Abstract:
In one aspect, a system for delivering nitric oxide to a patient can include a first gas source including nitrogen dioxide mixed in air or oxygen, a second gas source supplying compressed air, a ventilator coupled to the first and second gas sources, where the ventilator can be resistant to nitrogen dioxide, and where the ventilator provides a gas flow having a proper amount of nitrogen dioxide, one or more conversion devices operably coupled to the ventilator, where the conversion devices covert nitrogen dioxide into nitric oxide, and a patient interface operably coupled to the conversion devices, where the patient interface delivers nitric oxide to the patient.

Description:
CLAIM OF PRIORITY 
     This application claims the benefit of prior U.S. Provisional Application No. 61/090,616, filed on Aug. 21, 2008, which is incorporated by reference in its entirety. 
    
    
     TECHNICAL FIELD 
     This description relates to systems for generating nitric oxide. 
     BACKGROUND 
     Nitric oxide (NO), also known as nitrosyl radical, is a free radical that is an important signaling molecule. For example, NO causes smooth muscles in blood vessels to relax, thereby resulting in vasodilation and increased blood flow through the blood vessel. These effects are limited to small biological regions since NO is highly reactive with a lifetime of a few seconds and is quickly metabolized in the body. 
     Typically, NO gas is supplied in a bottled gaseous form diluted in nitrogen gas (N 2 ). Great care has to be taken to prevent the presence of even trace amounts of oxygen (O 2 ) in the tank of NO gas because NO, in the presence of O 2 , is oxidized into nitrogen dioxide (NO 2 ). Unlike NO, the part per million levels of NO 2  gas is highly toxic if inhaled and can form nitric and nitrous acid in the lungs. 
     SUMMARY 
     Briefly, and in general terms, various systems generating nitric oxide are disclosed herein. According to one embodiment, the system includes a first gas source providing nitrogen dioxide mixed in air or oxygen, and a second gas source supplying compressed air and/or compressed oxygen. The system also includes a ventilator coupled to the first and second gas sources, wherein the ventilator is resistant to nitrogen dioxide. The ventilator regulates gas flow and allows for the adjustment of nitrogen dioxide concentration in the gas flow. The system further includes one or more conversion devices operably coupled to the ventilator where the conversion devices convert nitrogen dioxide into nitric oxide. A patient interface delivers nitric oxide to the patient and is operably coupled to the conversion devices. 
     In another embodiment, the system includes a humidifier that is placed prior to the first conversion device. In yet another embodiment, the humidifier is integral with the conversion device. Optionally, the system includes an active humidifier that is placed prior to a second conversion cartridge which is adjacent to the patient interface. 
     The system allows oxygen and nitric oxide levels to be varied independently. The system also includes safeguards in the event of system failure. In one embodiment, the main conversion cartridge in the system is designed to have sufficient capacity to convert the entire contents of more than one bottle of nitrogen dioxide in the event of system failure. In another embodiment, a second conversion cartridge is also included as a redundant safety measure where the second conversion cartridge is able to convert the entire contents of a bottle of nitrogen dioxide into nitric oxide. 
     Other features will become apparent from the following detailed description, taken in conjunction with the accompanying drawings, which illustrate by way of example, the features of the various embodiments. 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         FIG. 1  is a schematic view of one embodiment of a nitric oxide (NO) generating system. 
         FIG. 2  is a block diagram of one embodiment of a NO generating system. 
         FIG. 3  is a perspective view of one embodiment of a system for delivering NO to a patient. 
         FIG. 4  is a cross-sectional view of one embodiment of a NO generating device. 
         FIG. 5  is a block diagram of another embodiment of a NO generating device. 
     
    
    
     DETAILED DESCRIPTION 
     Various systems and devices for generating nitric oxide (NO) are disclosed herein. Generally, NO is inhaled or otherwise delivered to a patient&#39;s lungs. Since NO is inhaled, much higher local doses can be achieved without concomitant vasodilation of the other blood vessels in the body. Accordingly, NO gas having a concentration of approximately 2 to approximately 1000 ppm (e.g., greater than 2, 20, 40, 80, 100, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1200, 1400, 1600, 1800 and 2000 ppm) may be delivered to a patient. Accordingly, high doses of NO may be used to prevent, reverse, or limit the progression of disorders which can include, but are not limited to, acute pulmonary vasoconstriction, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, post cardiac surgery acute pulmonary hypertension, persistent pulmonary hypertension of a newborn, perinatal aspiration syndrome, haline membrane disease, acute pulmonary thromboembolism, heparin-protamine reactions, sepsis, asthma, status asthmaticus, or hypoxia. NO can also be used to treat chronic pulmonary hypertension, bronchopulmonary dysplasia, chronic pulmonary thromboembolism, idiopathic pulmonary hypertension, primary pulmonary hypertension, or chronic hypoxia. 
     Currently, approved devices and methods for delivering inhaled NO gas require complex and heavy equipment, and they are limited in their output to 80 ppm of NO because of the presence of the toxic compound, nitrogen dioxide (NO 2 ). NO gas is stored in heavy gas bottles with nitrogen and no traces of oxygen. NO gas is mixed with air or oxygen with specialized injectors and complex ventilators, and the mixing process is monitored with equipment having sensitive microprocessors and electronics. All this equipment is required in order to ensure that NO is not oxidized into NO 2  during the mixing process since NO 2  is highly toxic. However, this equipment is not conducive to use in routine hospital and non-medical facility settings since the size, cost, complexity, and safety issues restrict the operation of this equipment to highly-trained professionals who are specially trained in its use. 
       FIGS. 1-2  illustrate one embodiment of a system  100  that generates NO from NO 2 . The system  100  may be used in a medical setting such as, but not limited to, an operating theatre or an intensive care unit. The system  100  includes a gas source  102  containing NO 2  premixed in air  106  or oxygen  108 . As shown in  FIG. 1 , the system  100  includes two gas sources  102  where one bottle is a standby in the event the first bottle becomes depleted. Alternatively, the system  100  may include a single gas source capable of producing NO. In another embodiment, the system  100  may include a plurality of gas sources capable of producing NO. Optionally, if more than one gas source is provided with the system  100 , a valve (not shown) is coupled to the gas sources and allows for switching between the gas sources. 
     The system  100  includes a ventilator  104  connected to the gas sources  102  capable of producing NO in addition to a gas source of compressed air  106  and oxygen  108 , as shown in  FIG. 1 . The ventilator  104  also includes components such as mixing valves  117 ,  118  that are resistant to NO 2  gas. In one embodiment, the mixing valves  117 ,  118  used in the ventilator  102  are manufactured by Bio-Med Devices of Guilford, Conn. The ventilator  104  is also provided with controls to independently vary the concentration of NO 2  and oxygen  108 . Accordingly, the mixing valves  117 ,  118  and the ventilator  104  regulate and adjust the concentration of the gas so that it is at a proper concentration to be converted into a therapeutic dose of NO at the main conversion cartridge  110 . Additionally, the ventilator  104  can be adjusted to provide the proper gas flow pattern. 
     As shown in  FIGS. 1-2 , the gas passes through the main conversion cartridge  110  where NO 2  in the gas flow is converted to NO. In one embodiment, a passive humidifier (not shown) is positioned to the main cartridge  110 . The passive humidifier operates at a dew point of approximately less than 18° C. (not shown) that may be separate or integral with the main cartridge  110 . The NO gas generated by the main conversion cartridge  110  then flows through an active humidifier  114 , which provides moisture to the patient and also extends the lifespan of the conversion cartridge  112 . The humidified NO gas then filters through a secondary cartridge  112  (also referred to as a recuperator) to convert any NO 2  in the gas lines into NO. The NO gas (in air or oxygen) is then delivered to a patient via a patient interface  116 . The patient interface  116  may be a mouth piece, nasal cannula, face mask, or fully-sealed face mask. The active humidifier brings the moisture content of the NO gas (and air/oxygen) up to a dew point of approximately 32 to 37° C., thereby preventing moisture loss from the lungs. 
     As shown in  FIGS. 1-2 , a single humidifier  114  is positioned between the conversion cartridges  110 ,  112 . In another embodiment, the system  100  may include humidifiers  114  placed prior to each conversion cartridge  110 ,  112 . As shown in  FIGS. 1-2 , the humidifier  114  is a separate device, but it is contemplated that the humidifier may be an integral component of each conversion cartridge (not shown). According to one embodiment, the humidifier  114  used in the system  100  is manufactured by Fisher and Pykell. 
     Additionally, the system  100  may include one or more safety features. In one embodiment, the main conversion cartridge  110  is sized so that it has excess capacity to convert NO 2  into NO. For example, the main conversion cartridge  110  is sized to convert the entire contents of more than one gas source  102  of NO 2  gas. If the main conversion cartridge  110  were to fail, the recuperator cartridge  112  has sufficient capacity to convert the entire contents of a gas bottle  102 . In yet another embodiment, NO 2  and the NO gas concentrations may be monitored after the main conversion cartridge  110 . In one embodiment, the gas concentrations of NO and NO 2  may be monitored by one or more NO and NO 2  detectors manufactured by Cardinal Healthcare, Viasys Division. If any NO 2  is detected, visual and/or auditory alarms would be presented to the operator. The alarms will allow the operator to correct the problem, but the recuperator cartridge  112  would convert any NO 2  that was present in the gas lines back into NO. This function is important at very high NO levels (&gt;40 ppm) as well as during start up of the system  100 . Additionally, the recuperator cartridge  112  makes it unnecessary to flush the lines to remove NO 2 , since the NO 2  in the lines would be converted to NO by the recuperator prior to delivery to a patient. 
       FIG. 3  illustrates another embodiment of a system  300  for delivering NO to a patient. The system  300  is provided on a wheeled stand  302 . The system  300  includes a ventilator  104  that is resistant to NO 2  gas. The system  300  also includes two gas sources  102  for providing NO 2  gas. Additionally, a third gas source  306  is also mounted in the center of the stand  302 . The third gas source  306  contains NO 2  in air or oxygen at an appropriate concentration. The third gas source  306  is also connected to the ventilator  104  by gas plumbing  304  and is in a standby mode. In the event of a disruption of the NO 2  gas, compressed air, or compressed oxygen, an automatic series of valves would shut down the feed of gas to the ventilator  104  and replace it with gas from the back up gas source  306 . This safety feature is on standby mode and may be implemented within the time frame of a single breath. If the ventilator  104  malfunctions, the third gas source  306  is available as substitute for the system  300 . The third gas source  306  includes a NO conversion cartridge  308  and may be used to deliver NO to the patient by means of a handheld ventilator (not shown). 
     Conversion Cartridges 
       FIG. 4  illustrates one embodiment of a device  400  that generates NO from NO 2 . The device  100 , which may be referred to as a NO generation cartridge, a GENO cartridge, a GENO cylinder, or a recuperator, includes a body  402  having an inlet  404  and an outlet  406 . The inlet  404  and outlet  406  are sized to engage gas plumbing lines or directly couple to other components such as, but not limited to, gas tanks, regulators, valves, humidifiers, patient interfaces, or recuperators. Additionally, the inlet  404  and outlet  406  may include threads or specially designed fittings to engage these components. 
     As shown in  FIG. 4 , the body  402  is generally cylindrical in shape and defines a cavity that holds a porous solid matrix  408 . According to one embodiment, the porous solid matrix  408  is a mixture of a surface-activated material such as, but not limited to, silica gel and one or more suitable thermoplastic resins. The thermoplastic resin, when cured, provides a rigid structure to support the surface-activated material. Additionally, the porous thermoplastic resin may be shaped or molded into any form. 
     According to one embodiment, the porous solid matrix  408  is composed of at least 20% silica gel. In another embodiment, the porous solid matrix  408  includes approximately 20% to approximately 60% silica gel. In yet another embodiment, the porous solid matrix  408  is composed of 50% silica gel. As those skilled in the art will appreciate, any ratio of silica gel to thermoplastic resin is contemplated so long as the mechanical and structural strength of the porous solid matrix  408  is maintained. In one embodiment, the densities of the silica gel and the thermoplastic resin are generally similar in order to achieve a uniform mixture and, ultimately, a uniform porous solid matrix  408 . 
     As shown in  FIG. 4 , the porous solid matrix  408  also has a cylindrical shape having an inner bore  412 . In other embodiments, the porous solid matrix may have any shape known or developed in the art. The porous solid matrix  408  is positioned within the body  402  such that a space  414  is formed between the body and the porous solid matrix  408 . At the inlet end  404  of the body  402 , a diverter  410  is positioned between the inlet and the porous solid matrix  408 . The diverter  410  directs the gas flow to the outer diameter of the porous solid matrix  408  (as shown by the white arrows). Gas flow is forced through the porous solid matrix  408  whereby any NO 2  is converted into NO (as shown by the darkened arrows). NO gas then exits the outlet  406  of the device  400 . The porous solid matrix  408  allows the device  400  to be used in any orientation (e.g., horizontally, vertically, or at any angle). Additionally, the porous solid matrix  408  provides a rigid structure suitable to withstand vibrations and abuse associated with shipping and handling. 
       FIG. 5  illustrates another embodiment of a conversion cartridge  500  that generates NO from NO 2 . The conversion cartridge  500  includes an inlet  505  and an outlet  510 . Porous filters or a screen and glass wool  515  are located at both the inlet  505  and the outlet  510 , and the remainder of the cartridge  500  is filled with a surface-active material  520  that is soaked with a saturated solution of antioxidant in water to coat the surface-active material. In the example of  FIG. 5 , the antioxidant is ascorbic acid. 
     In a general process for converting NO 2  to NO, an air flow having NO 2  is received through the inlet  505  and the air flow is fluidly communicated to the outlet  110  through the surface-active material  520  coated with the aqueous antioxidant. As long as the surface-active material remains moist and the antioxidant has not been used up in the conversion, the general process is effective at converting NO 2  to NO at ambient temperatures. 
     The inlet  505  may receive the air flow having NO 2 , for example, from a pressurized bottle of NO 2 , which also may be referred to as a tank of NO 2 . The inlet  505  also may receive an air flow with NO 2  in nitrogen (N 2 ), air, or oxygen (O 2 ). The inlet  505  may also receive the air flow having NO 2  from an air pump that fluidly communicates an air flow over a permeation or a diffusion tube (not shown). The conversion occurs over a wide concentration range. Experiments have been carried out at concentrations in air of from about 0.2 ppm NO 2  to about 100 ppm NO 2 , and even to over 1000 ppm NO 2 . In one example, a cartridge that was approximately 5 inches long and had a diameter of 0.8-inches was packed with silica gel that had first been soaked in a saturated aqueous solution of ascorbic acid. Other sizes of the cartridge are also possible. The moist silica gel was prepared using ascorbic acid (i.e., vitamin C) designated as A.C.S. reagent grade 99.1% pure from Aldrich Chemical Company and silica gel from Fischer Scientific International, Inc., designated as S8 32-1, 40 of Grade of 35 to 70 sized mesh. Other sizes of silica gel also are effective as long as the particles are small enough and the pore size is such as to provide sufficient surface area. 
     The silica gel was moistened with a saturated solution of ascorbic acid that had been prepared by mixing 35% by weight ascorbic acid in water, stirring, and straining the water/ascorbic acid mixture through the silica gel, followed by draining. In one embodiment, the silica gel is dried to about 30% moisture by weight. It has been found that the conversion of NO 2  to NO proceeds well when the silica gel coated with ascorbic acid is moist. The conversion of NO 2  to NO does not proceed well in an aqueous solution of ascorbic acid alone. 
     The cartridge filled with the moist silica gel/ascorbic acid was able to convert 1000 ppm of NO 2  in air to NO at a flow rate of 150 ml per minute, quantitatively, non-stop for over 12 days. A wide variety of flow rates and NO 2  concentrations have been successfully tested, ranging from only a few ml per minute to flow rates of up to approximately 5,000 ml per minute, up to flow rates of approximately 80,000 ml per minute. The reaction also proceeds using other common antioxidants, such as variants of vitamin E (e.g., alpha tocopherol and gamma tocopherol). 
     The various embodiments described above are provided by way of illustration only and should not be construed to limit the claimed invention. Those skilled in the art will readily recognize various modifications and changes that may be made to the claimed invention without following the example embodiments and applications illustrated and described herein, and without departing from the true spirit and scope of the claimed invention, which is set forth in the following claims.