, the gas sample line port 6 can be used to receive a gas sample line connected to the breathing circuit. In this regard, the gas sample line is used to draw gas from the breathing circuit so that the NO, NO2, and O2 concentrations can be measured and monitored in real-time.

[0069] According to an embodiment, the user interface display 7 can be used to set a desired NO concentration or another parameter. In this regard, the user interface display 7 can be touchscreen. In this regard, touching the parameter to be set on the display 7 can activate or open a menu to set the parameter. For example, touching the display 7 can open a graphic with + and / or - symbols and / or a menu of possible selections (e.g., 5, 10 or 20 ppm) which allow increasing or decreasing the NO concentration. According to another embodiment, the desired NO concentration can also be set with the knob 7a. The user interface display 7 can also be used to display the status of one or more of (i) NO sources, (ii) NO2 fdter, (iii) gas sample line, (iv) the bagging system, (v) the set NO concentration, (vi) the measured NO concentration, (vii) the measured NO2 concentration, (viii) the measured O2 concentration, and / or (ix) power supply, which will be described in more detail in relation to FIG. 2.

[0070] According to an embodiment, like the port lights 2a, 3a, and 4a, the light bar 7b can be controlled by an electronic control circuit programmed to operate a corresponding light engine to display a visible light of a color, where the displayed colors represent different conditions. In this regard, the light bar 7b ensures that any important conditions, such as an alarm state, are visually apparent in busy multi-patient environments. According to an embodiment, the light bar 7b remains off when the system is not in a state of alarm, and then can turn a first warning color (e.g., red) when a more urgent alarm is triggered (e g., when the battery has only a few minutes of life remaining) or another warning color (e.g., amber) when the alarm is less urgent (e.g., the NO2 filter needs to be replaced soon).

[0071] According to an embodiment, the speakers 7c can be used to provide an audio alarm in combination with the visual indication provided by the port lights 2a, 3a, and 4a, the user interface display 7, and / or the light bar 7b.

[0072] FIG. 2 is an illustration of the graphical user interface display, according to an embodiment of the invention. As depicted in the figure, the user interface display 7 displays a user interface layout 10 including a plurality of dedicated areas, such as: (i) an NO source status area 11, (ii) NO2 filter status area 12, (iii) gas sample line status area 13, (iv) bagging system status area 14, (v) set NO concentration area 15, (vi) measured NO concentration area 16, (vii) measured NO2 concentration area 17, (viii) measured O2 concentration area 18, (ix) power supply status area 19, and (x) a text area 20.

[0073] According to an embodiment, the NO source status area 11 depicts the status of the one or more NO sources being used. Specifically, the area 11 depicts whether a primary NO source is being used or whether a backup or secondary NO source is used. In this regard, if the primary NO source is being used, the top NO source graphic Ila will be illuminated. Similarly, if the backup or secondary source is being used, then the bottom NO source graphic lib will be illuminated. The NO source can be from a container storing NO or an NO generator. According to an embodiment, the NO generator can generate the NO gas from nitrogen (N2) and oxygen (O2) present in ambient air, liquid dinitrogen tetroxide (N2O4), gaseous nitrogen dioxide (NO2), or nitric acid (HNO3).

[0074] According to an embodiment, the NO2 filter status area 12 depicts the status of the NO2 filter being used. The status the NO2 filter can be provided in terms of hours / time and / or percentage of time remaining before the filter should be changed. According to an embodiment, the status of the filter can also be depicted with a ball float graphic that moves in a certain direction around a circle as the NO2 filter is being consumed. For example, as depicted in FIG. 2. the ball float graphic can move counterclockwise as the NO2 filter is being consumed. However, in another embodiment, the ball float graphic can move clockwise, or can be represented by another graphic and move vertically, horizontally, diagonally, etc.

[0075] According to an embodiment, the gas sample line status area 13 depicts the status of a connected gas sample line. The area 13 includes a bar graph 13a, which comprises a first visual indicator 13b, e.g., a ball float, and a second visual indicator 13c, e.g., a horizontal line. In this regard, the ball 13b can be associated with a first contrasting color above and a second contrasting color below it. The ball 13b can descend as the gas sample line is being used. The line 13c can be an indicator of the time to replace the gas sample line. As such, the placement of the ball 13b is an indication of the functional life of the gas sample line. Of course, alternative illustrations can be used. The bar graph can be inverted, replaced with a dial or circle or with a numerical indicator, such as a percentage of life remaining, etc. The urgency of the replacement can be communicated with color. Amber, for example, can be used to indicate that replacement needs to be completed soon, whereas red can be used to indicate that the part should be replaced immediately. These indicators will aid in preventing users from performing unnecessary' maintenance or ignoring required maintenance, thereby avoiding gas monitoring failures, high priority alarms, and / or bedside clinical crises. Further, it can also prevent excessive gas sample line replacement from based on an institutionalized replacement schedule, resulting in lower related therapy costs, user maintenance, and / or unplanned bedside visits to address gas monitoring sample line failure related alarms.

[0076] According to an embodiment, the bagging system area 14 depicts the status of the connected manual resuscitator. The bagging system area can include at least one of a measured flow graphic 14a and NO2 filter graphic 14b. The measured flow graphic 14a depicts the flow of the gas going through the gas port 3. Similarly, the NO2 filter graphic 14b depicts the status of the NO2 filter associated with the gas port 3. The status of the NO2 filter can be provided in terms of hours / time and / or percentage of time remaining before the filter should be changed. According to an embodiment, the status of the filter can also be depicted with a ball float graphic that moves in a certain direction around a circle as the NO2 filter is being consumed. For example, the ball float graphic can move counterclockwise as the NO2 filter is being consumed. However, in another embodiment, the ball float graphic can move clockwise around the circle, or can be represented by another graphic and move vertically, horizontally, diagonally, etc. Like the gas sample line, the urgency of the need to replace the NO2 filter can be communicated with color. Amber, for example, can be used to indicate that replacement needs to be completed soon, whereas red can be used to indicate that the part should be replaced immediately.

[0077] According to an embodiment, the set NO concentration area 15 depicts the desired NO concentration set by the user. As described above, the NO concentration can be set using the user interface display 7 or the knob 7a.

[0078] According to an embodiment, the measured NO concentration area 16 depicts the real-time measured concentration and, optionally, the upper limit 16a and lower limit 16b of a range beyond which an alarm will sound (e.g., 15 to 55 ppm).

[0079] According to an embodiment, the measured NO2 concentration area 17 depicts the real-time measured NO2 concentration and, optionally, the upper limit 17a beyond which an alarm will sound (e.g., 3 ppm).

[0080] According to an embodiment, the measured O2 concentration area 18 depicts the realtime measured O2 concentration and, optionally, the upper limit 18a and lower limit 18b of a range beyond which an alarm will sound (e.g., 50 to 90%).

[0081] According to an embodiment, the power supply status area 19 depicts the status of the remaining battery life in the system 1. This can be provided as graphic 19a that visually depicts a depleting battery as the battery is being consumed. The remaining battery life can also be presented in terms of time remaining in hours and / or percentage. Further, when the battery power begins to run low (e.g., within 30 minutes of exhaustion), the graphic 19a can turn to a first warning color, e.g., amber, and then to a second warning color, e.g., red, if the power status is more critical (e.g., when less than 10 minutes of battery power remains). Similarly, the graphic 19a can also depict when the battery is being charged.

[0082] According to an embodiment, the text area 20 can depict descriptive banners associated with one or more conditions, such as “Bagging Mode On,” “Replace Gas Sample Line,” “Replace NO2 Filter,” “Bagging Flow Reversed,” “NDM Flow Sensor Failure,” etc.

[0083] According to an embodiment, during normal operation of the system 1, the NO is being output via the gas port 2 at the desired NO concentration. In this regard, the port light 2a will be illuminated in a first color, e.g., blue, once the gas delivery is within 20% of the set concentration. The concentration of the gas delivery' can be determined based on the flow of the NO gas being delivered through the gas port 2. The flow can be determined, for example, by a mass flow controller providing the NO gas through the gas port 2.

[0084] According to an embodiment, during bagging mode, the NO is being output via the gas ports 2 and 3. In this regard, the concentration being output at the gas port 3 can be set based on the desired NO concentration for the gas port 2. Bagging mode can commence once the low pressure Air / O2 mixture is provided to the gas port 4. This gas can then be combined with NO and delivered out the gas port 3, which is then connected to a manual resuscitator. The port light 3a will be illuminated in the first color once the gas delivery through the gas port 3 is within 20% of the desired NO concentration. Under failed conditions, the port light 3a can change colors, e.g., from blue to red. Under clinically short time periods of NO delivery, this method of direct indication of NO delivery can lessen the need for gas monitoring. The display can include one or more additional graphics when the gas port 3 is active, such as a graphic that pictures an ambulatory' bag with the word “on,” e.g., graphics 14a and / or 14b, and / or a banner with identifying w ords, such as “Bagging Mode On” in the text area 20. In addition, the measure and / or set gas flow rate associated with the bagging system can also be illustrated, as depicted in 14a.

[0085] According to an embodiment, in the event of a failure associated with the primary NO source, the system 1 can switch to a backup mode. For example, the switch can occur if NO levels fall outside of the desired range, etc. The switch can also occur if there is a failure of another component(s), e.g., NDM flow sensor. The switch can occur automatically or activated manually. Backup mode maintains NO delivery out of the main delivery port, i.e.. gas port 3, at certain concentration and flow rate. In this regard, the port light 3a can be illuminated with a warning color (e.g.. red or amber). Further, to provide additional indications that backup mode has been activated, the graphic lib can be illuminated, while the graphic I la can be depicted with an X over it. Further, the text area 20 can also display a message describing the particular failure, e.g., “NDM Flow Sensor Failure.” The light bar 7b can also flash temporarily to indicate the change in status.

[0086] According to an embodiment, if a gas port is not correctly plumbed, the corresponding port light can change to a warning color, such as red, to indicate zero gas being delivered through the gas port. This can result in reverse flow being detected, e.g., by the corresponding mass flow controller, flow sensor, or pressure sensor (e.g., by detecting the pressure from going positive pressure to negative pressure). In the case of the gas port 3 being incorrectly plumbed, the text area 20 can also display a warning banner, e.g., “Bagging Flow Reversed”. Again, color can be used to highlight the warning.

[0087] According to an embodiment, the system 1 can be used with NO generation and delivery systems that can generate NO from room air. The NO generation system can be a plasma-based generation system, such as the LungFit® systems. The plasma-based NO generation system can generate NO from room air and deliver it to a mechanical ventilator breathing circuit in a controlled concentration, e.g., from 0. 1 to 500 ppm NO. An attached NO delivery module (NDM) measures the gas flow in the ventilator breathing circuit and delivers a controlled flow of NO enriched gas into the breathing circuit. The device also incorporates a gas monitoring system (with user-set alarms) for measuring the gas concentrations of NO, nitrogen dioxide (NO2) and oxygen (O2) in the ventilator breathing circuit just prior to inhalation by the patient, via a gas sample line.

[0088] The plasma-based system can be comprised of three sub-systems: the NO generator with the NO2 filter; the NO backup and bagging system; and the gas sampling and monitoring system. The NO generator subsystem produces NO from the O2 and nitrogen (N2) in ambient room air. Ambient air (containing approximately 21% O2 and 79% N2) for the NO generation is drawn into the device by a gas pump. This air is passed through a particulate filter (removing dust particles) and then to a flow meter that measures the air gas flow. The pump and the flow meter are connected to a micro-controller that ensures the required gas flow of air passes through the NO plasma chamber. In other embodiments, instead of a pump and flow meter, a mass flow controller can be used. At the outlet of the NO generator is an NO2 filter. Its function is to remove NO2 from the NO-containing gas flow before it is delivered to the ventilatory circuit. Electronic circuitry in each filter is used to log filter usage to ensure it has not been depleted due to previous use. There can be a one 1-micron filter on the inlet of the filter and one on the outlet of the NO2 filter. A single filter can provide a predetermined time of NO2 filtering, regardless of NO concentration and ventilator settings. The NDM can measure gas flow in the ventilator breathing circuit (flow sensor) and deliver NO gas mixture into the inspiratory limb of the ventilator breathing circuit (injector line and adapter). The NDM can be placed close to the ventilator gas outlet to allow for proper mixing of NO enriched gas from the NDM with the ventilator delivered gas flow. The gas sampling system includes a gas monitoring module, with alarms, for measuring and monitoring the NO, NO2 and the O2 concentrations in the ventilator circuit. This can be done by sampling the gas flow in the inspiratory limb of the ventilator breathing circuit, downstream of the NDM, near the patient connection. The gas sample line is attached on one end to the inspiratory limb of the ventilator breathing circuit near the patient connection and to a gas sample port at the other. A gas pump draws gas from the ventilator breathing circuit. The gas sample line can include a hydrophobic filter and synthetic polymer-based tubing (e.g., sulfonated tetrafluoroethylenebased fluoropolymer-copolymer). The integrated backup NO delivery system is a completely independent backup NO generating system that is separate from the main delivery system; it has its own NO generator and gas flow delivery system. The backup NO deliver}’ system is generally utilized in the event of a failure of the main NO deliver}7system. The backup NO delivery system can also deliver NO to the bagging system connector. The bagging system connector has two tubing fittings: one for connecting to an air / oxygen source through oxygen tubing or equivalent to provide an external flow of air / oxygen and the other to connect to a manual resuscitator for manually ventilating a patient. The flow from the backup NO module is added to this air / oxygen flow which dilutes the NO concentration down to therapeutic levels. Final NO concentration will depend on the amount of external flow added.

[0089] The plasma-based system can generate NO from ambient air using a pulsating plasma or electric discharge. U.S. Patent No 9,573,110 by Montgomery et al., for example, describes such a plasma-based system, which is incorporated herein by reference, and described in more detail below.

[0090] In the following detailed description the term ”air“ will be used to generally describe the oxygen and nitrogen gas mixture used in plasma chambers to generate NO, but also other gas mixtures containing oxygen and nitrogen that may have been produced from alternative gas sources such gas containers that are commonly used in anesthesia machines and may include alternate concentrations. The plasma-based system includes a plasma chamber with a gas inlet for a gas flow of air, or other oxygen and nitrogen containing gases, to enter the plasma chamber, two electrodes separated by a gap, an electronic control circuit connected to the electrodes to generate an electric discharge across the gap to produce NO, and an outlet for the NO containing gas mixture to exit the chamber.

[0091] The plasma-based system produces NO in accurately controlled amounts over a wide range of gas flow rates and NO concentrations by controlling one or both of the pulse frequency (number of complete electric discharges per second) and / or the pulse duration (length of each complete electric discharge) of electric pulse discharges across the electrode gap. The amount of NO generated is proportional to both the frequency and the duration of the electric pulse discharges and so either one by itself or in combination with the two can provide a wide control range of NO generation.

[0092] The electronic control circuit starts each electric discharge pulse with a short phase of high voltage to initially ionize the gases and to allow electric current to start flowing across the electrode gap, this is then followed by a second phase of the pulse, which is of a lower voltage and current. The first high voltage phase of the pulse can be kept to a small period of time that is just long enough to initially ionize the gases between the electrodes and to allow electric current to flow in the electrode gap. In the second phase of the pulse, the voltage and the current can be reduced to lower values and this phase corresponds to the adjustable duration phase of the electric pulse discharge. The apparatus can be designed so that the majority of the NO is generated during the more efficient second phase. There are a number of stable voltage and current combinations that can be used in this second phase of discharge and they have different advantages and disadvantages. This type of electric discharge with intermittent pulse operation with controlled frequency and / or duration at a controlled, predominantly low current provides benefits including one or more of: it produces NO efficiently by only producing the amount of NO needed for the application without the need for additional diluent gases; it produces NO without significant increase in the temperature of the gases going to the biological system and therefore does not need cooling apparatus; and it significantly reduces electrode wear due to vaporization of the electrode because the average electric current is low. The low current and intermittent pulse electric discharge generates NO efficiently without generating high levels of NO2.

[0093] Another desired feature of the plasma-based system is to generate NO more efficiently with lower power consumption. One approach to improve the NO generating efficiency is to provide a magnetic field across the electrode gap. This can be achieved by using either electric coils or permanent magnets to provide the magnetic field across the electrode gap. With a magnetic field crossing perpendicular to the gap, an increase in the quantity of NO generated of up to 45% for the same electric discharge pulse settings was show n. Specific examples of improved efficiency will be given in the detailed description section of the invention.

[0094] FIG. 3 shows the plasma chamber 101 with a reactor housing 102 which has a reactor gas inlet port 108 and a first electrode 112 on one side and a reactor gas outlet port 110 and a second electrode 120 on the other side. The electrodes can be insulated with non-electrically conducting material 114 and 122 if the chamber housing is made of a material that is electrically conducting. The electrodes can have an electrode tip 116 and 124 made of a material that is resistant to high temperatures and is less susceptible to vaporization, oxidization and wear. Materials for the electrode tips can be selected from the noble metal group of the periodic table that includes tungsten and platinum. The electrodes are connected to the electronic control circuit with the insulated electrical cables 118 and 126.

[0095] In one embodiment of the system, the plasma chamber can have magnets 130 and 132 located on the reactor housing 102 so they are adjacent to the air gap between the electrodes 112 and 120, each magnet with the opposite pole facing the chamber so they reinforce the magnetic field across the air gap. One embodiment of the invention has a magnet on each side of the air gap, although a single stronger magnet that exerts the same magnetic field strength across the air gap is equally applicable. The magnetic field across the air gap is believed to cause dispersal of the electrical discharges across the air gap, which results in a larger plasma cross-sectional area and more efficient generation of NO. In one embodiment the magnets are rare earth magnets made from neodymium iron and boron.

[0096] The reactor housing 102 can have a port 134 that allows a photodiode 138 to be in optical communication with the inside of the plasma chamber 101. The optical communication can be provided so the photodiode is mounted directly to the port 134 in the reactor housing or more preferably a fiber optic cable 136 is mounted to the plasma chamber port and then to the photodiode so said photodiode can be located away from the plasma chamber and the electrical disturbances cause by the pulse electric discharges. The photodiode 138 provides a signal that is proportional to the light energy falling on its active surface. When the pulsed electric discharges occur, light is generated in the ionized plasma and the photodiode detects this light. The light signal from the photodiode occurs at the same frequency and pulse duration as the electric discharge as long as the discharge takes place. FIG. 4 is a schematic diagram of the NO generator. There are three main subsystems that make up the NO generator, the NO generator unit 150, the outlet filter assembly 178 and the NO applicator 184. The NO generator unit is where the NO is generated in controlled amounts and where it is delivered to the generator gas outlet port 176. The generator unit 150 has a main electronic control circuit 160 that interfaces to the main electrical components of the system and provides the main system control features. In one embodiment of the invention, this is a microprocessor based control circuit executing a stored program held in a non-transitory medium, but it is not intended to limit the invention only to microprocessor based control circuits, analog circuits could also be used. Attached to the electronic control circuit are the main user controls comprising of an input setting unit 152 a visual display unit 154, a visual alarm indicator 156 and an audible alarm sounder 158, these components are used to provide the desired settings to the main control, display any preprogrammed settings that may have been automatically set from the preprogrammed filter memory and provide audible and visual alarms when there are fault conditions. The main components in contact with the air flow though the device are the generator gas inlet 162 where the air is drawn into the unit, the inlet filter 164 which is used to filter the air and remove any unwanted contaminants, the air pump 166 is used to draw the air in from the gas inlet port 162 and to adjust the amount of air flow that is passed through the plasma chamber 101 under the control of the electronic control circuit 160. If the air pump 166 provides un-calibrated control of the gas flow, a gas flow meter 170 can be used to provide the electronic control circuit an accurate indication of the gas flow so the pump can be finely adjusted by the electronic control circuit 160 until the gas flow is at the desired set value. If the gas pump 166 provides oscillatory gas flow output as in the case of a piston pump then a damping chamber 168 can be provided to smooth out the oscillations. The gas flow then passes through the plasma chamber 101 where the electric control circuit 160 controls the frequency and duration of the electric discharges across the electrodes 112 and 120 such that NO is generated in the air passing through the chamber. The gas leaving the plasma chamber 101 passes through a second flow meter 172, which is used by the electronic control circuit to provide an independent check that the flow through the plasma chamber is correct. If there has been a failure in the gas pump 166 (indicated by a zero flow rate) or the first flow meter 170 or 172 (indicated by different readings between flow meter 170 and flow meter 172) such that the gas flow through the plasma chamber is not correct, then the electronic control circuit can initiate a visual and / or audible alarm to alert the user to the failure. To detect if there has been a failure in the electric discharge circuits there is the photodiode 138 and / or the electrode current and / or voltage sensing circuit 161 that are connected to the electronic control circuit 160, which can determine if the right frequency and pulse duration has been achieved. After the outlet gas flow meter 172 there is an optional pressure trigger sensor 174 connected to the gas flow conduit. This pressure trigger sensor 174 can be used by the electronic control circuit 160 to control the NO delivery as a bolus (when the pressure trigger sensor is activated) rather than as a known concentration in a continuous gas flow rate of air. The different modes of delivery will be described in more detail later in the specification. The gas flow continues past the pressure trigger sensor 174 to the gas outlet port 176, where it connects to the outlet filter assembly 178 and out through the NO applicator 184, where it is applied to the biological system 192.

[0097] The outlet filter assembly 178 has an inlet filter port 180, which connects to the gas outlet port of the NO generator unit 150, a chamber containing adulterant filter material 182, and an outlet port 186, which connects to the NO applicator 184. Adulterant filter materials include materials such as soda lime, activated charcoal, activated alumina and silica gel soaked in ascorbic acid. These materials and others known in the art to remove NO2 from gases containing NO while leaving the NO levels substantially unchanged may be used.

[0098] Such materials may have a fixed capacity for removing or converting NO2 before their effectiveness is diminished and they therefore require replacement after a period of use. The size of the filter and the amount of NO2 they are exposed to will impact the usage time before they need replacing. The filter assembly 78 in addition includes a readable programmable memory 190, which connects to the NO generator unit through a filter electrical connection 188. The other side of connector 188 connects to the electrical control circuit 60 where the readable programmable memory 190 can be read and reprogrammed by the electrical control circuit 160 as the filter is consumed. One embodiment of the readable programmable memory is an EEPROM, which has a serial interface for reading and programming the memory. An alternative embodiment is where each individual EEPROM (and hence filter assembly) has its own unique identifier included in a small amount of read only memory (ROM). An example of this type of memory is part number 24AA02E48T from Microchip Technology, this is a 2 KBIT EEPROM with each memory chip having its own MAC address permanently programmed into a small section of read only memory. This type of EEPROM with its unique identifier programmed into ROM means that no two filter assemblies will have the same identifier and the identifier will not be able to be updated during use as can occur with the data in the EEPROM memory. This can provide additional protection against reusing spent filters, as individual filter identifiers can be stored in the NO generator when they are used and then the generator will prevent filters with the same identifiers being used in the future for example, as might occur if the EEPROM usage data were improperly altered by a corrupted system. An alternative embodiment is where a microcontroller with embedded EEPROM and FLASH memory is used instead of just a serial memory device. This embodiment has the advantage that the reprogramming of the memory can be performed locally by the micro-controller and reduce the processing overhead of the electronic control circuit 160. An example of this type of micro-controller is the ATtiny25 / 45 / 85 fromAtmel.

[0099] Generally, the EEPROM may store usage information obtained from the electronic control circuit 160 that reveals the historical concentrations of NO being produced and thus the likely exhaustion rate of the filter 182. Thus, when the filter 182 is used for high NO concentrations and / or high flow rates this will be recorded and the user instructed to replace the filter more frequently than if the filter 182 is used for low NO concentration and / or low flow rate applications. This exhaustion information may be derived both from the concentration value determined by the electronic control 160 and the flow rates determined from flow sensors 172 and 170. The EEPROM may also include a proprietary code indicating that it is authorized equipment preventing spoofing of the apparatus with devices that may not provide the desired filtering. The proprietary code may, for example, use any number of techniques including public-key encryption techniques that prevent easy duplication of spurious codes.

[0100] FIG. 5 shows a schematic of the electric discharge drive circuit that is part of the electronic control circuit 160. This represents one embodiment of the drive circuit and people of ordinary skill in the art will appreciate there are other circuit possibilities that can achieve the same function. To establish the high voltage required to initially ionize the air between the electrodes 112 and 120, a capacitor discharge circuit 1116 discharges cunent through a transformer 1118 when triggered by a pulse trigger controller 1114. This results in a high voltage on the other side of the transformer 1118 which is sufficient to cause dielectric breakdown and ionize the gas and initiate current across the electrodes 112 and 120. The discharge pulse duration is maintained by a second circuit, which is powered by a high voltage DC power supply 1100. In the case that the instantaneous current draw is high, the DC pow er supply 1100 is buffered by a capacitor 1102 to smooth out any high current fluctuations. The DC voltage and current is controlled by the state of a transistor 1104 driven by a pulse duration control circuit 1112 which controls the pulse duration by controlling the amount of time the transistor is on. The drive circuit functions as follows, the electronic control circuit 160 calculates the desired electric discharge frequency and pulse duration that will generate the desired quantity of NO, it then triggers each discharge with the pulse trigger controller 1114 which causes a quick high voltage pulse from the transformer 1118, at the same time the electronic control circuit turns on the transistor 1104 for the desired pulse duration with the pulse duration control circuit 1112. The resulting pulse discharge voltage across the electrodes is the desired initial high voltage spike to ionize the gas between the electrodes followed by the desired lower voltage and current for maintaining the desired pulse duration. The actual voltage and current can be controlled by the electronic control circuit 1160 if the pulse duration control circuit 1112 works in a pulse width modulation (PWM) mode during the on phase of the pulse discharge. If this PWM mode is used it is desirable to use an inductor 1108 to smooth out the modulated current during the electric discharge pulse. The interface circuit 1110 j oins the two control circuits prior to applying the discharge voltage to the electrode. It is desirable that this interface circuit 1110 use high voltage diodes to prevent the high voltage spikes from the pulse transformer damaging the transistor 1104. The diode 1106 provides an additional mechanism that grounds any high voltage spike greater than its breakdown voltage or negative transients to prevent them from reaching the pulse duration control circuit 1112. It can be appreciated that this circuit provides a great deal of flexibility7in controlling not only the pulse frequency and the pulse duration but also the voltage and current levels during the pulse duration phase of the electric discharge. This allows the electronic control circuit to optimize the electric discharge frequency and pulse duration settings to maximize the effectiveness at generating the desired quantity7of NO while at the same time minimizing the electric discharge current and so reducing the gas temperature and the electrode wear.

[0101] FIG. 6A is a schematic diagram of the nitric oxide generator, showing the components of the system and their electrical and pneumatic connections, according to another embodiment of this invention. As depicted in the figure, an NO generator unit 151 can include the gas inlet port 162, the inlet filter 164, the air pump 166, a mass flow controller 171 (including a flow sensor 171a and a valve 171b), pressure sensors 163 and 165, the plasma chamber 101, a voltage controller 103, a current sensor 104, the gas outlet port 176, the electronic control circuit 160, the port lights 2a, 3a, 4a, the graphical user interface 7 / visual display unit 154, the light bar 7b / the visual alarm indicator 156, and the speakers 7c / the audible alarm sounder 158. The NO generator 151 operates as follows. First, the air pump 166 draws the air through the gas inlet port 162, which is then filtered by the inlet filter 164. The filtered air is then provided to the mass flow controller 171, which can be optionally positioned between the pressure sensors 163 and 165. According to an embodiment, the mass flow controller 171 can control the flow rate of air through the plasma chamber 101, and therefore, the flow rate of the generated NO gas through the gas outlet port 176. Further, by controlling the flow rate of the NO gas through the gas outlet port 176, the mass flow controller 171 can also control the resultant concentration of the NO gas that is output. As such, the flow rate provided by mass flow controller 171 can be used to determine and confirm the concentration of the NO gas that is output. This information can be used by the electronic control circuit 160 to determine whether or not (i) any of the port lights 2a, 3a, and 4a should be illuminated and which color, (ii) any alarm or other information should be displayed on the user interface 7 or the visual display unit 154, (iii) the light bar 7b or the visual alarm indicator 156 should be illuminated and with which color.

[0102] According to an embodiment, the pressure sensors 163 and 165 can be used to track the pressures upstream and dow nstream of the mass flow controller 171. For example, the pressure sensor 163 can be used in conjunction with the air pump 166 to maintain a certain pressure upstream of the mass flow controller 171, e.g., 20-30 pounds per square in gauge (psig). Further, the pressure sensor 165 can indicate (i) the pressure that the plasma chamber 101 is operating at and (ii) the type of applicator 184 being used, e.g., high pressure (high frequency ventilation), low' pressure (mechanical ventilation).

[0103] According to an embodiment, the NO generator unit 151 can also include a ballast (not shown) between the air pump 166 and the mass flow controller 171. In this regard, the ballast can be used to stabilize the pressure that the mass flow' controller 171 operates with, e.g., during peak flow' demand.

[0104] According to an embodiment, the current sensor 104 is configured to sense all or part of the generated plasma current from the plasma chamber 101 and then provide this sensed information to the electronic control circuit 160. Based on the sensed information, the electronic control circuit 160 can control the plasma chamber 101 via the voltage controller 103, thereby creating a feedback loop for the plasma chamber 101. According to an embodiment, the voltage controller 103 is an open-loop voltage controller. In this regard, the electronic control circuit 160 can control the voltage controller 103 such that plasma chamber 101 generates one or more electrical pulses in the plasma chamber, w ith the one or more electrical pulses forming a plasma current. The electronic control circuit 160 can then control the current sensor 104 such that it senses at least one peak of the one or more electrical pulses in the formed plasma current. Then, upon determining that the sensed at least one peak exceeds or falls below one or more predefined limits, the electronic control circuit 160 can generate one or more further electrical pulses that differ with the generated one or more electrical pulses in at least one of: (i) duty cycle, (ii) pulse duration, and (iii) generated electric charge. According to an embodiment, the predefined limits will depend upon a variety of factors including the concentration of the treatment, other drugs, compounds, gases or materials used in combination with the treatment, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical professional, e.g., physician, nurse, or respiratory therapist, having ordinary skill in the art may readily determine the limits. Further, the sensed information can also be used to determine the concentration of NO gas being generated by the plasma chamber 101. In this regard, the concentration of the NO gas can be determined based on the electric charge associated with the plasma current. The electronic control circuit 160 can use this information to determine whether or not (i) any of the port lights 2a, 3a, and 4a should be illuminated and which color, (ii) any alarm or other information should be displayed on the user interface 7 or the visual display unit 154, (iii) the light bar 7b or the visual alarm indicator 156 should be illuminated and with which color. For example, the electronic control circuit 160 can control the color that the port light 2a will be illuminated with based on the concentration of the NO gas information provided by the current sensor 104. In this regard, if the current sensor 104 indicates via the sensed charge that the plasma chamber 101 is generating NO gas at or around the set concentration, then the port light 2a can be illuminated at a first color. However, if the NO gas generated is at different concentration from the set concentration or if there is no NO gas being generated, then the port light 2a can be illuminated at a second or third color, respectively. Further, the user interface 7 or the visual display unit 154 can also use the sensed information to indicate the operational status or service life of the plasma chamber 101. As such, the sensed information can inform the user when it is time to replace the plasma chamber 101. In this regard, if the sensed plasma current information is below a threshold percentage (e.g., 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%) less than the expected current information for a particular concentration of NO gas, then that may indicate that there may be significant wear on the electrodes, indicating that they need to be repaired or replaced. According to an embodiment, the threshold percentage w ill depend upon a variety of factors including the concentration of the treatment, other drugs, compounds, gases or materials used in combination with the treatment, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical professional, e.g., physician, nurse, or respirator}' therapist, having ordinary skill in the art may readily determine the limits.

[0105] As depicted in FIG. 6B, the electronic control circuit 160 can include a first timer 1 0a for controlling the timing of the voltage controller 103 and a second timer 160b for controlling the timing of the current sensor 104. According to an embodiment, the first and second timers 160a and 160b can be operated at the same frequency but are slightly out of phase. In this regard, the first timer 160a can run slightly ahead of the second timer 160b. According to an embodiment, the first and second timers 160a and 160b can be implemented as either software or hardware modules in the electronic control circuit 1 0.

[0106] FIG. 6C depicts the interaction between the electronic control circuit 160, the voltage controller 103, the current sensor 104. and the plasma chamber 101 in additional detail. According to an embodiment, the current sensor 104 can comprise a differential amplifier 104a and an analog-to-digital converter (ADC) 104b. In this regard, the differential amplifier 104a can be connected across a resistor that is in series with the plasma chamber 101, and the ADC 104b can provide the sensed information to the electronic control circuit 160.

[0107] According to an embodiment, the voltage controller 103 can be one of a metal-oxide- semiconductor field-effect transistor (MOSFET), triode for alternating current (TRIAC), etc. In this regard, if a DC current is used, then the voltage controller 103 can be a MOSFET. However, if an AC current is used, then the voltage controller 103 can be a TRIAC.

[0108] FIG. 6D depicts the timing diagrams for the voltage controller and the current sensor. In this regard, the timing signal provided by the first timer 160a is represented by the ANODE signal, while the timing signal provided by the second timer 160b is represented by current sense signal.

[0109] The ANODE signal is based on a number of parameters, such as the spark period (or Tsprk), the trigger delay (Dtrig), the trigger signal, the injection delay (Dinj), the injection sequence window, and the injection signal, which will be described in further detail below. The spark period refers to that period of time that a plasma current may be activated and maintained. In an embodiment, the spark period ranges from .01 to 2.000 ms, preferably 1 to 1000 ms, preferably 10 to 100 ms. The spark period can repeat at a particular frequency, fsprk. In an embodiment, the spark frequency ranges from .5 to 100 Hz. The trigger delay refers to the period of time before the start of the high voltage trigger. The trigger delay ranges from 1 to 10 ps, preferably 1 to 5 ps. preferably 2 ps. The trigger signal corresponds to the high voltage trigger, e.g., up to 20 kV, and is active for a period of time, Wtrig, sufficient enough to ionize the gases between the electrodes and to allow electric current to flow in the electrode gap. According to an embodiment, the high voltage trigger ranges from the breakdown voltage - approximately 11 kV - to 20 kV. In an embodiment, the trigger signal ranges from 1 to 10 ps, preferably 1 to 5 ps, preferably 4 ps. The injection delay refers to the period of time from the end of the trigger signal to the start of the low voltage current injection sequence used to maintain the current across the electrodes. In an embodiment, the injection delay ranges from 5 to 15 ps, preferably 10 ps. The injection sequence window refers to the period of time, Winj, that the low voltage current injection sequence is active. In an embodiment, the injection sequence window ranges from 10 ps to 100 ms. The injection signal corresponds to the low voltage current injection sequence, e.g., up to 1 kV pulses. The injection signal is a PWM signal, in which the period, Tmj, frequency, fmj, and duty cycle, DuCyinj, are adjustable. In an embodiment, the injection signal period ranges from 1 to 10 ps, while the injection signal frequency ranges 100 to 1000 kHz. Further, the injection signal duty cycle can be set a predefined value, e.g., 50 %. In this regard, the individual pulses of the inj ection signal can all be the same width. In another embodiment, one or more of the individual pulses can be of variable width - this allows for adjustments in response to transient plasma behavior immediately after the trigger signal. For example, a plurality of pulses can start with a higher duty cycle and then decrease each successive pulse. In another embodiment, each of the individual duty cycles can be dynamically adjusted to maintain a fixed plasma current through adjustable voltage control.

[0110] According to an embodiment, any of the above parameters can be modified at any time, where the modified parameters are reflected in the next spark period. In an embodiment, the modified parameters can be introduced at least 1 ms before the next spark period, e.g., via an interrupt signal. Further, any parameter modifications can also trigger an interrupt signal to check if the current spark period needs to be extended or truncated so that the new spark period can be immediately implemented. This allows for a real-time response to changing flow rates during administration to a patient. For example, the current spark period can be modified based on whether the patient is in an inspiratory or expiratory' phase of their breathing. In this regard, the current spark period can be extended during the inspiratory phase and truncated during the expiratory phase. As such, the NO is generated only when it’s needed. According to an embodiment, the breathing phases can be detected with a breathing flow sensor, e.g., NDM flow sensor or flow sensor 187c (described in more detail below).

[0111] The current sense signal is timed to measure one or more of the individual pulses of the ANODE signal. In an embodiment, the current sense signal can operate at the same frequency as the injection signal. Further, the pulses of current sense signal can all include the same duty cycle. In this regard, the duty cycle of the current sense signal is of a shorter width than the duty cycles of the ANODE signal. Further, the current sense signal is timed such that a falling edge of the current sense signal overlaps with a rising edge of the ANODE signal, thereby allowing a measurement of the peak current of each or a portion of the individual pulses of the ANODE signal. In some embodiments, the peak current of each pulse is sampled. In other embodiments, the peak current of every second, third, fourth, fifth, sixth, seventh, eighth, ninth, or tenth pulse is sampled. In an embodiment, measurement of the ANODE signal can begin with the second pulse of the ANODE signal.

[0112] According to an embodiment, the average of the sampled pulses for a particular injection sequence window can be used in determining whether or not the above parameters should be modified for the next spark period. In this regard, the average current value can be used to perform an automatic duty cycle calibration to adjust the duty' cycle parameter for a desired plasma current. For example, the average current value can be used to adjust the first 16 variable length duty cycle values at the start of the injection sequence to more quickly settle the plasma to the desired injection current. According to another embodiment, the average current value can also be used to determine the total charge for a particular injection sequence window, where the total charge is calculated as the average current value multiplied by the time period of the injection sequence window.

[0113] According to an embodiment, any modifications to the ANODE signal can result in proportional modifications to the current sense signal. For example, any changes to the ANODE signal’s duty cycle(s) may result in proportional changes, by the electronic control circuit 160, to the duty cycle(s) in the current sense signal.

[0114] FIG. 6E depicts portions of the timing diagrams for the voltage controller and the current sensor in relation to the generated plasma current, according to an embodiment of this invention. Specifically, the figure depicts oscilloscope readings for (i) the injection signal portion of the ANODE signal, i.e., signal 1600a, which is running at 800 kHz(ii) the corresponding portion of the current sense signal, i.e., signal 1600b, and (iii) the generated plasma current signal 1600 resulting from the injection signal. As depicted in the figure, the current sense signal 1600b is timed so that it’s falling edge coincides with at least one peak of the generated plasma current 1600, thereby allowing the current sensor 104 to sense / measure the at least one peak of the generated plasma current 1600. In this regard, as further depicted in the figure, the cunent sense signal 1600b with a fundamental frequency of 400 khz is timed so that the current sensor 104 senses / measures every other peak of the generated plasma current 1600.

[0115] FIG. 7A is a schematic diagram of a nitric oxide generation system, including two nitric oxide generators, according to an embodiment of this invention. As depicted in the figure, a nitric oxide generation system 301 includes a first subsystem for generating NO 310, a second subsystem for generating NO 320, an electronic control circuit 160, the port lights 2a, 3a, 4a, the graphical user interface 7 / visual display unit 154, the light bar 7b / the visual alarm indicator 156, the speakers 7c / the audible alarm sounder 158, valve 275, gas outlet ports 176 and 276, bagging gas inlet port 277, the filter 178, NO delivery module (NDM) 187, breathing apparatus 189 (e.g., mechanical ventilator, high frequency ventilator, high flow nasal cannula), gas sample line 193, and gas sampling system 400. According to an embodiment, the solid lines between the components represent pneumatic connections, while the dashed lines represent electrical connections.

[0116] According to an embodiment, the first subsystem 310 can include the gas inlet port 162, the inlet filter 164, the air pump 166, a mass flow controller 171 (including a flow sensor 171a and a valve 171b), the pressure sensors 163 and 165, the plasma chamber 101, the voltage controller 103, and the current sensor 104. According to another embodiment, the first subsystem 310 can also include a ballast (not shown) between the air pump 166 and the mass flow controller 171.

[0117] According to an embodiment, the second subsystem 320 can include the gas inlet port 262, the inlet filter 264, the air pump 266, a flow sensor 171 , the plasma chamber 201 , the voltage controller 203, and the current sensor 204. The current sensor 204 is configured to sense all or part of the generated plasma current from the plasma chamber 201 and then provide this sensed information to the electronic control circuit 160. Based on the sensed information, the electronic control circuit 160 can control the plasma chamber 201 via the voltage controller 203, thereby creating a feedback loop for the plasma chamber 201. According to an embodiment, the sensed information can also be used to determine the concentration of NO gas being generated by the plasma chamber 201. In this regard, the concentration of the NO gas can be determined based on the electric charge associated with the plasma current. The electronic control circuit 160 can use this information to determine whether or not (i) any of the port lights 2a, 3a, and 4a should be illuminated and which color, (ii) any alarm or other information should be displayed on the user interface 7 or the visual display unit 154. (iii) the light bar 7b or the visual alarm indicator 156 should be illuminated and with which color. For example, the electronic control circuit 160 can control the color that the port light 3a will be illuminated with based on the concentration of the NO gas information provided by the cunent sensor 204. In this regard, if the current sensor 204 indicates via the sensed charge that the plasma chamber 201 is generating NO gas at or around the set concentration, then the port light 3a can be illuminated with a first color. However, if the NO gas generated is at different concentration from the set concentration or if there is no NO gas being generated, then the port light 3a can be illuminated with a second or third color, respectively.

[0118] According to an embodiment, the timing of the voltage controller 203 can be controlled by the first timer 160a, while the timing of the current sensor 204 can be controlled by the second timer 160b.

[0119] According to an embodiment, the valve 275 can be a three-way valve. In this regard, the valve 275 can be used to direct generated NO gas from either one of the first subsystem 310 or the second subsystem 320 to either the gas outlet port 176 or the gas outlet port 276. As such, the valve 275 can be used to switch between four distinct gas delivery modes: (1) main NO delivery mode; (2) bagging NO delivery mode; (3) main NO and bagging delivery mode; and (4) backup NO deliver}' mode.

[0120] According to an embodiment, during the main NO delivery mode, the valve 275 is closed and only the first subsystem 310 is active. As such, the NO gas generated by the first subsy stem 310 is provided to the gas outlet port 176 to treat patient 192.

[0121] According to an embodiment, during the bagging NO delivery mode, the valve 275 is configured such that it only receives NO gas generated by the second subsystem 320 and an air / oxygen source via the bagging gas inlet port 277. The valve 275 then provides the gas mixture of the NO and air / oxygen to the gas outlet port 276, which can be connected to a manual resuscitator, e.g.. ambulator)’ bag.

[0122] According to an embodiment, during the main NO and bagging delivery mode, the valve 275 is configured such that (i) NO gas generated by the first subsystem 310 is provided to the gas outlet port 176 and (ii) the gas mixture of the NO gas generated by the second subsystem 320 and the air / oxygen from the bagging gas inlet port 277 to the gas outlet port 276.

[0123] Lastly, during the backup NO delivery mode, the valve 275 is configured such that it only receives NO gas generated by the second subsystem 320 and provides it to the gas outlet port 176. According to an embodiment, backup NO delivery' mode can be triggered automatically’. In this regard, backup NO delivery mode can be triggered upon detection of a disruption with the first subsystem 310. The disruption can be a complete or partial cessation of NO gas generation by the plasma chamber 101. The disruption can also be a result of an overgeneration of NO gas by the plasma chamber 101. The disruption can also be based on the electric charge associated with the plasma current. According to an embodiment, the NO gas generated by the second subsystem 310 can be based on an air flow rate associated with the mass flow controller 171. In this regard, the air flow rate can be a historical average air flow rate data that is calculated based on historical flow rate data tracked over a certain time period, e.g., from 1 second to 5 minutes. According to an embodiment, the NO gas generated by the second subsystem 310 can be provided at either a fixed or variable concentration.

[0124] According to an embodiment, the first subsystem 310 and the second subsystem 320 can use one or more of the same components during one or more of the above gas delivery modes. For example, instead of separate gas inlet ports 162 and 262, only one gas inlet port can be used.

[0125] According to an embodiment, NO gas output via the gas outlet port 176 is filtered through the filter 178 and then provided to the NDM 187. The NDM 187 is connected to (i) the inspiratory limb of a patient wye for a patient 192 and (ii) the breathing apparatus 189, which is also connected to the expiratory limb of the patient wye, thereby creating a breathing circuit for the patient 192.

[0126] According to an embodiment, the gas sample line 193 can also be connected to the inspiratory limb of the patient wye in order to provide the combined gas to the gas sampling system 400 for the measurement NO, NO2, and O2 in the combined gas just prior to inhalation by the patient. The gas sampling system 400 can then provide this measurement information to electronic control circuit 160 so that it can then be displayed on the graphical user interface 7 / visual display unit 154.

[0127] FIG. 7B is a schematic diagram of the NDM depicted in FIG. 7 A. according to an embodiment of this invention. As depicted in the figure, the NDM 187 includes an NO gas inlet port 187a, a breathing gas inlet port 187b, a flow sensor 187c, and a combined gas outlet port 187d. According to an embodiment, the NO gas inlet port 187a is configured to receive the filtered NO gas from the filter 178; the breathing gas inlet port 187b is configured to receive breathing gas from the breathing apparatus 189; the flow sensor 187c is configured to sense the breathing gas flow rate from the breathing apparatus 189; and the combined gas outlet port 187d is configured to provide a combined flow of breathing gas and NO to the patient 192. According to an embodiment, the flow rate can be sampled every 1 ms to 1000 ms. For example, the flow rate can be sampled every 2 ms. According to an embodiment, the flow sensor 187c can transmit the sensed breathing gas flow rate data to the electronic control circuit 160. The sensed breathing flow rate data can then be used by the electronic control circuit 160 to determine whether or not (i) any of the port lights 2a. 3a, and 4a should be illuminated and which color, (ii) any alarm or other information should be displayed on the user interface 7 or the visual display unit 154, (iii) the light bar 7b or the visual alarm indicator 156 should be illuminated and with which color. For example, the information can indicate if there is a failure with the flow sensor 187c and, therefore, require that the system 301 operate in backup NO delivery mode.

[0128] According to an embodiment, the sensed breathing gas flow rate data can also be used to optimize the spark frequency during constant (steady) and variable (unsteady) flow states. In this regard, the electronic control circuit 160 can determine the flow state based on the flow rate of change detected by the flow sensor 187c. For example, a zero flow rate change indicates a constant flow state, while a nonzero flow rate change indicates a variable flow state.

[0129] Under constant flow states (e.g., ventilation via a high flow nasal cannula, spontaneous breathing patient utilizing a continuous positive airway pressure device), the spark frequency can be modified depending on the flow rate detected by the flow sensor 187c. In this regard, a lower flow rate can correspond to a lower spark frequency, while a higher flow rate can correspond to a higher spark frequency, thereby reducing the wear on the plasma chamber 101 components during lower flow rate applications. According to an embodiment, if the flow rate is up to a first predefined value, the spark frequency can be maintained at a first frequency. If the flow' rate is between the first predefined value and a second predefined value, the spark frequency can be maintained at a second frequency. Similarly, if the flow rate is at or above the second predefined value, the spark frequency can be maintained at a third frequency. According to an embodiment, the first and second predefined values will depend upon a variety of factors including the concentration of the treatment, other drugs, compounds, gases or materials used in combination with the treatment, the age, sex, w eight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical professional, e.g., physician, nurse, or respiratory therapist, having ordinary skill in the art may readily determine the limits. In this regard, the first and second predefined values are values between 1 and 100 LPM, while the first, second, and third frequency are values betw een .5 to 100 Hz. For example, the first and second predefined values can be 30 LPM and 40 LPM, respectively, while the first, second, and third frequencies can be 10 Hz, 20 Hz, and 30 Hz. respectively. As such, (i) if the flow volume is up to 30 LPM, the spark frequency will be set to 10 Hz, (ii) if the flow volume is between 30 LPM and 40 LPM, the spark frequency will be set to 20 Hz, and (iii) if the flow volume is at or above 40 LPM, the spark frequency will be set to 30 Hz.

[0130] During certain constant flow applications involving high frequency ventilation (e.g., high frequency jet ventilation), flow pulses can reach several hundred per minute, with peak flow reaching 20 LPM over a duration of less than .05 milliseconds resulting in an average flow rate of less than 3 LPM. However, maintaining constant or near constant flow has proved to be quite challenging in such high frequency ventilation applications. According to an embodiment, the sensed breathing gas flow rate data can also be used to control the flow to constant or near constant. Specifically, the breathing gas flow rate data can be used in conjunction with pressure data from the pressure sensor 165 to determine (i) if the average flow rate data over a certain period of time is less than a predefined flow rate amount and (ii) if a high frequency application is resulting in a plasma chamber pressure exceeding a predefined pressure amount, and, assuming both conditions are true, the electronic control circuit 160 will control the flow of the delivered NO such that it is maintained at a rolling average of the flow rate data over the certain period of time. According to an embodiment, the predefined flow rate and pressure amounts will depend upon a variety of factors including the concentration of the treatment, other drugs, compounds, gases or materials used in combination with the treatment, the age. sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well, known in the medical arts. A medical professional, e g., physician, nurse, or respiratory therapist, having ordinary skill in the art may readily determine the limits. For example, the predefined flow rate can be .5 LPM to 4 LPM, e.g., 3 LPM, the certain period of time can be 1 to 10 seconds (e g., 10 seconds), and the predefined pressure amount can be 0. 1 to 10 psig (e.g., .9 psig). In this regard, (i) if the average flow rate over, for example, a 10 second period is less than, for example, 3 LPM and (ii) the detected plasma chamber pressure is greater than, for example, .9 psig, the flow7of the delivered NO will be controlled such that it is maintained at a rolling average of the flow rate over a 10 second period. Further, because the detected flow rate is less than 30 LPM, the spark frequency will be maintained at a lower frequency, e.g., 10 Hz, thereby reducing the w ear on the plasma chamber 101 components during these high frequency applications.

[0131] Under variable flow states, such as during mechanical ventilation, the spark frequency can be modified depending on the phase of the mechanical ventilation breath cycle, where the spark frequency can be higher during the inspiratory phase, which comprises 1 / 3 of the breath cycle, and lower during the expiratory phase, which comprises 2 / 3 of the breath cycle, thereby reducing the wear on the plasma chamber 101 components during each expiratory phase of the mechanical ventilation breath cycle. In this regard, the higher spark frequency can be set after a rising edge of the inspirator}' phase is detected, while the lower spark frequency can be set after a falling edge of the inspiratory phase is detected. According to an embodiment, the rising and falling edges of the inspiratory phases can be determined based on the flow rate of change detected by the flow sensor 187c. Specifically, the rising edge can be inferred from a positive flow rate change exceeding a predefined rate, while the falling edge can be inferred from a negative flow rate change exceeding a similar rate. For example, the predefined flow rate of change can be . 1 to 4 LPM / second. In this regard, (i) if the detected flow rate of change exceeds, for example, 4 LPM / second, the spark frequency will be set to a higher frequency, e.g., 30 Hz, and (ii) if the detected flow rate of change exceeds, for example, negative (-) 4 LPM / second, the spark frequency will be set to a lower frequency, e.g., 10 Hz. According to an embodiment, this detection of rising and falling edges minimizes NO generation error arising from fixed frequency trigger spark periods by enabling the controller to reset the tngger spark period in real time, thereby minimizing overshoot and undershoot.

[0132] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

THE CLAIMS1 . A nitric oxide gas delivery system, the system comprising: a first nitric oxide (NO) gas generator, wherein the first NO gas generator includes a plasma chamber enclosing two electrodes separated by a gap; a plurality’ of port lights surrounding a plurality of corresponding gas outlet ports, wherein each of the port lights are configured to display a color; and an electronic control circuit, wherein the electronic control circuit is configured to enable the plurality of port lights to display the color based on a status of a plasma current across the two electrodes.

2. The system of claim 1, wherein the plurality of port lights are illuminated upon activation of the corresponding gas ports.

3. The system of claim 1, wherein the color displayed by the port lights indicates whether a set concentration of NO gas is being delivered through the corresponding gas port.

4. The system of claim 3, wherein the plurality' of port lights are configured to: (i) display a first color if the NO gas is being delivered through the corresponding gas port at the set concentration, (ii) display a second color if the NO gas is being delivered through the corresponding gas port at a concentration different from the set concentration, and (iii) display a third color if the NO gas is not being delivered through the corresponding gas port at all.

5. The system of claim 1, wherein the gas outlet is selected from a NO delivery outlet or a manual resuscitation bagging outlet.

6. The system of claim 5, wherein the gas outlet is the manual resuscitation bagging outlet.

7. The system of claim 1, wherein the status of the plasma current is determined by a current sensor.

8. The system of claim 1, wherein the status of the plasma current indicates a concentration of the NO gas being delivered through the corresponding gas port.

9. The system of claim 8, wherein the concentration of the NO gas is determined based on an electric charge associated with the plasma current.

10. The system of claims 1, further comprising a second NO gas generator.

11. The system of claim 10, wherein the first and second NO gas generators are operated simultaneously.

12. The system of claim 10, wherein only one of the first and second NO gas generators is operated at a time.

13. The system of claim 12, wherein one of the plurality of port lights displays a first color during the operation of the first NO gas generator and displays a second color during the operation of the second NO gas generator.

14. An apparatus for generating nitric oxide gas, the apparatus comprising: a plasma chamber enclosing two electrodes separated by a gap; a gas inlet port for introducing a flow of reactant gas comprising oxygen and nitrogen into the plasma chamber; an electronic control circuit configured to: generate one or more electrical pulses across the two electrodes to produce a product gas comprising a desired concentration of nitric oxide, wherein the one or more electrical pulses form a plasma current; sense at least one peak of the one or more electrical pulses in the formed plasma current: and upon determining that the sensed at least one peak exceeds or falls below one or more predefined limits, generate one or more further electrical pulses that differ with the generated one or more electrical pulses in at least one of: (i) duty cycle, (ii) pulse duration, and (iii) generated electric charge; and a gas outlet port for delivering the product gas comprising nitric oxide for use thereof.

15. The apparatus of claim 14, further comprising: a voltage controller in communication with the electronic control circuit to generate the one or more electrical pulses and the one or more further electrical pulses.

16. The apparatus of claim 15, wherein the voltage controller is one of a metal-oxide- semiconductor field-effect transistor (MOSFET) and triode for alternating current (TRIAC).

17. The apparatus of claim 15, further comprising: a current sensor in communication with the electronic control circuit to sense the at least one peak of the one or more electrical pulses in the formed plasma current.

18. The apparatus of claim 17, wherein the current sensor comprises a differential amplifier and an analog-to-digital converter (ADC).

19. The apparatus of claim 18, wherein the differential amplifier is connected across a resistor is series with the plasma chamber.

20. The apparatus of claim 17, wherein the electronic control circuit includes first and second timers, wherein the first timer controls the timing for the voltage controller based on a first timing signal and the second timer controls the timing for the current sensor based on a second timing signal.

21. The apparatus of claim 20, wherein the first and second timers run at the same frequency.

22. The apparatus of claim 20, wherein the duty cycle of the second timing signal is of a shorter width than the duty cycle of the first timing signal.

23. The apparatus of claim 20, wherein modifications to the first timing signal results in proportional modifications to the second timing signal.

24. A method for generating nitric oxide gas, the method comprising: receiving a flow of reactant gas comprising oxygen and nitrogen into a reaction chamber enclosing two electrodes separated by a gap;generating one or more electrical pulses across the two electrodes to produce a product gas comprising a desired concentration of nitric oxide, wherein the one or more electrical pulses form a plasma current; sensing at least one peak of the one or more electrical pulses in the formed plasma current; and upon determining that the sensed at least one peak exceeds or falls below one or more predefined limits, generating one or more further electrical pulses that differ with the generated one or more electrical pulses in at least one of: (i) duty cycle, (ii) pulse duration, and (iii) generated electric charge.

25. The method of claim 24, wherein the one or more electrical pulses and the one or more further electrical pulses are generated based on a first timing signal.

26. The method of claim 25, wherein the at least one peak of the one or more electrical pulses are sensed based on a second timing signal.

27. The method of claim 26, wherein the first timing signal is at the same frequency as the second timing signal.

28. The method of claim 26. wherein the duty cycle of the second timing signal is of a shorter width than the duty cycle of the first timing signal.

29. A nitric oxide gas delivery system, the system comprising: at least one nitric oxide (NO) gas generator, wherein the NO gas generator includes a plasma chamber enclosing two electrodes separated by a gap; at least one gas outlet port for delivering the NO gas generated by the at least one NO gas generator; an NO delivery module in fluid communication with the at least gas outlet port, wherein the NO delivery module comprises a breathing gas flow sensor configured to detect a breathing gas flow rate; an electronic control circuit configured to modify a spark frequency between the two electrodes based on the detected breathing gas flow rate.

30. The system of claim 29, wherein the electronic control circuit is configured to: (i) increase the spark frequency if the detected breathing gas flow rate exceeds a predefined value and (ii) decrease the spark frequency if the detected breathing gas flow rate falls below the predefined value.

31. The system of claim 29, wherein the electronic control circuit is configured to: (i) increase the spark frequency if a detected breathing gas flow rate of change exceeds a positive predefined threshold and (ii) decrease the spark frequency if a detected breathing gas flow rate of change exceeds a negative predefined threshold.

32. The system of claim 29, further comprising: a pressure sensor configured to detect a pressure at the plasma chamber.

33. The system of claim 32, wherein, upon determining that (i) an average breathing gas flow rate over a period of time is less than a predefined flow rate amount and (ii) the detected pressure at the plasma chamber exceeds a predefined pressure amount, the electronic control circuit is further configured to control the flow rate of the generated NO such that it is maintained at an average of the flow rate over the period of time.

34. The system of claim 29, wherein the electronic control circuit is further configured to determine a flow state of the generated NO based on a detected breathing gas flow rate of change.

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