Abstract:
A device for the topical delivery of nitric oxide gas to an infected area of skin includes a source of nitric oxide gas, a bathing unit, a flow control valve, and a vacuum unit. The bathing unit is adapted to surround the area of the infected skin and form a substantially air-tight seal with the skin surface. The bathing unit is also in fluidic communication with the source of nitric oxide. The flow control valve is position downstream of the source of nitric oxide and upstream of the bathing unit. The flow control valve controls the amount of nitric oxide gas that is delivered to the bathing unit. The vacuum unit is positioned downstream of the bathing unit and is used to withdraw gas from the bathing unit. Application of nitric oxide gas to the infected area of skin reduces pathogen levels in the infected area and promotes the healing process.

Description:
FIELD OF THE INVENTION  
         [0001]    The field of the invention relates devices and methods for treating infected tissue. More specifically, the invention relates to devices and methods for treating surface and subsurface infections with topical nitric oxide exposure.  
         BACKGROUND OF THE INVENTION  
         [0002]    The treatment of infected surface or subsurface lesions in patients has typically involved the topical or systemic administration of anti-infective agents to a patient. Antibiotics are one such class of anti-infective agents that are commonly used to treat an infected abscess, lesion, wound, or the like. Unfortunately, an increasingly number of infective agents such as bacteria have become resistant to conventional antibiotic therapy. Indeed, the increased use of antibiotics by the medical community has led to a commensurate increase in resistant strains of bacteria that do not respond to traditional or even newly developed anti-bacterial agents. Even when new anti-infective agents are developed, these agents are extremely expensive and available only to a limited patient population.  
           [0003]    Another problem with conventional anti-infective agents is that some patients are allergic to the very compounds necessary to their treat their infection. For these patients, only few drugs might be available to treat the infection. If the patient is infected with a strain of bacteria that does not respond well to substitute therapies, the patient&#39;s life can be in danger.  
           [0004]    A separate problem related to conventional treatment of surface or subsurface infections is that the infective agent interferes with the circulation of blood within the infected region. It is sometimes the case that the infective agent causes constriction of the capillaries or other small blood vessels in the infected region which reduces bloodflow. When bloodflow is reduced, a lower level of anti-infective agent can be delivered to the infected region. In addition, the infection can take a much longer time to 10 heal when bloodflow is restricted to the infected area. This increases the total amount of drug that must be administered to the patient, thereby increasing the cost of using such drugs. Topical agents may sometimes be applied over the infected region. However, topical anti-infective agents do not penetrate deep within the skin where a significant portion of the bacteria often reside. Topical treatments of anti-infective agents are often less effective at eliminating infection than systemic administration (i.e., oral administration) of an anti-infective pharmaceutical.  
           [0005]    In the 1980&#39;s, it was discovered by researchers that the endothelium tissue of the human body produced nitric oxide (NO), and that NO is an endogenous vasodilator, namely, and agent that widens the internal diameter of blood vessels. NO is most commonly known as an environmental pollutant that is produced as a byproduct of combustion. At high concentrations, NO is toxic to humans. At low concentrations, researchers have discovered that inhaled NO can be used to treat various pulmonary diseases in patients. For example, NO has been investigated for the treatment of patients with increased airway resistance as a result of emphysema, chronic bronchitis, asthma, adult respiratory distress syndrome (ARDS), and chronic obstructive pulmonary disease (COPD).  
           [0006]    NO has also been investigated for its use as a sterilizing agent. It has been discovered that NO will interfere with or kill the growth of bacteria grown in vitro. PCT International Application No. PCT/CA99/01123 published Jun. 2, 2000 discloses a method and apparatus for the treatment of respiratory infections by NO inhalation. NO has been found to have either an inhibitory and/or a cidal effect on pathogenic cells.  
           [0007]    While NO has shown promise with respect to certain medical applications, delivery methods and devices must cope with certain problems inherent with gaseous NO delivery. First, exposure to high concentrations of NO is toxic, especially exposure to NO in concentrations over 1000 ppm. Even lower levels of NO, however, can be harmful if the time of exposure is relatively high. For example, the Occupational Safety and Health Administration (OSHA) has set exposure limits for NO in the workplace at 25 ppm timeweighted averaged for eight (8) hours. It is extremely important that any device or system for delivering NO include features that prevent the leaking of NO into the surrounding environment. If the device is used within a closed space, such as a hospital room or at home, dangerously high levels of NO can build up in a short period of time.  
           [0008]    Another problem with the delivery of NO is that NO rapidly oxidizes in the presence of oxygen to form NO 2 , which is highly toxic, even at low levels. If the delivery device contains a leak, unacceptably high levels NO 2  of can develop. In addition, to the extent that NO oxides to form NO 2 , there is less NO available for the desired therapeutic effect. The rate of oxidation of NO to NO 2  is dependent on numerous factors, including the concentration of NO, the concentration of O 2 , and the time available for reaction. Since NO will react with the oxygen in the air to convert to NO 2 , it is desirable to have minimal contact between the NO gas and the outside environment.  
           [0009]    Accordingly, there is a need for a device and method for the treatment of surface and subsurface infections by the topical application of NO. The device is preferably leak proof to the largest extent possible to avoid a dangerous build up of NO and NO 2  concentrations. In addition, the device should deliver NO to the infected region of the patient without allowing the introduction of air that would otherwise react with NO to produce NO 2 . The application of NO to the infected region preferably decreases the time required to heal the infected area by reducing pathogen levels. The device preferably includes a NO and NO 2  absorber or scrubber that will remove or chemically alter NO and NO 2  prior to discharge of the air from the delivery device.  
         SUMMARY OF THE INVENTION  
         [0010]    In a first aspect of the invention, a device for the topical delivery of nitric oxide gas to an infected area of skin includes a source of nitric oxide gas, a bathing unit, a flow control valve, and a vacuum unit. The bathing unit is in fluid communication with the source of nitric oxide gas and is adapted for surrounding the area of infected skin and forming a substantially air-tight seal with the skin surface. The flow control valve is positioned downstream of the source of nitric oxide and upstream of the bathing unit for controlling the amount of nitric oxide gas that is delivered to the bathing unit. The vacuum unit is positioned downstream of the bathing unit for withdrawing gas from the bathing unit.  
           [0011]    In a second aspect of the invention, the device according to the first aspect of the invention includes a controller for controlling the operation of the flow control valve and the vacuum unit.  
           [0012]    In a third aspect of the invention, the device according to the first aspect of the invention further includes a source of dilutent gas and a gas blender. The dilutent gas and the nitric oxide gas are mixed by the gas blender. The device also includes a nitric oxide gas absorber unit that is positioned upstream of the vacuum unit. The device also includes a controller for controlling the operation of the flow control valve and the vacuum unit.  
           [0013]    In a fourth aspect of the invention, a method of delivering an effective amount of nitric oxide to an infected area of skin includes the steps of providing a bathing unit around the infected area of skin, the bathing unit forming a substantially air-tight seal with the skin. Gas containing nitric oxide is then transported to the bathing unit so as to bathe the infected area of skin with gaseous nitric oxide. Finally, at least a portion of the nitric oxide gas is evacuated from the bathing unit.  
           [0014]    It is an object of the invention to provide a delivery device for the topical delivery of a NO-containing gas to an infected area of skin. It is a further object of the device to prevent the NO-containing gas from leaking from the delivery device. The method of delivering an effective amount of nitric oxide gas to the infected area of skin kills bacteria and other pathogens and promotes the healing process. 
       
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0015]    [0015]FIG. 1 illustrates a schematic representation of the NO delivery device according to one aspect of the invention.  
         [0016]    [0016]FIG. 2 illustrates a bathing unit surrounding the foot of a patient.  
         [0017]    [0017]FIG. 3 illustrates a bathing unit surrounding the hand of a patient.  
         [0018]    [0018]FIG. 4 illustrates a bathing unit including an agitator located therein. 
     
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS  
       [0019]    Referring now to FIG. 1, a NO delivery device  2  is shown connected to a patient  4 . In its most general sense, the NO delivery device  2  includes a bathing unit  6  that is fluidically connected to a NO gas source  8 , a flow control valve  22 , and a vacuum unit  10 . FIG. 1 illustrates one preferred embodiment of the invention.  
         [0020]    In FIG. 1, the NO gas source  8  is a pressurized cylinder containing NO gas. While the use of a pressurized cylinder is the preferably method of storing the NO-containing gas source  8 , other storage and delivery means, such as a dedicated feed line (wall supply) can also be used. Typically, the NO gas source  8  is a mixture of N 2  and NO. While N 2  is typically used to dilute the concentration of NO within the pressurized cylinder, any inert gas can also be used. When the NO gas source  8  is stored in a pressurized cylinder, it is preferable that the concentration of NO in the pressurized cylinder fall within the range of about 800 ppm to about 1200 ppm. Commercial nitric oxide manufacturers typically produce nitric oxide mixtures for medical use at around the 1000 ppm range. Extremely high concentrations of NO are undesirable because accidental leakage of NO gas is more hazardous, and high partial pressures of NO tends to cause the spontaneous degradation of NO into nitrogen. Pressurized cylinders containing low concentrations of NO (i.e., less than 100 ppm NO) can also be used in accordance the device and method disclosed herein. Of course, the lower the concentration of NO used, the more often the pressurized cylinders will need replacement.  
         [0021]    [0021]FIG. 1 also shows source of dilutent gas  14  as part of the NO delivery device  2  that is used to dilute the concentration of NO. The source of dilutent gas  14  can contain N 2 , O 2 , Air, an inert gas, or a mixture of these gases. It is preferable to use a gas such as N 2  or an inert gas to dilute the NO concentration since these gases will not oxidize the NO into NO 2  as would O 2  or air. The source of dilutent gas  14  is shown as being stored within a pressurized cylinder. While the use of a pressurized cylinder is shown in FIG. 1 as the means for storing the source of dilutent gas  14 , other storage and delivery means, such as a dedicated feed line (wall supply) can also be used.  
         [0022]    The NO gas from the NO gas source  8  and the dilutent gas from the dilutent gas source  14  preferably pass through pressure regulators  16  to reduce the pressure of gas that is admitted to the NO delivery device  2 . The respective gas streams pass via tubing  18  to an optional gas blender  20 . The gas blender  20  mixes the NO gas and the dilutent gas to produce a NO-containing gas that has a reduced concentration of NO. Preferably, the NO-containing gas that is output from the gas blender  20  has a concentration that is less than about 200 ppm. Even more preferably, the concentration of NO-containing gas that is output from the gas blender  20  is less than about 100 ppm.  
         [0023]    The NO-containing gas that is output from the gas blender  20  travels via tubing  18  to a flow control valve  22 . The flow control valve  22  can include, for example, a proportional control valve that opens (or closes) in a progressively increasing (or decreasing if closing) manner. As another example, the flow control valve  22  can include a mass flow controller. The flow control valve  22  controls the flow rate of the NO-containing gas that is input to the bathing unit  6 . The NO-containing gas leaves the flow control valve  22  via flexible tubing  24 . The flexible tubing  24  attaches to an inlet  26  in the bathing unit  6 . The inlet  26  might include an optional one way valve  64  (see FIG. 3) that prevents the backflow of gas into the tubing  24 .  
         [0024]    Still referring to FIG. 1, the bathing unit  6  is shown sealed against the skin surface of a patient  4 . The infected area  30  which can be an abscess, lesion, wound, or the like, is enclosed by the bathing unit  6 . The bathing unit  6  preferably includes a seal portion  32  that forms a substantially air-tight seal with the skin of the patient  4 . Substantially air-tight is meant to indicate that the NO-containing gas does not leak out of the bathing unit  6  in significant amounts (i.e., no more than about 5% of the NO-containing gas delivered to the bathing unit  6 ). The seal portion  32  may comprise an inflatable seal  61 , such as that shown in FIGS. 2 and 3, or alternatively the seal portion  32  may comprise a flexible skirt or the like that conforms to the surface of the patient  4 . The seal portion  32  also might include an adhesive portion that adheres to the skin surface of a patient  4 . In other envisioned embodiments, the sealing portion  32  may merely comprise the interface of the bathing unit  6  with the surface of the patient&#39;s  4  skin.  
         [0025]    The bathing unit  6  can be made of a virtually limitless number of shapes and materials depending on its intended use. The bathing unit  6  might be formed as a rigid structure, such as that shown in FIG. 1, that is placed over the infected area  30 . Alternatively, the bathing unit  6  can be formed of a flexible, bag-like material that is inflatable over the infected area  30 . FIG. 2 shows such a structure in the shape of a boot that is placed over the patient&#39;s  4  foot. FIG. 3 shows another inflatable bathing unit  6  that is formed in the shape of a mitten or glove that is worn over the patient&#39;s  4  hand.  
         [0026]    In one preferred embodiment of the invention, the bathing unit  6  includes an NO sensor  34  that measures the concentration of NO gas within the bathing unit  6 . The NO sensor  34  preferably reports this information to a controller  36  via signal line  38 . An optional NO 2  sensor  40  can also be included within the bathing unit  6 . The NO 2  sensor  40  preferably reports the concentration of NO 2  to the controller  36  via signal line  42 . The sensors  40 ,  42  can be a chemilluminesence-type, electrochemical cell-type, or spectrophotometric-type sensor.  
         [0027]    The bathing unit  6  also includes an outlet  44  that is used to remove gas from the bathing unit  6 . The outlet  44  is preferably located away from the gas inlet  26  such that NO gas does not quickly enter and exit the bathing unit  6 . Preferably, the inlet  26  and outlet  44  are located in areas of the bathing unit  6  such that the NO gas has a relatively long residence time. Flexible tubing  46  is connected to the outlet  44  and provides a conduit for the removal of gases from the bathing unit  6 .  
         [0028]    In one preferred embodiment of the invention, the flexible tubing  46  is in fluid communication with an absorber unit  48 . The absorber unit  48  preferably absorbs or strips NO from the gas stream that is exhausted from the bathing unit  6 . It is also preferable for the absorber unit  48  to also absorb or strip NO 2  from the gas stream that is exhausted from the bathing unit  6 . Since these gases are toxic at high levels, it is preferable that these components are removed from the delivery device  2  prior to the gas being vented to the atmosphere. In addition, these gases can react with the internal components of the vacuum unit  10  and interfere with the operation of the delivery device  2 .  
         [0029]    The now clean gas travels from the absorbing unit  48  to the vacuum unit  10  via tubing  50 . The vacuum unit  10  provides a negative pressure within the tubing  50  so as to extract gases from the bathing unit  6 . The vacuum unit  10  is preferably controllable with respect to the level of vacuum or suction supplied to the tubing  50  and bathing unit  6 . In this regard, in conjunction with the flow control valve  22 , the amount of NO gas within the bathing unit  6  can be regulated. Preferably, the vacuum unit  10  is coupled with the controller  36  via a signal line  52 . The controller  36 , as discussed below, preferably controls the level of output of the vacuum unit  10 . The gas then passes from the vacuum unit  10  to a vent  54  that is open to the atmosphere.  
         [0030]    It should be understood that the absorbing unit  48  is an optional component of the delivery device  2 . The gas laden with NO and NO 2  does not have to be removed from the gas stream if there is no concern with local levels of NO and NO 2 . For example, the gas can be exhausted to the outside environment where high concentrations of NO and NO 2  will not develop. Alternatively, a recirculation system (not shown) might be used to recycle NO within the bathing unit  6 .  
         [0031]    Still referring to FIG. 1, the delivery device  2  preferably includes a controller  36  that is capable of controlling the flow control valve  22  and the vacuum unit  10 . The controller  36  is preferably a microprocessor-based controller  36  that is connected to an input device  56 . The input device  56  is used by an operator to adjust various parameters of the delivery device such as NO concentration, residence time of NO, pressure within the bathing unit  6 , etc. An optional display  58  can also be connected with the controller  36  to display measured parameters and settings such as the set-point NO concentration, the concentration of NO within the bathing unit  6 , the concentration of NO 2  within the bathing unit  6 , the flow rate of gas into the bathing unit  6 , the flow rate of gas out of the bathing unit  6 , the total time of delivery, and the like.  
         [0032]    The controller  36  preferably receives signals from sensors  34 ,  40  regarding gas concentrations if such sensors  34 ,  40  are present within the delivery device  2 . Signal lines  60 ,  52  are connected to the flow control valve  22  and vacuum unit  10  respectively for the delivery and receipt of control signals.  
         [0033]    In another embodiment of the invention, the controller  36  is eliminated entirely. In this regard, the flow rate of the gas into the bathing unit  6  and the flow rate of the gas out of the bathing unit  6  are pre-set or adjusted manually. For example, an operator can set a vacuum output that is substantially equal to the flow rate of the gas delivered to the bathing unit  6  via the flow control valve  22 . In this manner, NO gas will be able to bathe the infected area  30  without any build-up or leaking of NO or NO 2  gas from the delivery device  2 .  
         [0034]    [0034]FIG. 2 illustrates a bathing unit  6  in the shape of a boot that is used to treat an infected area  30  located on the leg of the patient  4 . The bathing unit  6  includes an inflatable seal  61  that surrounds the leg region to make a substantially air-tight seal with the skin of the patient  4 . This embodiment shows a nozzle  62  that is affixed near the inlet  26  of the bathing unit  6 . The nozzle  62  directs a jet of NO gas onto the infected area  30 . The jet of gaseous NO aids in penetrating the infected area  30  with NO to kill or inhibit the growth of pathogens. FIG. 3 shows another embodiment of the bathing unit  6  in the shape of a mitten or glove. The bathing unit  6  is also inflatable and contains an inflatable seal  61  that forms a substantially air-tight seal around the skin of the patient  4 . FIG. 3 also shows an optional one way valve  64  located in the inlet  26 . As seen in FIGS. 3 and 4, the inlet  26  and outlet  44  are located away from one another, and preferably on opposing sides of the treated area such that freshly delivered NO gas is not prematurely withdrawn from the bathing unit  6 .  
         [0035]    For treatment of an infected area  30 , the bathing unit  6  is placed over the infected area  30 . An air-tight seal is then formed between the skin of the patient  4  and the bathing unit  6 . If the bathing unit  6  has an inflatable construction, the bathing unit  6  must be inflated with gas. Preferably, the bathing unit  6  is initially inflated only with the dilutent gas to prevent the leaking of NO and NO 2  from the device  2 . Once an adequate air-tight seal has been established, the operator of the device initiates the flow of NO from the NO gas source  8  to the bathing unit  6 . As described above, this may be accomplished manually or via the controller  36 .  
         [0036]    Once the bathing unit  6  has started to fill with NO gas, the vacuum unit  10  is turned on and adjusted to the appropriate output level. For an inflatable bathing unit  6 , the output level (i.e., flow rate) of the vacuum unit  10  should be less than or equal to the flow rate of NO gas entering the bathing unit  6  to avoid deflating the bathing unit  6 . In embodiments of the device where the bathing unit  6  is rigid, the vacuum unit  10  can be set to create a partial vacuum within the bathing unit  4 . In this regard, the partial vacuum helps to form the air-tight seal between the skin of the patient  4  and the bathing unit  6 . Of course, the vacuum unit  10  can also be set to withdraw gas at a substantially equal rate as the gas is delivered to the bathing unit  6 . An effective amount of NO is delivered to the bathing unit  6  to kill pathogens and/or reduce the growth rate of the pathogens in the infected area  30 . Pathogens include bacteria, viruses, and fungi.  
         [0037]    [0037]FIG. 4 shows another embodiment of the invention in which the bathing unit  6  includes an agitator  66  that is used to create turbulent conditions inside the bathing unit  6 . The agitator  66  preferably is a fan-type of mechanism but can include other means of creating turbulent conditions within the bathing unit  6 . The agitator  66  aids in refreshing the infected area  30  with a fresh supply of NO gas.  
         [0038]    While embodiments of the present invention have been shown and described, various modifications may be made without departing from the scope of the invention. The invention, therefore, should not be limited, except to the following claims, and their equivalents.