Abstract:
A respiratory nitric oxide meter includes a respiratory connector designed to be supported in contact with a subject and to pass respiratory gases as the subject breathes. A flow pathway receives and passes the respiration gases. One end of the pathway is in fluid communication with the respiratory connector, and the other end is in fluid communication with a reservoir of respiratory gases. A nitric oxide concentration sensor generates electrical signals as a function of the instantaneous fraction of nitric oxide as the respiration gases pass through the flow pathway.

Description:
REFERENCE TO RELATED APPLICATION 
     This application claims priority from U.S. provisional patent application Ser. Nos. 60/159,285, filed Oct. 13, 1999; 60/228,388, filed Aug. 28, 2000; and 60/236,829, filed Sep. 29, 2000, the entire contents of all of which are incorporated herein by reference. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates generally to the detection of nitric oxide in a gaseous mixture and, more specifically, to the detection of nitric oxide in a flow pathway. 
     BACKGROUND OF THE INVENTION 
     Definition of Nitric Oxide 
     Nitric oxide, NO, is a colorless gas useful in the detection and treatment of a variety of medical conditions such as asthma. Nitric oxide, NO, should not be confused with nitrous oxide, N 2 O, or nitrogen dioxide, NO 2 . Nitrogen and oxygen also form other compounds, especially during combustion processes. These typically take the form of NO x  where x represents an integer. These forms are generally referred to as NOX. Detection of nitric oxide, NO, is the primary focus of the present application. Nitric oxide has a variety of beneficial uses and detection of nitric oxide, especially in small concentrations, is necessary for the proper administration of nitric oxide and diagnosis of disease. 
     Use of Nitric Oxide in Treatment of Physiological Conditions 
     Nitric oxide is beneficial in both the treatment and diagnosis of asthma and other forms of lung disorders. Asthma is a chronic disease characterized by intermittent, reversible, widespread constriction of the airways of the lungs in response to any of a variety of stimuli that do not affect the normal lung. A variety of drugs are commonly used to treat asthma. It is known that inhalation of nitric oxide (NO) is therapeutically beneficial in the prevention and treatment of asthma attacks and other forms of bronchoconstriction, of acute respiratory failure, or of reversible pulmonary vasoconstriction as discussed in U.S. Pat. No. 5,873,359 to Zapol et al, incorporated herein by reference. U.S. Pat. Nos. 5,904,938 and 6,063,407, both to Zapol et al. and incorporated herein by reference, disclose the use of inhaled nitric oxide in the treatment of vascular thrombosis and retinosis. Typically, treatment utilizing nitric oxide includes the introduction of nitric oxide as a portion of the respiratory gases being inhaled by the patient. The nitric oxide concentration is usually in the range of 1 to 180 parts per million (ppm). The difficulty presented in the administration of controlled amounts of nitric oxide is the determination of the concentration being introduced. It has traditionally been very difficult to quickly and accurately determine the concentration of nitric oxide in the gas mixture, especially where the concentration of nitric oxide is very low. 
     U.S. Pat. No. 5,839,433 to Higenbottam, incorporated herein by reference, describes the use of nitric oxide in the treatment of certain lung diseases and conditions. As discussed in the specification, a drawback to the administration of gaseous nitric oxide is that it rapidly converts to nitrogen dioxide, a potentially harmful substance. Consequently, it is often preferable to intubate the patient so that nitric oxide is administered directly to the lungs. Whether or not intubated, it is very important to accurately monitor the amount of nitric oxide being introduced to the lungs. The Higenbottam reference proposes an improvement wherein the nitric oxide is introduced as a short pulse of known volume, rather than continuously during inhalation. 
     U.S. Pat. No. 5,531,218 to Krebs, incorporated herein by reference, discusses the benefits of nitric oxide inhalation in the treatment of various disorders, including adult respiratory distress syndrome, (ARDS). The specification discloses a system for administering nitric oxide that includes a source of nitric oxide, an analyzer for analyzing nitric oxide concentration, and a control unit, with the analyzer and the control unit cooperating to maintain the appropriate nitric oxide concentration. However, this system relies on the use of nitric oxide sensors utilizing infrared absorption measurement, electrochemical sensors, or chemiluminescence detectors. Each of these analyzers have drawbacks and cannot provide instantaneous nitric oxide concentration measurements. 
     Use of Nitric Oxide in Diagnosis 
     Nitric oxide may also be used in the diagnosis of various physiological conditions. For example, the reversibility of chronic pulmonary vasorestriction may be diagnosed by administering known quantities of nitric oxide and monitoring changes in pulmonary arterial pressure (PAP) and cardiac output as described in U.S. Pat. No. 5,873,359 to Zapol et al. 
     Endogenous production of nitric oxide in the human airway has been shown to be increased in patients with asthma and other inflammatory lung diseases. Expired nitric oxide concentrations are also elevated in patients with reactive airways disease. Therefore, detection of nitric oxide is beneficial in diagnosing these conditions. However, proper diagnosis requires accurate measurement of nitric oxide in parts per billion (ppb) of gas-phase nitric oxide. 
     Determination of the level of nitric oxide is useful in the diagnosis of inflammatory conditions of the airways, such as allergic asthma and rhinitis, in respiratory tract infections in humans and Kartagener&#39;s syndrome. It also has been noted that the level of nitric oxide in the exhalation of smokers is decreased. U.S. Pat. No. 5,922,610 to Alving et al., incorporated herein by reference, discusses the detection of nitric oxide in diagnosing these conditions, as well as gastric disturbances. 
     In addition to the above, nitric oxide may be used in the determination of lung function. For example, U.S. Pat. No. 5,447,165 to Gustafsson, incorporated herein by reference, explains that nitric oxide in exhalation air is indicative of lung condition. As one test of lung function, a subject may inhale a trace gas, such as nitric oxide. Then the concentration and time-dispersment of the gas in the exhalation air is measured. The shape of the curve representing the time dependent gas concentration in the exhalation air is indicative of lung function or condition. Obviously, it is necessary to have an accurate determination of both the concentration and the time-dependence of the concentration to allow for the most accurate diagnosis. 
     During exhalation, gas mixture changes during the breath. The initial portion of the exhalation is “dead space” air that has not entered the lungs. This includes the respiratory gases in the mouth and respiratory passages above the lungs. Also, some portion of the exhalation measured by an analytical instrument may be attributed to dead air in the mask and flow passages of the apparatus. As a breath continues, respiratory gases from within the lungs are exhaled. The last portion of respiratory gases exhaled is considered alveolar air. Often it is beneficial to measure gas concentrations in alveolar air to determine various pulmonary parameters. For example, nitric oxide, as an indicator of various disease states, may be concentrated in the alveolar air. However, nitric oxide is also produced by various mucus membranes and therefore nitric oxide may be present in both the dead air space and in the alveolar air. During an exhalation, the dead air space may be overly contaminated with nitric oxide due to residence in the mouth and nasal cavities where nitric oxide is absorbed from the mucus membranes. Therefore, it is necessary to distinguish the various portions of exhalation for proper diagnosis. U.S. Pat. No. 6,038,913 to Gustafsson et al., incorporated herein by reference, discusses having an exhalation occur with very little resistance during an initial “dead space” phase of exhalation and then creating resistance against the remaining portion of the exhalation. 
     Nitric Oxide Measurement Methods 
     Numerous approaches have been used and proposed for monitoring the concentration of nitric oxide in a gas mixture. These include mass spectroscopy, electrochemical analysis, calorimetric analysis, chemiluminescence analysis, and piezoelectric resonance techniques. Each of these approaches have shortcomings that make them poorly suited to widespread use in the diagnosis and treatment of disease. 
     Mass spectroscopy utilizes a mass spectrometer to identify particles present in a substance. The particles are ionized and beamed through an electromagnetic field. The manner in which the particles are deflected is indicative of their mass, and thus their identity. Mass spectroscopy is accurate but requires the use of very expensive and complicated equipment. Also, the analysis is relatively slow, making it unsuitable for real time analysis of exhalations. Preferably, in the breath by breath analysis of nitric oxide, it is desirable to quickly and accurately measure the nitric oxide concentration in the flow path as the gas mixture flows through the flow path. Mass spectroscopy requires sampling of portions of the gas mixture rather than analyzing the nitric oxide concentration in the flow pathway itself. Mass spectroscopy cannot be considered an instantaneous or continuous analysis approach. It requires dividing the exhalation into multiple discrete samples and individual analysis of each sample. This does not create a curve of the nitric oxide concentration but instead creates a few discreet points. Sampling-based systems are especially deficient when detecting gases in very low concentrations since large samples are required. 
     Electrochemical-based analysis systems use an electrochemical gaseous sensor in which gas from a sample diffuses into and through a semi-permeable barrier, such as membrane, then through an electrolyte solution, and then to one of typically three electrodes. At one of the three electrodes, a sensing redox reaction occurs. At the second, counter, electrode, a complimentary and opposite redox reaction occurs. A third electrode is typically provided as a reference electrode. Upon oxidation, or reduction, of the nitric oxide at the sensing electrode, a current flows between the sensing and counter electrode that is proportional to the amount of nitric oxide reacting at the sensing electrode surface. The reference electrode is used to maintain the sensing electrode at a fixed voltage. A typical electrochemical-based gas analyzer for detecting nitric oxide is shown is U.S. Pat. No. 5,565,075 to Davis et al, incorporated herein by reference. Electrochemical-based devices have high sensitivity and accuracy, but typically have a response time in excess of 30 seconds. This is significantly too slow to allow breath by breath, or continuous, analysis of respiration gases. 
     Colorimetric analysis relies on a chemical reaction by a gas which provides a corresponding change in pH, thereby triggering a color change in an indicator. This approach requires expendable chemical substances. Also, this approach is often disturbed by the presence of other gases, particularly the relative amount of humidity present. Response times are too slow for analysis during a breath. 
     Chemiluminescent-based devices depend on the oxidation of nitric oxide by mixing the nitric oxide with ozone, O 3 , to create nitrogen dioxide and oxygen. The nitrogen dioxide is in an excited state immediately following the reaction and releases photons as it decays back to a non-excited state. By sensing the amount of light emitted during this reaction, the concentration of nitric oxide maybe determined. An example of a chemiluminescent-based device is shown in U.S. Pat. No. 6,099,480 to Gustafsson, incorporated herein by reference. Chemiluminescent devices have response times as fast as about two hundred milliseconds, have high sensitivity, repeatability, and accuracy. However, like with mass spectroscopy, and electrochemical analysis, chemiluminescent analysis requires sampling of the gas mixture rather than continuous analysis of the gas concentration in the flow path itself. Also, chemiluminescent devices are typically very large and expensive. 
     Piezoelectric resonance techniques are sometimes referred to as MEMS (microelectro-mechanical systems) sensor devices. Basically, a micro-etched cantilevered beam is coated with a “capture” molecule that is specific to the gas being analyzed. In theory, the capture molecule will capture the gas being analyzed in proportion to its ambient concentration. This alters the mass of the micro-etched cantilevered beam. Changes in mass of the beam may theoretically be detected based on changes in its resonant frequency. The change in resonant frequency should be directly proportional to the concentration of the gas being studied. A system for detecting air pollutants is disclosed in U.S. Pat. No. 4,111,036 to Frechette et al., incorporated herein by reference. While the theory behind piezoelectric resonance techniques is rather simple, there has been no known success to date in the analysis of nitric oxide concentrations. 
     U.S. Pat. No. 6,033,368 to Gaston IV et al. discloses an analyzer for measuring exhaled nitrogen oxides, nitrite and nitrate in very low concentrations. The analyzer includes a chilled exhalation passage which causes lung fluid vapors to collect. The resulting liquid is then analyzed using standard calorimetric assays. While somewhat simpler than other methods, the Gaston apparatus remains complicated, requiring prefreezing of the chilling apparatus, and subsequent analysis of the collected liquid. 
     Each of the above-described approaches for the use and detection of nitric oxide would benefit from a nitric oxide meter capable of continuously determining the nitric oxide concentration of a flow of respiratory gases in a flow pathway without the need for sampling the mixture. Most preferably, such a meter would provide nearly instantaneous response times so that analysis may be made during a breath or on a breath-by-breath basis. 
     SUMMARY OF THE INVENTION 
     The present invention overcomes many of the shortcomings of the prior art by providing a nitric oxide meter designed to provide continuous, or breath-by-breath, analysis. The nitric oxide meter includes a respiratory connector designed to be supported in contact with a subject so as to pass respiratory gases when the subject breathes. A flow pathway receives and passes respiration gases. One end of the flow pathway has in fluid communication with the respiratory connector, and the other end is in fluid communication with a source and sink of respiratory gases. A nitric oxide concentration sensor generates electrical signals as a function of the instantaneous fraction of nitric oxide in the respiration gases as the gases pass through the flow pathway. In some embodiments of the present invention, a flow meter is also provided in the respiratory nitric oxide meter. The flow meter may be an ultrasonic flow meter including a pair of spaced-apart ultrasonic transducers. In other embodiments of the present invention, the respiratory nitric oxide meter forms part of a system for the controlled administration of nitric oxide to the subject. This system includes a nitric oxide regulator designed to selectively introduce nitric oxide into inhalation gases in the pathway. The system may also include a controller which controls the regulator based on signals received from the nitric oxide concentration sensor so as to maintain the instantaneous fraction of nitric oxide in the inhalation gases within prescribed limits. 
     According to one aspect of the present invention, there is provided a respiratory nitric oxide meter for measuring the nitric oxide content of respiration gases for a subject, said meter comprising: a respiratory connector configured to be disposed in fluid communication with the respiratory system of the subject so as to pass inhalation and exhalation respiratory gases as the subject breathes; a flow pathway operable to receive and pass the respiration gases, the flow pathway having a first end in fluid communication with the respiratory connector and a second end in fluid communication with a reservoir of respiratory gases; a nitric oxide concentration sensor operable to generate electrical signals as a function of the instantaneous fraction of nitric oxide in the respiration gases as the gases pass through the flow pathway; and a one-way valve located between the respiratory connector and the first end of the flow pathway. The one-way valve is presettable in a first position effective to pass inhalation gases directly into the respiratory connector bypassing the flow pathway, and to pass exhalation gases through the flow pathway so as to contact the nitric oxide concentration sensor, to thereby sense the nitric oxide concentration in the exhalation gases. The one-way valve is also presettable in a second position effective to pass exhalation gases directly from the respiratory connector bypassing the flow pathway, and to pass inhalation gases through the flow pathway so as to contact the nitric oxide concentration sensor, to thereby sense the nitric oxide concentration in the inhalation gases. 
     The reservoir of respiratory gases may be the atmosphere, or another separate source of respiratory gases. 
     According to another aspect of the present invention, there is provided a respiratory nitric oxide meter for measuring the nitric oxide content of respiration gases for a subject, the meter comprising: a respiratory connector configured to be disposed in fluid communication with the respiratory system of the subject so as to pass exhalation respiration gases as the subject breathes; a flow pathway operable to receive and pass the exhalation respiration gases, the pathway having a first end in fluid communication with the respiratory connector and a second end in fluid communication with a reservoir of respiratory gases; a flow meter configured to generate electrical signals as a function of the instantaneous flow of respiration gases passing through the flow pathway; and a nitric oxide concentration sensor operable to generate electrical signals as a function of the instantaneous fraction of nitric oxide in the exhalation respiration gases as the gases pass through the flow pathway; the nitric oxide concentration sensor having a response time of less than 200 ms to enable instantaneous analysis of the exhalation respiratory gases during a single breath. 
     Further features of the invention will be apparent from the description below. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     FIG. 1 is a perspective view of the first embodiment of a respiratory nitric oxide meter according to the present invention; 
     FIG. 2 is a cross-sectional view of the meter of FIG. 1 taken along lines  2 — 2 ; 
     FIG. 3 is an exploded perspective view of an embodiment of a nitric oxide sensor for use with a nitric oxide meter; 
     FIG. 4 is a cross-sectional side view of the sensor of FIG. 3 taken along lines  4 — 4 ; 
     FIG. 5 is a perspective view of a first alternative embodiment of a respiratory nitric oxide meter according to the present invention; 
     FIG. 6 is a perspective view of a second alternative embodiment of a nitric oxide meter according to the present invention; 
     FIG. 7 is a cross-sectional view of the meter of FIG. 6 taken along lines  7 — 7 ; 
     FIG. 8 is a perspective view, partially exploded, of a third alternative embodiment of the nitric oxide meter according to the present invention; 
     FIG. 9 is a view of a nitric oxide metering system according to the present invention with the meter portion shown in cross-section; and 
     FIG. 10 is a schematic of a nitric oxide administration system utilizing a nitric oxide meter according to the present invention. 
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The present invention provides a respiratory nitric oxide meter that allows the measurement of the instantaneous nitric oxide concentration in a gaseous mixture as the mixture flows through a flow pathway. Unlike the prior art, the present invention is not a sampling based analyzer, but instead measures the concentration of nitric oxide in the flow pathway itself and has a sufficiently fast response time so as to allow analysis on a breath-by-breath basis and to allow the monitoring of the changes in nitric oxide concentration during a single breath. For the purposes of the present invention, the nitric oxide sensors used as part of the nitric oxide meter are considered instantaneous, with instantaneous being defined as fast enough to allow monitoring of changes in the nitric oxide concentration during a single breath. Investigation has indicated that response times of approximately 200 milliseconds (ms) or less are preferred in order to track changes in nitric oxide concentration, with 100 ms or less being even more preferred. Many of the prior art sensors and analyzers have response times on the order of several seconds, making them unsuitable for breath-by-breath analysis of the nitric oxide concentration of either inhalation of exhalation gases. Also, many are sampling based analyzers and therefore analyze discrete samples. The present invention also allows close correlation between nitric oxide measurements and flow measurements, something not easily accomplished with prior art systems. 
     Referring to FIGS. 1 and 2, a first embodiment of a respiratory nitric oxide meter is generally shown at  10 . The meter  10  includes a body  12  and a respiratory connector, such as a mask  14 , extending from the body  12 . Preferably, the meter  10  is a lightweight, handheld or wearable unit. In use, the user grasps the body  12  and brings the mask  14  into contact with their face so that respiratory gases pass through the meter  10 . Though not shown, straps may be provided for interconnecting the meter  10  with the user&#39;s face and head without the need to support it with a hand. 
     With the mask  14  in contact with the user&#39;s face, the user&#39;s inhalations and/or exhalations pass through the body  12  for analysis of the nitric oxide concentration. The meter  10  preferably includes a display  16  as well as a control button  18  for controlling operation of the meter  10 . 
     Depending on the application, the meter  10  may be used to pass inhalation gases, exhalation gases, or both. In situations where it is preferred to pass only inhalation or exhalation gases, but not both, a valve  19  may be provided on the mask for allowing passage of the gases not to be analyzed. For example, the valve  19  may be one-way valve that allows the passage of fresh air into the mask  14  upon inhalation but blocks exhalation, such that exhalation gases pass through the body  12  of the meter  10 . By reversing the valve  19 , exhalations may be passed through the valve while inhalations enter through the body  12 . A second one-way valve may be provided in the body  12  for further directing gases. It will thus be seen that when one-way valve  19  is preset in the first-mentioned position, it is effective to pass inhalation gases directly into the mask respiratory connector  14 , bypassing body  12 , and to pass exhalation gases through body  12 ; whereas when the valve  19  is in the second-mentioned position, it is effective to pass exhalation gases from mask  14  bypassing body  12 , and to pass inhalation gases through body  12 . As described more particularly below, body  12  includes a flow tube containing a nitric oxide concentration sensor, such that when the one-way valve is preset in its first position, the meter senses the nitric oxygen concentration in the exhalation gases, whereas when the valve is in its second position, the meter senses the nitric oxide concentration in the inhalation gases. Without the valve  19 , or with the valve disabled, both inhalation and exhalation gases pass through the body  12 , such that the nitric oxygen concentration in both the exhalation gases and inhalation gases is sensed. 
     Referring now to FIG. 2, the meter  10  is shown in cross-section so as to illustrate the internal construction. A flow pathway is formed through the body  12  by a generally straight flow tube  20 . At one end, the flow tube  20  is interconnected with the mask  14 , and its other end is open to the surrounding air or interconnected with another reservoir of respiratory gases, such as another source and/or sink of respiratory gases. The term “reservoir” as used herein thus also includes the surrounding air. The body  12  includes an outer shell  22  which surrounds the majority of the flow tube  20  so as to provide an improved cosmetic appearance and to support a variety of additional components. As shown, the flow tube  20  is a generally cylindrical tube with a generally constant cross-section throughout its length. Consequently, inhalation and exhalation gases flow very freely into and out of the mask  14 , thereby creating little resistance to natural respiration. A nitric oxide sensor  24  is disposed in the side of the flow tube  20  so as to be in contact with respiratory gases passing through the flow tube. The sensor  24  has a sensing face  25  positioned in a window or opening in the side of the tube. 
     In some embodiments of the present invention, a flow meter is also provided so as to measure the flow of respiratory gases through the flow tube  20 . Many types of flow meters may be used. However, in the preferred embodiment, an ultrasonic-based flow meter is used. Ultrasonic flow meters measure the instantaneous flow velocity of gas in a flow tube, thereby allowing determination of flow volumes. In the embodiment shown in FIG. 2, a pair of spaced-apart ultrasonic transducers  26  and  28  are disposed in the ends of a pair of side passages  30  and  32  which branch off of the flow tube  20 . Ultrasonically transparent covers  27  may be provided where the side passages  26  and  28  intersect the flow tube  20  to reduce or prevent flow disturbances at the intersections. The ultrasonic transducers  26  and  28  and the side branches  30  and  32  are arranged such that ultrasonic pulses traveling between the transducers  26  and  28  pass through the flow tube  20  at an angle to its central axis. That is, ultrasonic pulses traveling between the transducers  26  and  28  travel along a path which is angled to the path of flow of respiratory gases through the flow tube  20 . As shown, the side passages  30  and  32  essentially form an interrupted tube which intersects the flow tube  20  at an angle. As will be clear to those of skill in the art, ultrasonic pulses traveling between the transducers  26  and  28  have a component of their direction of travel which is parallel to the direction of flow of respiratory gases through the flow tube  20 . 
     Measurement of flow velocity using ultrasonic pulses is described in U.S. Pat. Nos. 5,419,326; 5,503,151; 5,645,071; and 5,647,370, all to Harnoncourt et al, which are incorporated herein by reference. In the Harnoncourt patents, ultrasonic transducers are positioned so as to transmit pulses through a flowing fluid in a direction that has a component in the flow direction. Specifically, with fluid flowing through a tube, the transducers are positioned in the side walls of the tube at an angle such that ultrasonic pulses are transmitted at an angle to the fluid flow. Flow speed may be calculated based on the fact that ultrasonic pulses traveling with the flow travel faster while ultrasonic pulses traveling against the flow travel slower. Mathematical corrections are made for the fact that the ultrasonic pulses are traveling at an angle to the flow. Preferably, pulses are alternately transmitted in a direction with the flow and in a direction against the flow so that a time difference may be calculated. The present invention may use ultrasonic transducers comprising a metalized polymer film and a perforated metal sheet. In one preferred embodiment, the ultrasonic flow measurement system is supplied by NDD of Zurich, Switzerland and Chelmsford, Mass. 
     Ultrasonic pulses are transmitted with and against the direction of flow, resulting in measurement of upstream and downstream transit times. If the gas flow rate is zero, the transit times in either direction through the gas are the same, being related to the speed of sound and distance traveled. However, with gas flow present, the upstream transit times differ from the downstream transit times. For constant flow, the difference between sequential upstream and downstream transit times is directly related to the gas flow speed. Further details of this approach to ultrasonic flow sensing may be obtained by reference to Applicant&#39;s co-pending patent application Ser. No. 09/630,398, which is incorporated herein in its entirety by reference. Processing circuitry and additional sensors may be provided within the housing  12  for processing signals from the ultrasonic sensors  26  and  28 , as also described in Applicant&#39;s co-pending application referred to above. Also, a fan  29  may be provided to force fresh air over some of the internal circuitry. As shown, the nitric oxide sensor  24  is positioned in the wall of the flow tube  20  approximately midway between the ultrasonic transducers  26  and  28 . Therefore, the same portion of the flow is measured for flow speed and nitric oxide concentration at the same time, allowing coordination of the data. 
     Referring now to FIGS. 3 and 4, one embodiment of a nitric oxide sensor  24  is shown. Preferably, instantaneous nitric oxide concentration is measured at the same time flow is measured. In the presently preferred embodiment of the present invention, a fluorescence-based nitric oxide sensor is used to determine the partial pressure of nitric oxide in the respiration gases passing through the flow tube  20 . 
     Fluorescence based oxygen sensors are known in the art, for example as described by Colvin (U.S. Pat. Nos. 5,517,313; 5,894,351; 5,910,661; and 5,917,605; and PCT International Publication WO 00/13003, all of which are incorporated herein by reference). A sensor typically comprises an oxygen permeable film in which oxygenindicating fluorescent molecules are embedded. In U.S. Pat. Nos. 5,517,313 and 5,894,351, Colvin describes sensors using a silicone polymer film, and suggests using a ruthenium complex, tris(4,7-diphenyl-1,10-phenanthroline)ruthenium (II) perchlorate, as the oxygen indicator fluorophore molecule. The orange-red fluorescence of this ruthenium complex is quenched by the local presence of oxygen. Oxygen diffuses into the oxygen permeable film from the gas flowing over the film, inducing fluorescence quenching. The time response of the quenching effect, relative to concentration changes of oxygen in the gas outside the film, is related to the thickness of the film. Thin films are preferred for a rapid response, as described in U.S. Pat. No. 5,517,313. 
     Referring now to FIGS. 3 and 4, the fluorescence based nitric oxide sensor used in the present embodiment is shown generally at  24 . FIG. 3 is an exploded view and FIG. 4 is a cross sectional view. The presently preferred sensor is based on the technology described in the Colvin patents but has a chemistry adapted to detection of nitric oxide. A circuit board  40  has a plurality of pins  42  extending downwardly for interconnecting the sensor with other components. An LED  44  is mounted generally to the center of the top of the circuit board. A pair of photodiodes  46  and  48  are also mounted to the top of the circuit board. The photodiodes are mounted symmetrically on opposite sides of, and a short distance from, the LED  44 . An optical filter is mounted on top of each photodiode; filter  50  is mounted on photodiode  46  and filter  52  is mounted on photodiode  48 . The optical filters preferably are bonded to the photodiodes with an optically clear adhesive. 
     A heat spreader  54 , preferably a thin copper sheet with down-turned edges, is mounted to the top of the circuit board. The heat spreader has a downwardly extending foot  56  at each of its four corners, each of which engage a hole  58  in the circuit board  40 . The feet and the down-turned edges of the heat spreader  54  support the central portion of the heat spreader a short distance above the circuit board, leaving a gap therebetween. The LED  44 , the photodiodes  46  and  48 , and the filters  50  and  52  are disposed in this gap between the circuit board and the heat spreader. Two round holes  60  are cut in the heat spreader, one hole being directly above each of the photodiodes  46  and  48 . Two pieces of glass substrate  62  and  64  are mounted to the top of the heat spreader, with one piece being mounted directly on top of each of the holes  60 . As shown, these pieces of substrate  62  and  64  are square. A circle of fluorescent film is formed on top of each of the pieces of substrate; film circle  66  is formed on substrate  62  and film circle  68  is formed on substrate  64 . A gas impermeable glass cover  70  is disposed over film circle  66  and bonded to the glass substrate  62  with epoxy  72 . Therefore, film circle  66  is sealed in by the cover  70  above and the epoxy  72  at the edges. This results in one of the film circles,  68 , being exposed to the surrounding atmosphere, while the other film circle,  66 , is sealed in and not exposed. Therefore, film circle  66  does not react to changes in nitric oxide concentration while film circle  68  does. Film circle  68  will be referred to as a sensing region and film circle  66  will be referred to as a reference region. The substrates  62  and  64  and the materials applied to them form the sensing face of the sensor. 
     Referring again to FIG. 4, the gap between the circuit board  40  and the heat spreader  54 , as well as the holes  60 , are filled with an optically clear waveguide material  74 . The waveguide material  74  serves to optically couple the LED  44  to the glass substrates  62  and  64 , making the substrates an integral part of the waveguide. The waveguide material also optically couples the sensing region  68  and reference region  66  to the filters  50  and  52  and the photodiodes  46  and  48 . The result is a continuous optical waveguide that optically couples these components. Suitable waveguide materials are manufactured by Norland Products of New Brunswick, N.J., and by Epoxy Technology of Bilerica, Mass., the latter under the name EPOTEK®. 
     In order to avoid problems with condensation forming on the sensing region  68  and the reference region  66 , the regions are preferably both warmed using the heat spreader  54 . For this purpose, small heaters  76 , comprising resistors, are mounted to the circuit board  40  adjacent each of the foot mounting holes  58 . The heat spreader feet  56  are soldered into the holes, and to the heaters  76  so that heat is transferred into the spreader. A thermistor  78  is mounted to the circuit board  40  in a position such that it contacts one of the down-turned edges of the heat spreader  54  when the sensor is assembled. The thermistor may be soldered to the edge to improve heat transfer. The thermistor is then used to monitor the temperature of the heat spreader, and the heaters are controlled so as to maintain a generally constant temperature. An EEPROM, containing calibration data for the sensor, may be mounted to the underside of the circuit board. 
     The fluorescent films  66  and  68  are formed of materials whose fluorescence or absorbance characteristics change as a function of nitric oxide concentration. As an example, thiol or sulfhydryl may be joined to a fluorophore such as pyrene giving sulfhydrylpyrene). In this respect, an article entitled “Determination of Nitric Oxide Levels by Fluorescence Spectroscopy” by G. Gabor and N. Allon, published in the  Biochemical, Pharmacological, and Clinical Aspects of Nitric Oxide  (Edited by B. A. Weissman et al., Plenum Press, New York, 1995) is incorporated herein in its entirety. 
     Radiation from the LED is transmitted to the sensing region  68  and the reference region  66  by the optical waveguide material  74 . The wavelength emission of the LED  44  is chosen to induce fluorescence from the fluorescent film regions  66  and  68 . Fluorescence emissions from the sensing and reference regions, preferably shifted in wavelength compared to the LED radiation, are detected by the two photodiodes. Photodiode  46  detects fluorescence from the reference region  66 , and photodiode  48  detects fluorescence from the sensing region  68 . The optical filters  50  and  52  overlie the photodiodes, to pass the fluorescence radiation while rejecting other wavelengths, in particular the excitation radiation from the LED. The optical filters  50  and  52  may be an epoxy coating, a glass filter, or a polymeric-based sheet material. Preferably, a prefabricated polymeric-based sheet material is used. The emissions from the LED  44  and the fluorescence emissions from the films  66  and  68  pass through holes  60  in the plate  54 . Preferably, the film circles  66  and  68 , the holes  60 , and the active areas of the photodiodes  46  and  48  are all circles of similar diameter. 
     During nitric oxide sensing measurements, the substrates  62  and  64  and sensing region  68  and reference region  66  preferably are maintained at a temperature sufficient to reduce problems associated with moisture condensation. The heating of the substrate is achieved by passing electrical current through the four surface-mounted resistors  76 . The temperature of the copper plate  54  is monitored by the thermistor  78 , allowing the heating current through the resistors and temperature to be regulated. If moisture was eliminated from the gas flow by some means, e.g. chemical drying, water absorbing/adsorbing substances, membranes, filters, foam sheets, etc., or prevented from condensing on the fluorescent film, such as by some surface treatment (a nitric oxide-permeable hydrophobic film or other approaches), then the sensor need not be heated. 
     The thin fluorescent films used in the nitric oxide sensor respond very rapidly to changes in nitric oxide concentration thereby providing the sensor with instantaneous response, as that term is defined herein. The sensor has a response time preferably less than or equal to 200 milliseconds, and most preferably less than or equal to 100 ms. Even faster response times may be preferable for certain applications. 
     Additional details concerning the present approach to component gas concentration sensing may be obtained by reference to the discussion of a similar oxygen sensor in Applicant&#39;s co-pending patent application Ser. No. 09/630,398, incorporated herein in its entirety by reference. As will be clear to those of skill in the art, other types of nitric oxide concentration sensors may be used as long as they have an instantaneous response and are not sampling-based sensors. Also, the concentration of other component gases may be monitored using a meter similar to the one illustrated in the present invention. For example, an oxygen sensor may be added or may be substituted for the nitric oxide sensor so as to construct a calorimeter is accordance with Applicant&#39;s co-pending patent application Ser. No. 09/630,398. 
     In the simplest embodiment of the present invention, the nitric oxide concentration sensor is provided on the side of the flow tube, and flow sensors are not provided. In this embodiment, instantaneous nitric oxide concentrations may be monitored during respiration providing a curve of nitric oxide concentrations. This data may be useful in the diagnosis and treatment of various diseases without obtaining flow data. In a more complicated, and preferred, embodiment of the present invention, flow sensors as previously discussed are also included. The flow sensors allow for determination of many additional parameters, including many respiratory parameters such as flow rate, flow volume, lung capacity, and others. For example, by including flow sensors, the meter can be used as a spirometer. The peak flow, the forced vital capacity (FVC), and the forced expiratory volume during the first second (FEV  1 ) may be derived from the collected data. The nitric oxide data, such as the time dependent concentration, may be combined with these parameters. A modified version of the present invention may also be used to determine functional residual capacity as explained in U.S. Pat. Nos. 5,540,233 to Larsson et al and 5,957,128 to Hecker et al, both of which are incorporated herein by reference. 
     Referring now to FIG. 5, a first alternative embodiment of a nitric oxide meter according to the present invention is generally shown at  90 . This embodiment of the present invention differs from the previous embodiment in that the flow pathway or flow tube  92  is generally rectangular in cross-section. This illustrates that the flow tube does not necessarily have to be circular in cross-section. 
     Referring now to FIGS. 6 and 7, a second alternative embodiment of a nitric oxide meter according to the present invention is generally shown at  100 . This embodiment has a configuration similar to the configuration of the calorimeter described in Applicant&#39;s co-pending patent application Ser. No. 09/630,398. Details of this embodiment may be obtained by referenced to the co-pending application. Basically, the meter  100  includes a body  102  with a mask  104  extending therefrom. A display  106  is arranged on one side of the body  102  and a combination control button and indicator light  108  is disposed on another side of the body  102 . Referring to FIG. 7, a cross-section of this embodiment is illustrated. Unlike with the previous embodiment, the flow pathway is not a straight through design. Instead, the respiration gases follow a path generally indicated by arrows A through G through the body  102  and mask  104  of the meter  100 . The flow tube  110  is arranged perpendicularly to the flow of respiration gases to and from the mask  104 . An inlet conduit  112  interconnects the mask  104  with the flow tube housing  114 . Ultrasonic flow sensors  116  and  118  are arranged above and below the ends of the flow tube  110  so as to measure the flow coaxially. Unlike the embodiment of FIGS. 1 and 2, calculation of flow velocity does not require correction for the flow sensors being arranged at an angle to the flow. This embodiment also differs from the previous embodiments in that the nitric oxide sensor  120  is positioned adjacent the flow pathway but below the bottom end of the flow tube  110 . A nitric oxide meter according to the present invention may also be constructed in accordance with the other embodiments of the calorimeter discussed in Applicant&#39;s co-pending application Ser. No. 09/630,398, by substituting a nitric oxide sensor, as previously described, for the oxygen sensor used with a calorimeter. Other calorimeter designs that may be modified according to the present invention are disclosed in U.S. Pat. Nos. 4,917,108; 5,038,792; 5,178,155; 5,179,958; and 5,836,300, all to Mault, a co-inventor of the present application, are incorporated herein by reference. 
     As will be clear to those of skill in the art, it may be beneficial to provide a nitric oxide meter which may be sanitarily used by multiple users without significant risk of transfer of germs. Referring again to FIG. 2, the mask  14  may include a biological filter  15  disposed therein to prevent the transfer of biological materials into the body  12  of the meter  10  from the mask  14 . One example of a biological filter material  15  is Filtrete® from 3M. The use of the biological filter material allows the mask  14  and/or the filter material  15  to be changed between users so as to provide sanitation. Other approaches to providing sanitary respiratory devices are described in Applicant&#39;s copending patent application Ser. No. 09/630,398. 
     Referring now to FIG. 8, a third alternative embodiment of a nitric oxide meter according to the present invention is generally shown at  130 . This embodiment is also designed for use by multiple users while providing sanitation. It includes a disposable portion  132  and a reusable portion  134 . The disposable portion includes a flow tube  136 , which is generally cylindrical and of constant cross-section, extending perpendicularly from a respiratory connector such as a mask  138 . A pair of openings  140  are disposed in the upper side of the flow tube  136  near opposite ends of the flow tube. Extending downwardly within the flow tube from the openings  140  are ultrasonically transparent, sanitary barrier socks  142 . Alternatively, the socks could be replaced with more rigid structures with ultrasonically transparent windows therein. A third opening  144  is disposed in the upper side of the flow tube and has a piece of sanitary barrier material  146  disposed therein. 
     The reusable portion  134 , is configured to mate with the upper side of the flow tube  136 . The reusable portion has an elongated arcuate body  135  with a pair of ultrasonic transducers  148  extending downwardly from the body  135  on posts  150 . The ultrasonic transducers  148  and posts  150  are sized and positioned so as to enter the openings  140  in the disposable portion  132  when the reusable portion  134  is mated therewith. When the two portions are coupled, the ultrasonic transducers  148  are positioned approximately in the center of the flow tube  136  within the sanitary barrier socks  142 . The ultrasonic transducers  148  are preferably of the small, micromachined type and work as previously described. However, because they are positioned within the flow tube itself, the pulses traveling between the ultrasonic sensors are coaxial with the flow and do not require correction based on ultrasonic pulses traveling at an angle to the flow. A nitric oxide sensor, as previously described, is also supported on the body  135  of the reusable portion  134 , and is generally indicated at  152 . It is sized and positioned so as to fit into the third opening  144  in the upper side of the flow tube so that it is in contact with the flow within the flow tube, but protected from biological contamination by the filter material  146 . A display  154  may also be provided on the reusable portion  134 . In this embodiment, the reusable portion  134  may be retained for multiple uses and users while the disposable portion is specific to an individual user. As explained in Applicant&#39;s co-pending patent application Ser. No. 09/630,398, the meter of FIGS. 6 and 7 may also include a disposable and a reusable portion. 
     Referring now to FIG. 9, another embodiment of a nitric oxide meter according to the present invention is generally shown at  160 . This embodiment is similar to the first embodiment of the present invention in that the meter  160  includes a generally cylindrical flow tube  162  with the ultrasonic flow sensors being disposed in side passages angled to the flow tube. However, in this embodiment, a disposable insert  164  which includes a mouthpiece  166  and a sanitary sleeve  168 . The sleeve portion  168  of the insert  164  slides into the flow tube  162  so as to line the flow tube. The sleeve is ultrasonically transparent so that the ultrasonic flow sensors can monitor flow through the sleeve  168 . A nitric oxide sensor  170  is disposed in the underside of the flow tube  162  so as to be in contact with flow through the sleeve  168 . The sleeve is either porous to nitric oxide or includes a window having material that. allows the passage of nitric oxide. As a further aspect of the present invention, data processing, storage, and analysis may be performed by a remote computing device such as a personal digital assistant (PDA)  172 . The PDA  172  is docked into an interface  174  which is wired to the sensor body. Alternatively, data may be transferred between the sensor and the PDA by wireless means or by transfer of memory modules which store data, as described in Applicant&#39;s co-pending patent application Ser. No. 09/669,125, incorporated herein in its entirety by reference. Also, the nitric oxide meter may communicate with other remote devices, such as stationary or portable computers and remote devices such as servers via the Internet or dock or interconnect with a PDA, as also described in the co-pending application. These alternatives apply to all embodiments of the present invention. 
     Referring now to FIG. 10, an additional aspect of the present invention will be discussed. As explained in the Background, administration of nitric oxide to the respiratory system of a patient is beneficial in the treatment of some disorders. A system for the controlled administration of nitric oxide to a patient is generally shown at  200  in FIG.  10 . The system includes a respiration gas source  202  which is interconnected with respiratory connector  204  by a conduit  206 . The respiratory connector may be of any type, such as a mask or a connector for intubating the patient. A nitric oxide source  208  is also provided and is interconnected with the conduit  206  by a control valve  210 . A nitric oxide meter  212  according to the present invention is disposed in the conduit  206  so that respiration gases mixed with nitric oxide flowing through the conduit  206  pass through the meter  212 . A control system  214  is interconnected with the meter  212  and the control valve  210  so as to provide feedback control of the nitric oxide administration system. Meter  212  may be constructed according to any of the embodiments of the present invention and includes a nitric oxide sensor operable to determine the instantaneous concentration of nitric oxide in the respiration gases flowing through the meter. The output of the meter  212  is fed to the control system  214 . The control system  214  then controls the control valve  210  so as to maintain the desired concentration of nitric oxide flowing through the conduit  206 . As will be clear to those of skill in the art, the system  200  may be used with any of the approaches of administering controlled amounts of nitric oxide as described in the prior art. For example, pulses of nitric oxide may be administered to the patient rather than having continuous flow. The meter  212  is useful in determining the changing quantity of nitric oxide during such an administration procedure. As will be clear to those of skill in the art, the system  200  may also be configured as a forced respiration system for patients requiring assistance in respiration or as part of an anesthesia system. Alternatively, the nitric oxide meter  212  may monitor both inhalation and exhalation. In this case the meter is preferably very close to the connector  204  to minimize dead air space. Instead, two meters may be used. 
     As will be clear to those of skill in the art, various alterations may be made to the above-described embodiments of the present invention without departing from its scope or teaching. For example, the nitric oxide meters could include graphic displays to show profiles of nitric oxide, breath flow, or other parameters for a period of time such as a single breath or one minute. Data may also be averaged over multiple breaths to provide an averaged profile. The meter, or other devices used with the meter, may include a memory and a processor to store flow profiles or nitric oxide profiles indicative of various physiological conditions including a healthy normal state and various physiological disorders. The meter or associated computational device may then compare the patient&#39;s data with the stored profiles in order to make a preliminary diagnosis. A PDA may interconnect with the nitric oxide meter and provide the necessary display and processing as well as diagnosis. Other alternatives will also be clear to those of skill in the art. It is the following claims, including all equivalents, which define the scope of the present invention.