Patent Application
20240027336
The present disclosure relates to the measurement of nitric oxide gas, particularly as related to nitric oxide therapies.
Nitric oxide therapy has shown promise in several areas of medicine, especially in the field of pulmonology. In particular, research has shown that nitric oxide therapy may aid in the treatment of pulmonary arterial hypertension (PAH). PAH is a sometimes-fatal condition characterized by increased blood pressure in the lungs resulting from obstructions in the arteries of the lung. Pharmacological treatment of PAH is not particularly effective, with at least 50% of patients dying during 2-5 years depending on the stage of the disease. While the precise mechanisms of disease progression are not entirely clear, several factors have been implicated in the pathology of PAH. One of the most important mediators is Nitric Oxide (NO), a lack of which has been found to contribute to pulmonary artery vasoconstriction, vascular remodeling, and right ventricular failure associated with PAH pathology.
The vasodilator and anti-proliferative actions of NO make it an attractive tool for pharmacological treatment of PAH. Administration of NO gas by inhalation has been shown to be beneficial to patients with PAH, particularly in children with congenital heart diseases. However, inhaled NO therapies are hampered by high costs, technical difficulties, and inconsistent patient response. Rapid withdrawal of inhaled NO therapy can also have deleterious effects with levels of oxygenation and pulmonary hypertension returning to levels worse than those seen prior to the commencement of therapy.
Nitric oxide has other possible applications in gene therapy. Currently, gene-based therapy is recognized as a powerful new therapeutic weapon for treating pulmonary arterial hypertension. Genetic manipulation may be supplemental to standard pharmacotherapy or be used as a stand-alone treatment. However, genetic material must be transferred into cells and expressed at a desired level to provide therapeutic benefits. NO may play a role in improving gene transduction in gene therapies for treating PAH.
Accurate NO level sensing is paramount for NO generation, especially for medical applications. Numerous approaches have been used and proposed for monitoring the concentration of nitric oxide in a gas mixture. Existing methods include mass spectroscopy, electrochemical analysis, calorimetric analysis, chemiluminescence analysis, and piezoelectric resonance techniques. However, each of these approaches have shortcomings that make them poorly suited for 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 produced or delivered NO levels. 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. However, 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. Such 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 a 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 in U.S. Pat. No. 5,565,075 to Davis et al, incorporated herein by reference. Electrochemical-based devices have high sensitivity and accuracy but require frequent calibration and associated service costs and delays.
Chemiluminescent-based sensors depend on the oxidation of nitric oxide by mixing nitric oxide with ozone, O3, to create nitrogen dioxide (NO2) 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 may be 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 are typically very large and expensive and their accuracy is sensitive to environmental factors.
The most convenient and reliable gas analysis method for sensors of this field is direct optical measurements of gas components by adsorption of light at certain wave lengths. The main advantage of this method is stability of adsorption in time because the adsorption coefficient is fundamentally constant. Accordingly, stable measurements can be provided without frequent calibration so long as the optical instruments are kept clean. Current gas analyzers 10 based on light adsorption (see
Accordingly, it is a principal object of the present invention to overcome at least some of the disadvantages of prior art plasma generation systems. This is provided in one embodiment by a sensor for measuring nitric oxide concentration in a sample, the sensor comprising: an ozone source for oxidizing nitric oxide within a sample to form NO2; and one or more light adsorption measurement systems for determining NO2 levels in the sample in the nitric oxide analyzer before and after oxidizing.
In one embodiment, the light adsorption measurement system comprises a light source positioned to pass light through the sample within the sensor. In another embodiment, the sensor further comprises a light sensor positioned to receive light from the light source passed through the sample within the sensor.
In one embodiment, the light source emits light having a wavelength of about 350 nm to about 400 nm. In another embodiment, the light source comprises one or more LEDs.
In one embodiment, the sensor further comprises a processor configured to receive adsorption data from the one or more light adsorption measurement systems and determine an NO2 level therefrom. In another embodiment, the sensor comprises one or more mirrors for reflecting light to pass through the sample one or more times before entering the light sensor, thereby increasing the beam length for measurement of low concentrations of NO2.
In one embodiment, a first light adsorption measurement system is positioned upstream of the ozone source and a second light adsorption measurement system is positioned downstream of the ozone source.
In another embodiment, the processor is in communication with the ozone source and is configured to control ozone introduction to the sample through a valve or pump and to determine NO2 levels before and after introducing ozone to the sample.
In one independent embodiment, a method for measuring nitric oxide concentration in a sample is provided, the method comprising: oxidizing nitric oxide within a volume of sample using ozone to form NO2; measuring light adsorption by NO2 within the sample to determine NO2 levels in the sample in the nitric oxide analyzer before and after oxidizing; and subtracting NO2 levels determined before oxidizing from NO2 levels determined after oxidizing to determine a nitric oxide concentration in the sample.
In one embodiment, the method further comprises passing light through the sample from a light source within the sensor. In another embodiment, the method further comprises measuring light intensity in light from the light source passed through the sample within the sensor using a light sensor.
In one embodiment, the light source emits light having a wavelength of about 350 nm to about 400 nm. In another embodiment, the light source comprises one or more LEDs.
In one embodiment, a first light adsorption measurement system is positioned upstream of the ozone source and a second light adsorption measurement system is positioned downstream of the ozone source, the method comprising subtracting NO2 levels from the first light adsorption measurement system from NO2 levels from the second light adsorption measurement system.
In another embodiment, the method further comprises measuring NO2 levels in the sample, then introducing ozone the sample, then measuring NO2 levels in the sample again to determine NO2 levels before and after oxidizing.
In one embodiment, the method further comprises passing the light through the sample a plurality of times before receiving the light with the light sensor.
In one embodiment, determining nitric oxide levels is according to the formula C2*(C2N/C1N)−C1, where: C1N is the NO2 level from the first light adsorption measurement system before introduction of ozone; C2N is the NO2 level from the second light adsorption measurement system before introduction of ozone, C1 is the NO2 level from the first light adsorption measurement system after oxidation with ozone; and C2 is the NO2 level from the second light adsorption measurement system after oxidation with ozone.
In another embodiment, the method further comprises cyclically introducing ozone to the sample to oxidize the NO2 therein, wherein determining nitric oxide levels is according to the formula CNO=(Ln(Imax/Imin))*Kcal−CNO2, where: CNO2=(Ln(Imax/Iin))*Kcal; Iin is initial light intensity of light passed through the sample at the beginning of an ozone introduction cycle; Imin is minimal light intensity of light passed through the sample during the ozone introduction cycle; Imax is maximal light intensity of light passed through the sample during the ozone introduction cycle; and Kcal is a calibrating coefficient.
Additional features and advantages of the invention will become apparent from the following drawings and description.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, the patent specification, including definitions, governs. As used herein, the articles “a” and “an” mean “at least one” or “one or more” unless the context clearly dictates otherwise. As utilized herein, “and/or” means any one or more of the items in the list joined by “and/or”. As an example, “x and/or y” means any element of the three-element set {(x), (y), (x, y)}. In other words, “x and/or y” means “x, y or both of x and y”. As another example, “x, y, and/or z” means any element of the seven-element set {(x), (y), (z), (x, y), (x, z), (y, z), (x, y, z)}.
Further, unless expressly stated to the contrary, “or” refers to an inclusive or and not to an exclusive or. For example, a condition A or B is satisfied by anyone of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).
In addition, use of the “a” or “an” are employed to describe elements and components of embodiments of the instant inventive concepts. This is done merely for convenience and to give a general sense of the inventive concepts, and “a” and “an” are intended to include one or at least one and the singular also includes the plural unless it is obvious that it is meant otherwise.
As used herein, the term “about”, when referring to a measurable value such as an amount, a temporal duration, and the like, is meant to encompass variations of +/−10%, more preferably +/−5%, even more preferably +/−1%, and still more preferably +/MI % from the specified value, as such variations are appropriate to perform the disclosed devices and/or methods.
The following embodiments and aspects thereof are described and illustrated in conjunction with systems, tools and methods which are meant to be exemplary and illustrative, but not limiting in scope. In various embodiments, one or more of the above-described problems have been reduced or eliminated, while other embodiments are directed to other advantages or improvements.
For a better understanding of the invention and to show how the same may be carried into effect, reference will now be made, purely by way of example, to the accompanying drawings in which like numerals designate corresponding sections or elements throughout.
With specific reference now to the drawings in detail, it is stressed that the particulars shown are by way of example and for purposes of illustrative discussion of the preferred embodiments of the present invention only, and are presented in the cause of providing what is believed to be the most useful and readily understood description of the principles and conceptual aspects of the invention. In this regard, no attempt is made to show structural details of the invention in more detail than is necessary for a fundamental understanding of the invention, the description taken with the drawings making apparent to those skilled in the art how several forms of the invention may be embodied in practice. In the accompanying drawings:
Before explaining at least one embodiment in detail, it is to be understood that the invention is not limited in its application to the details of construction and the arrangement of the components set forth in the following description or illustrated in the drawings. The invention is applicable to other embodiments being practiced or carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.
Systems and methods of the disclosure provide more accurate and responsive nitric oxide sensors useful in providing fast feedback for control of nitric oxide generation in the medical field as well as other areas. As discussed above, light adsorption systems are the most desirable from a standpoint of ease-of-use, affordability, accuracy, and packaging but are not readily applied to nitric oxide. NO2, however, is readily detectable using such methods, having adsorption bands in the 400 nm wavelength range. Accordingly, in certain embodiments systems and methods of the disclosure may oxidize NO to NO2 and then use light adsorption sensors to measure the level of NO2 which can then be used to infer the amount of NO in the system. Multiple sensors may be used to determine pre and post oxidation levels of NO2 in the sample gas to provide a more accurate analysis of what amount of post-oxidized NO2 level is attributable to oxidized NO.
Systems and methods may include nitric oxide analyzers positioned in a measurement line comprising a pump and an outlet to vent measured gas from the system. Such analyzers may include an ozone source for oxidizing nitric oxide to form NO2 within the nitric oxide analyzer and one or more light adsorption measurement systems for determining NO2 levels in gas in the nitric oxide analyzer before and after oxidizing. The light adsorption measurement system may include a light source positioned to pass light through the sample and a light sensor positioned to receive light passed therethrough. The light may have a wavelength in the range of about 350 nm to about 400 nm and may come from, for example, an LED. The sensor may comprise a transparent portion to allow light to enter and leave the interior of the sample-filed sensor.
A computer system may be in communication with the light adsorption measurement system in order to receive adsorption data therefrom and calculate NO levels accordingly. In certain embodiments, a plurality of light adsorption measurement systems may be used with positioning before and after the ozone source in order to establish a baseline level of NO2.
Sensors of the disclosure may include one or more mirrors for reflecting light to pass through the sample one or more times before entering the light sensor, thereby increasing the beam length for measurement of low concentrations of NO2. Accordingly, small concentrations of NO2 can be detected in narrow sensor chambers.
In various embodiments, nitric oxide levels may be determined using the equation:
C2*(C2N/C1N)−C1 EQ. 1
where: C1N is the NO2 level from the first light adsorption measurement system before introduction of ozone; C2N is the NO2 level from the second light adsorption measurement system before introduction of ozone; C1 is the NO2 level from the first light adsorption measurement system after oxidation with ozone; and C2 is the NO2 level from the second light adsorption measurement system after oxidation with ozone.
In certain embodiments, nitric oxide levels may be determined according to equation:
C
NO=(Ln(Imax/Imin))*Kcal−CNO2 EQ. 2
where: CNO2=(Ln(Imax/Iin))*Kcal; Iin is initial light intensity of light passed through the sample at the beginning of an ozone introduction cycle; Imin is the minimal light intensity of light passed through the sample during the ozone introduction cycle; Imax is the maximal light intensity of light passed through the sample during the ozone introduction cycle; and Kcal is a calibrating coefficient.
As described above, accurate measurement of NO levels is important in many applications and especially in the medical field where inaccurate measurements can have serious implications to patient health. Systems and methods of the disclosure provide accurate and fast acting NO sensors for determining NO concentration in output gas from NO generators as well as other sources including in patient exhalation. In preferred embodiments, such sensors rely on the oxidation of NO to NO2 by, for example, the introduction of ozone to the output gas, as shown in
Particularly,
To calculate NO concentration by proxy of NO2 concentration after oxidation of NO by ozone, a baseline NO2 concentration may be established. To do this NO2 concentration may be measured optically in a first cuvette (e.g. NO2 meter 130) before oxidation and then after ozone flow admixing in a second cuvette (e.g. NO2 meter 140).
For optical measurements of NO2 concentration, light radiation emitted by, for example, an LED with a wavelength of about 400 nm is passed through the optical cuvette. NO2 concentration can be calculated based on observed light adsorption as follows:
I=Io*exp(−K*Cno2) EQ. 3
where I is light intensity after absorption, Io is light intensity without absorption (with zero NO2 concentration), Cno2 is NO2 concentration and K is a predetermined coefficient depending on the wavelength of light and units used and is proportional to cuvette length.
NO2 concentration may be calculated by the following procedure. First, the device may be zeroed by taking a base reading. In zeroing, the NO2 concentration in the cuvette is in one embodiment zero. For zeroing, the controller can take digital readings (Uo) of the signal from the amplifier amplifying the signal from the light sensor while NO2 concentration in the cuvette is zero. Using Uo, the following calculation is made:
N=Ln(Umax/Uo) EQ. 4
where Umax is maximal and Uo is the digital readings from zeroing.
Then the NO2 concentration can be calculated by:
C=(Ln(Umax/Uav)−N)*Kcal EQ. 5
where Uav is the average of actual digital readings of an ADC obtained during a certain time (time averaging can be entered in a program menu), Kcal is a calibrating coefficient (can be adjusted during calibration).
If the NO2 concentration is still zero and Uav is equal to Uo, NO2 readings are zero. In other cases the readings will be proportional to the NO2 concentration in the cuvette and can be made equal to the actual NO2 concentration by changing Kcal. NO concentration is calculated by comparison of readings in the first and second cuvettes by the following steps.
Two zeroing processes may be completed. In one embodiment, both cuvette channels are zeroed as described above. At initialization, the NO2 concentration in both cuvettes are in one embodiment zero. A mixture of NO and NO2 is then injected into the system. Ozone capacity is still set to zero. Then the NO2 concentration in both cuvettes is measured, as described above, and saved to memory as C1N and C2N. Then zeroing can be finished and the operation mode can start. In the operation mode, the sensor can calculate NO concentration by the following formula:
NO=C2*(C2N/C1N)−C1 EQ. 6
where C2 and C1 are the current NO2 readings from the first and second cuvette channels. The algorithm may be corrected to remove the influence of any oxidation of NO2 by ozone. Fortunately, the reaction rate of ozone with NO is faster than the reaction of ozone with NO2. The rate constant of NO+O3→NO2+O2 in the temperature range of 283-443 K was published in August 1980 by H. H. Lippmann, et al. The reaction NO+O3→NO2+O2 has been studied in a 220-m3 spherical stainless-steel reactor under stopped-flow conditions below 0.1 mtorr total pressure. Under the conditions used, the mixing time of the reactants was negligible compared with the chemical reaction time. The pseudo-first-order decay of the chemiluminescence owing to the reaction of ozone with a large excess of nitric oxide was measured with an infrared sensitive photomultiplier. One hundred twenty-nine decays at 18 different temperatures in the range of 283-443 K were evaluated. A weighted least-squares fit to the Arrhenius equation yielded k=(4.3±0.6)×10−12 exp[−(1598±50)/T] cm3/molecule sec (two standard deviations in brackets). The Arrhenius plot showed no curvature within experimental accuracy. Comparison with recent results suggests that a nonlinear fit, as proposed by these authors, is more appropriate over an extended temperature range.
The rate constant for the reaction O3+NO2→O2+NO3 over the temperature range 259-362° K was published by Robert E. Huie, et al, in an article titled “The rate constant for the reaction O3+NO2→O2+NO3 over the temperature range 259-362° K”, published August 1974. The rate constant for the reaction of ozone with nitrogen dioxide has been measured over the temperature range 259 to 362° K, using a stopped-flow system coupled to a beam sampling mass spectrometer. A fit of the data to the Arrhenius equation gave:
k=(9.44±2.46)×1010 exp[(−2509±76)/T]cm3mol−1 sec−1 EQ. 7
So, the reaction rate of NO+O3 is: k=(4.3±0.6)×10−12 exp[−(1598±50)/T] cm3/molecule sec=2.15 10−14 cm3/molecule sec for T=300 K, and the reaction rate of NO2+O3 is: k=(9.44±2.46)×1010 exp[(−2509±76)/T] cm3 mol−1 sec−1=0.157×10−12 exp[(−2509±76)/T]=0.0036×10−14 cm3/molecule sec.
Accordingly, the reaction rate of NO with ozone is about 500 times faster than the reaction rate of NO2 with ozone and NO2 will start to react only when NO is completely oxidized. To find this moment, ozone capacity can be modulated as shown in the graph of
During an ozone modulation cycle (e.g., over one minute), NO concentration can be calculated by the formula above. Ozone levels can initially increase and then start to decrease after the moment of complete oxidation of NO and beginning of oxidation of NO2. The maximal concentration of NO calculated in the cycle is accepted as the level of NO concentration.
In a second embodiment, as shown in
C
NO2=(Ln(Imax/Iin))*Kcal CNO=Ln(Imax/Imin))*Kcal−CNO2 EQ. 8
where Iin is initial light intensity during ozone generator operation cycle, Imin is minimal light intensity during ozone generator operation cycle, Imax is maximal light intensity during ozone generator operation cycle and Kcal is a calibrating coefficient (can be adjusted during device calibration).
In one embodiment, a single ozone generator 110 can be used for measurements of NO and NO2 concentration in several independent gas flows as shown in
In the embodiment shown in
Exemplary NO analyzer specifications are described below:
As one skilled in the art would recognize as necessary or best-suited for the systems and methods of the disclosure, systems and methods of the disclosure may include computing devices that may include one or more of processor (e.g., a central processing unit (CPU), a graphics processing unit (GPU), etc.), computer-readable storage device (e.g., main memory, static memory, etc.), or combinations thereof which communicate with each other via a bus. Computing devices may include mobile devices (e.g., cell phones), personal computers, and server computers. In various embodiments, computing devices may be configured to communicate with one another via a network.
Computing devices may be used to control the systems described herein including operation of valves and pumps and processing of sensor data from NO sensors, and filter-related sensors.
A processor may include any suitable processor known in the art, such as the processor sold under the trademark XEON E7 by Intel (Santa Clara, CA) or the processor sold under the trademark OPTERON 6200 by AMD (Sunnyvale, CA).
Memory preferably includes at least one tangible, non-transitory medium capable of storing: one or more sets of instructions executable to cause the system to perform functions described herein (e.g., software embodying any methodology or function found herein); data (e.g., data to be encoded in a memory strand); or both. While the computer-readable storage device can in an exemplary embodiment be a single medium, the term “computer-readable storage device” should be taken to include a single medium or multiple media (e.g., a centralized or distributed database, and/or associated caches and servers) that store the instructions or data. The term “computer-readable storage device” shall accordingly be taken to include, without limit, solid-state memories (e.g., subscriber identity module (SIM) card, secure digital card (SD card), micro SD card, or solid-state drive (SSD)), optical and magnetic media, hard drives, disk drives, and any other tangible storage media.
Any suitable services can be used for storage such as, for example, Amazon Web Services, cloud storage, another server, or other computer-readable storage. Cloud storage may refer to a data storage scheme wherein data is stored in logical pools and the physical storage may span across multiple servers and multiple locations. Storage may be owned and managed by a hosting company. Preferably, storage is used to store records as needed to perform and support operations described herein.
Input/output devices according to the disclosure may include one or more of a video display unit (e.g., a liquid crystal display (LCD) or a cathode ray tube (CRT) monitor), an alphanumeric input device (e.g., a keyboard), a cursor control device (e.g., a mouse or trackpad), a disk drive unit, a signal generation device (e.g., a speaker), a touchscreen, a button, an accelerometer, a microphone, a cellular radio frequency antenna, a network interface device, which can be, for example, a network interface card (MC), Wi-Fi card, or cellular modem, or any combination thereof. Input/output devices may be used to enter desired NO concentration levels and flow rates and to alert users regarding sensor readings and the need for filter replacement.
One of skill in the art will recognize that any suitable development environment or programming language may be employed to allow the operability described herein for various systems and methods of the disclosure. For example, systems and methods herein can be implemented using C++, C #, Java, JavaScript, Visual Basic, Ruby on Rails, Groovy and Grails, or any other suitable tool. For a computing device, it may be preferred to use native xCode or Android Java.
It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
Unless otherwise defined, all technical and scientific terms used herein have the same meanings as are commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods are described herein.
All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the patent specification, including definitions, will prevail. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
It will be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather the scope of the present invention is defined by the appended claims and includes both combinations and sub-combinations of the various features described hereinabove as well as variations and modifications thereof, which would occur to persons skilled in the art upon reading the foregoing description.
The present application claims priority from U.S. patent application Ser. 63/123,166, filed Dec. 9, 2020, and entitled “Nitric Oxide Measurement”, the entire contents of which incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/IL21/51478 | 12/9/2021 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63123166 | Dec 2020 | US |
