阅读说明：本技术 一种呼气氨检测方法和装置 (Expiratory ammonia detection method and device ) 是由 韩益苹 韩杰 于 2019-12-10 设计创作，主要内容包括：本发明提出一种呼气氨检测方法,在呼气氨测试前服用一种含有碱性试剂的制酸剂；对呼气从口或鼻出来进入仪器直到传感器的整个过程进行升温或恒温；在PID检测器前增加过滤器,检测样本过滤氨气前后的传感器信号,信号差就是氨气的贡献,进而得到消除干扰的氨气浓度值。一种呼气氨气检测装置,由气路单元和总控制单元组成,气路单元采集和测量分析呼气样本,总控制单元对气路单元进行控制,并进行信息的收集、处理、存储与通讯。(The invention provides a breath ammonia detection method, wherein an antacid containing an alkaline reagent is taken before breath ammonia detection; the whole process that the breath comes out of the mouth or the nose and enters the instrument until the sensor is heated or kept at a constant temperature is carried out; and a filter is added in front of the PID detector, the detection sample filters sensor signals before and after ammonia gas filtration, and the signal difference is the contribution of the ammonia gas, so that the ammonia gas concentration value with interference eliminated is obtained. The utility model provides an expiration ammonia detection device, comprises gas circuit unit and total control unit, and the gas circuit unit is gathered and is measured the analysis expiration sample, and total control unit controls the gas circuit unit to the collection, processing, storage and the communication of information.)

1. A breath ammonia detection method, by breath ammonia sampling method and breath ammonia analysis method make up, characterized by, administrate a antacid comprising alkaline reagent before breath ammonia test; the whole process that the breath comes out of the mouth or the nose and enters the instrument until the sensor is heated or kept at a constant temperature is carried out; and a filter is added in front of the PID detector, the detection sample filters sensor signals before and after ammonia gas filtration, and the signal difference is the contribution of the ammonia gas, so that the ammonia gas concentration value with interference eliminated is obtained.

2. The method for detecting ammonia in breath according to claim 1, wherein said antacid comprises an alkaline reagent and a hydrophilic and hydrophobic component, wherein said hydrophilic and hydrophobic component is coated on the surface of said alkaline reagent.

3. The method of claim 2, wherein the antacid is added with a hydrophilic component selected from polyethylene glycol (PEG), polyethylene glycol (PVA), dextran (dextran) and chitosan (chitosan), and a hydrophobic component selected from hydrophobically-associated polyacrylamide and hydrophobic silica aerogel.

4. The method of claim 1, wherein the filter material of the filter is a 4A or 5A molecular sieve.

5. The exhaled ammonia gas detection apparatus according to claim 4, wherein the filtering material of the gas filtering apparatus (120) is a 4A molecular sieve modified with ferric chloride.

6. The method of claim 1, wherein the PID detector is a PID sensor with photoionization energy in excess of 10.2 eV.

7. The expiratory ammonia gas detection device adopted by the expiratory ammonia detection method according to claim 1, which comprises a gas path unit (100) and a master control unit (200), wherein the gas path unit (100) comprises an expiratory tube (110), a pressure sensor (190), a three-way electromagnetic valve (150), a gas filtering device (120), a detector (130), an air pump (161) and a temperature control device (140), the expiratory tube (110), the three-way electromagnetic valve (150), the gas filtering device (120), the detector (130) and a one-way valve (181) are connected in series, the other interface of the three-way electromagnetic valve (150) is directly connected in front of the detector (130), and the pressure sensor (190) is connected to a pipeline between the expiratory tube (110) and the three-way electromagnetic valve (150); the temperature control device (140) controls the temperature of the whole gas circuit to ensure that the breath sample is not condensed; the exhalation tube (110) is a tube lined with an inert material; the gas filtering device (120) is internally provided with a filtering material and can absorb ammonia gas; the detector (130) is used for detecting the concentration of ammonia in the expired air and is a PID sensor; the general control unit (200) is composed of a control module (210), a screen and visual operation interface (220), a GPRS-4G communication module (230) and a data storage module (240), controls the gas circuit unit, and collects, processes, stores and communicates information.

8. The exhaled ammonia gas detection device according to claim 6, wherein the exhalation tube (110) is lined with an inert material temperature control device (140) to raise or keep the temperature of the exhaled breath from the mouth or the nose to the instrument until the temperature of the sensor is constant, so as to ensure that the sample gas is not condensed, and is externally wrapped with a heating wire to heat the exhalation tube to 38-55 ℃; keeping the three-way electromagnetic valve (150), the gas filtering device (120), the detector (130) and the pipeline at constant temperature of 37-40 ℃; when the air pump (161) is started to purge the filtering material for regeneration, the temperature of the gas filtering device (120) is independently controlled to be raised to 150 ℃ and 200 ℃, so as to help the desorption of the adsorbed ammonia gas.

9. An exhaled ammonia gas detection apparatus according to claim 5, wherein the detector (130) is a PID sensor with photoionization energy in excess of 10.2 eV.

10. The expiratory ammonia gas detection device adopted by the expiratory ammonia detection method according to claim 1, which comprises a gas path unit (100) and a master control unit (200), wherein the gas path unit (100) comprises an expiratory tube (110), a pressure sensor (190), a first electromagnetic valve (182), a second electromagnetic valve (183), a gas chamber (170), a three-way electromagnetic valve (150), a gas filtering device (120), an analysis pump (162), a detector (130) and a temperature control device (140), the expiratory tube (110), the first electromagnetic valve (182), the second electromagnetic valve (183) and the gas chamber (170) are connected in series, the three-way electromagnetic valve (150), the gas filtering device (120), the analysis pump (162) and the detector (130) are connected in series at two ends of the gas chamber (170), and the other interface of the three-way electromagnetic valve (150) is directly connected to the front of the analysis pump (162), the pressure sensor (190) is connected to a pipeline between the expiratory tube (110) and the three-way electromagnetic valve (150); the temperature control device (140) controls the temperature of the whole gas circuit to ensure that the breath sample is not condensed; the general control unit (200) is composed of a control module (210), a screen and visual operation interface (220), a GPRS-4G communication module (230) and a data storage module (240), controls the gas circuit unit, and collects, processes, stores and communicates information.

Technical Field

The present invention relates to the field of breath detection.

Background

Clinically, changes in the nitrogen and ammonia content of the blood are associated with liver, brain, kidney, stomach, duodenum, oral cavity, and lung dysfunction. When the ammonia level in blood is higher than the ammonia concentration in air, it diffuses from the blood into the lungs and appears in the exhaled breath. Therefore, the exhaled ammonia gas can be used as a biomarker of various diseases and metabolic processes, so that the method replaces blood detection and provides a noninvasive diagnosis means for clinic. In recent years, changes in the breath ammonia content have been used to detect a number of physiological conditions, such as detection of helicobacter pylori infection, evaluation of liver reserve function, and monitoring of renal failure hemodialysis effectiveness.

In 1997, S.Davies et al used SIFT-MS analysis to quantitatively analyze ammonia exhaled from patients with end-stage renal disease during dialysis for the first time, and concluded that the concentration change of ammonia exhaled from patients at the beginning and end of dialysis has good correlation with Kt/V. However, the SIFT-MS analysis technique used is a laboratory technique and the instrument is very expensive. In 2002, D.J. Kearney et al conducted studies on exhaled ammonia measurement for diagnosis of H.pylori infection, and found that after a subject took a 300mg urea capsule, the exhaled ammonia levels of H.pylori-infected patients were significantly different from those of healthy subjects, demonstrating the feasibility of exhaled ammonia measurement for diagnosis of H.pylori infection. The self-developed optical fiber ammonia sensor is adopted, the experiment is a technology, and the equipment is expensive.

US 2004/0077965A 1 discloses a method for diagnosing helicobacter pylori infection by using a highly sensitive colorimetric ammonia gas sensor, wherein the ammonia gas sensor is directly connected with breath, the surface material of the ammonia gas sensor is polytetrafluoroethylene, the change values of the substrate ammonia gas concentration level and the ammonia gas level of the breath of a subject can be recorded, a suitable reflectance spectrum instrument is used for measurement, and then the change values are compared with the values of negative/positive helicobacter pylori infectors to determine the helicobacter pylori infection state of the subject. US6312918 discloses a simple helicobacter pylori examination method in which gas in the stomach cavity is introduced into the mouth by the vomiting reflex for measurement and is sucked up through a gas detection tube by a metering suction pump to read a color change region in the gas detection tube. However, the colorimetric sensor and the gas detection tube have the problems of long color development time and large sample amount, and the actual breath test operation has certain difficulty, consumption-type detection, high single detection cost and poor accuracy, so that the colorimetric sensor and the gas detection tube are difficult to be applied to detection of ppb-level ammonia required by liver and kidney function monitoring.

US20140221863a1 proposes a highly sensitive nanosensor of metal oxides (MoO 3 or WO 3) prepared by a sol-gel method to detect ammonia in exhaled breath, down to 50 ppb. However, this method is still a laboratory technique and has not been commercialized.

US8922219B2 discloses the use of a PID detector to selectively determine the presence of various compounds or gases in a breath sample, including the detection of ammonia. However, this PID technique is not designed for exhaled ammonia detection, but mainly for VOC gas, because PID detects ammonia with poor selectivity, there is no way to distinguish signal contributions of various target gases.

Although there are many published documents and patent reports, there is no mature and stable product technology at present due to the problems of sensitivity, stability and consistency of exhaled ammonia in sampling and analysis.

The reference values for oral expiratory ammonia gas mentioned in the above studies are very wide, and the values tested vary from 0.1 to 3ppm even under controlled experimental (e.g. fasting) conditions, which is not favorable for the specific diagnosis of disease. The reason for this may be that the ammonia sampling has more influence factors:

1) ammonia is very soluble in water, and ammonia molecules and water molecules are combined into ammonia monohydrate (NH) through hydrogen bonds ₃•H ₂O), a small portion of the energy of the ammonia monohydrate is ionized to ammonium ions (NH) ₄ ⁺) And hydroxide ion (OH) ^-) NH in solution ₃And NH ₄ ⁺The relative amount of (A) depends on the pH of the solution, in acidic solution, H ⁺Can remove all NH ₃Conversion to NH ₄ ⁺Basifying the solution with NH ₄ ⁺Loss of H ⁺And is converted into NH ₃NH when the solution pH =9.3 ₃And NH ₄ ⁺Is half by half. Therefore, the change of pH value of gastric acid will affect NH ₃The antacid is administered before sampling.

2) The humidity of the breath is nearly 100%, once the breath is quickly condensed into saturated water vapor, a large amount of ammonia is dissolved in water, and the result is low.

3) The chemical properties of ammonia molecules are very active, and the pipeline wall and the surface inside an analytical instrument can easily provide binding sites for gas-phase ammonia molecules, so that adsorption-desorption balance is caused: if the gas phase ammonia concentration increases beyond the gas wall equilibrium concentration, adsorption occurs, and if the gas phase concentration decreases, ammonia molecules are desorbed.

Most of the detection technologies mentioned in the above researches belong to laboratory technologies, and few instruments are available on the market for directly detecting the concentration of ammonia in exhaled air, and few methods and instruments are available for accurately measuring the concentration of ammonia in the ppb concentration range. And the components in the breath are too many, which easily interferes the detection of ammonia, so that the accuracy and selectivity of the sensor are difficult to meet the requirements.

How to improve measuring accuracy and selectivity, how to solve the sampling problem, precision problem and the VOC interference problem that prior art exists, the accurate ammonia concentration is obtained in the test, is a key technology of expiration ammonia measurement.

Disclosure of Invention

The invention aims to provide a high-selectivity, high-precision and low-cost expiratory ammonia detection method, which is applied to clinical routine detection of expiratory ammonia, overcomes the defects of the existing instruments and technologies, and solves the problems of sampling, precision and VOC interference in the prior art.

Firstly, to solve the problem of sampling NH3, ammonia gas is very soluble in water and is easily converted into ammonium ions (NH) in a meta-acid solution ₄ ⁺) Therefore, consideration is needed to maintain high NH3 production in the more acidic gastric juice without converting to NH ₄ ⁺In the literature, it is proposed that gastric juice is alkalized by taking antacid, NH4+ is converted into NH3 under alkaline condition, and expiration NH3 is increased, but different literatures have different types, dosage and administration time of the antacid, so that the test values of expiration ammonia are greatly different, and a unified standard is not provided. If helicobacter pylori infection is detected, the helicobacter pylori infection is judged by calculating the difference value between the substrate ammonia concentration and the ammonia concentration after urea administration, so that an antacid taken by people is also needed, and the consistency of the pH value of gastric acid when a substrate breath sample is collected and a breath sample is taken after urea administration is ensured as much as possible. On the aspect, a large number of groping tests are carried out, and the type, the dosage and the taking time of the antacid have certain influence on the concentration of NH3 in two breath sampling.

The antacid consists essentially of one or more alkaline agents such as sodium bicarbonate, precipitated calcium carbonate, magnesium oxide, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminum silicate, aluminum hydroxide, magnesium aluminate metasilicate, magnesium aluminum silicate and the like. The drugs of common antacids are: mylanta gastrecta (Mg (OH) 2 and Al (OH) 3), Weishuping, Weibizhi, Stdanshu, Gaiweiping, Almaguene tablet, etc.

The antacid agents in the market are tested, after the antacid agents are taken, the change of the basic ammonia concentration generated at different time is tested, the basic ammonia concentration tested at different time is sampled and tested for 3 times at each time point to obtain an average value, the basic ammonia concentration tested at different time is found to have larger change, and a stable plateau does not exist, so that the gastric acid has larger change during the test period, the pH value of the gastric acid cannot be effectively maintained at a higher level, and the analysis reason may be that the adopted alkaline reagents cannot be quickly dissolved in water, enter the stomach or precipitate at the bottom of the stomach, and are quickly excreted into duodenum along with normal peristalsis. Therefore, an antacid is prepared, the condition that common alkaline reagents are insoluble in water is considered, the emulsion containing hydrophilic and hydrophobic components is added and coated on the surface of the alkaline reagent, the retention time of the alkaline reagent in the stomach is prolonged, the alkaline reagent is slowly released, the change of the basic ammonia concentration along with the time is tested, and the basic ammonia concentration is stabilized on a platform after half an hour.

The hydrophilic component added to the antacid may be polyethylene glycol (PEG), Polyethylene (PVA), dextran (dextran), or chitosan (chitosan). The hydrophobic component added in the antacid can be hydrophobic gel, which is hydrogel containing a certain amount of hydrophobic segments or hydrophobic groups in the gel, such as hydrophobic association polyacrylamide, hydrophobic silica aerogel, etc.

After the problem of ammonia generation is solved, how to ensure that the generated NH3 is not hydrolyzed in sampling is considered, because the humidity in the breath is nearly 100%, once the breath is quickly condensed into saturated water vapor, a large amount of ammonia is dissolved in water, and a large amount of experiments prove that two effective measures can be used, namely, nose breathing and oral cavity hydrolysis are avoided, and secondly, the nose outlet is immediately kept warm, the temperature of the whole device is maintained to be not lower than the temperature of the exhaled air, and the condensation of the exhaled air can be prevented.

Because the chemical property of ammonia gas molecules is very active, the gas path is made of any material, and the ammonia concentration can be influenced by the temperature control range of the gas path. Through experimental exploration, the constant temperature scheme adopted by people is as follows: heating or keeping constant temperature in the whole process from the expiration coming out of the mouth or the nose and entering the instrument to the sensor to ensure that the sample gas is not condensed, wherein the expiration pipe is a pipe lined with inert materials, and is externally wrapped with a heating wire to heat the expiration pipe to 38-55 ℃; and (4) keeping the ammonia sensor and the connecting pipeline at constant temperature of 37-40 ℃.

In addition, ensuring high sensitivity and specificity of ammonia breath determination requires a highly sensitive and highly selective ammonia sensor. The PID detection technology is selected to measure trace gas with the concentration range of ppb and can ensure higher sensitivity, but the PID is broad-spectrum and is generally used in industrial environment, so that the key technology for measuring the ammonia in the expiration is how to improve the selectivity of measurement and how to eliminate the response of the interference gas to the sensor. The selectivity can be improved by selecting proper photoionization energy, and the aim can be achieved by selecting a filter capable of filtering interference gas.

Due to the physicochemical properties of ammonia, it is not easy to find a material that can filter interfering gas components without adsorbing ammonia. By searching, the method for filtering ammonia gas can be adopted to detect the sensor signals before and after the ammonia gas is filtered by the sample, and the signal difference is the contribution of the ammonia gas, so that the ammonia gas concentration value with interference eliminated is obtained. The 4A molecular sieve adsorbs and filters ammonia at normal temperature, and the VOC is usually far more than 4A and is not adsorbed, so the 4A or 5A molecular sieve can be used as a material for filtering ammonia. Meanwhile, because the ionization energy of ammonia gas is 10.18eV, PID with the photoionization energy exceeding 10.2eV is selected, only NH3 and partial VOC can be detected, and interference of other components is not brought, so that the problem of measurement selectivity is solved. Through a large number of experiments, the adsorption effect of the iron chloride modified 4A molecular sieve on ammonia gas can reach 99%. In addition, the desorption regeneration problem of the molecular sieve is also considered, the temperature control device can independently control the temperature of the gas filtering device to rise to 150-.

Thus, we propose a method for breath ammonia detection, consisting of a breath ammonia sampling method and a breath ammonia analysis method, characterized in that an antacid comprising an alkaline reagent is administered prior to breath ammonia testing; the whole process that the breath comes out of the mouth or the nose and enters the instrument until the sensor is heated or kept at a constant temperature is carried out; and a filter is added in front of the PID detector, the detection sample filters sensor signals before and after ammonia gas filtration, and the signal difference is the contribution of the ammonia gas, so that the ammonia gas concentration value with interference eliminated is obtained.

If the helicobacter pylori infection is detected, the difference value of ammonia concentration before and after urea administration is required to be detected to judge the helicobacter pylori infection. Therefore, the antacid containing hydrophilic and hydrophobic components is added into the alkaline reagent of the antacid taken before the test of the ammonia in expiration, the hydrophilic and hydrophobic components are wrapped on the surface of the alkaline reagent, the retention time of the alkaline reagent in the stomach is increased, the alkaline reagent is slowly released, and the stability of the pH value of gastric acid in two sampling processes is ensured.

The application of the expiratory ammonia detection method solves the problems of sampling, precision and VOC interference in the prior art, so that the expiratory ammonia detection can be applied to clinical routine detection, can be applied to detection of helicobacter pylori infection, and can also be applied to detection of liver reserve function evaluation, renal failure hemodialysis effect monitoring and the like.

A breath ammonia detection device adopted by the breath ammonia detection method is composed of a gas circuit unit (100) and a master control unit (200), wherein the gas circuit unit (100) collects, measures and analyzes breath samples, and the master control unit (200) controls the gas circuit unit and collects, processes, stores and communicates information. The gas path unit (100) consists of an expiratory tube (110), a pressure sensor (190), a three-way electromagnetic valve (150), a gas filtering device (120), a detector (130), an air pump (161) and a temperature control device (140), wherein the expiratory tube (110), the three-way electromagnetic valve (150), the gas filtering device (120), the detector (130) and a one-way valve (181) are connected in series, the other interface of the three-way electromagnetic valve (150) is directly connected in front of the detector (130), and the pressure sensor (190) is connected to a pipeline between the expiratory tube (110) and the three-way electromagnetic valve (150); the temperature control device (140) controls the temperature of the whole air path to ensure that the breath sample is not condensed.

The exhalation tube (110) is a tube lined with an inert material, preferably polytetrafluoroethylene, which has a low ammonia adsorption on its surface. The gas filtering device (120) is internally provided with a filtering material and can absorb ammonia gas. The inner filling filtering material of the gas filtering device (120) is a 4A or 5A molecular sieve, preferably a ferric chloride modified 4A molecular sieve, and has a better ammonia adsorption effect. The detector (130) is for detecting the concentration of ammonia in the expired breath and is a PID sensor, preferably a PID sensor with a photoionization energy in excess of 10.2 eV. The temperature control device (140) is a heating wire wrapped outside the expiration pipe and heats the expiration pipe to 38-55 ℃; the three-way electromagnetic valve (150), the gas filtering device (120), the detector (130) and the pipeline are kept at constant temperature of 37-40 ℃. The temperature control device (140) can also independently control the temperature of the gas filtering device (120) to rise when the air pump (161) is started to sweep and regenerate the filtering material, so as to help the desorption of the adsorbed ammonia gas.

The general control unit (200) is composed of a control module (210), a screen and visual operation interface (220), a GPRS-4G communication module (230) and a data storage module (240). Patient information can be input on the screen and the visual operation interface (220), a test is started, and sampling and analysis results are displayed. The control module (210) controls whether the expired air passes through the gas filtering device (120) by controlling the opening and closing of the three-way electromagnetic valve, can monitor and record the pressure condition of the airflow in the sampling process, judges when the three-way electromagnetic valve is opened and closed, records the sampling time, can control the temperature of different parts according to requirements, collects and records analysis signals and gives a calculation result. The general control unit (400) can also be provided with a GPRS-4G communication module (430) to provide a networking function, and monitoring data can be uploaded to the cloud platform in time. The overall control unit (400) may also be provided with a data storage module (440) for storing data.

The scheme of the exhaled ammonia detection device overcomes the defects of the existing instruments and technologies, and can accurately sample and accurately analyze the ammonia component in exhaled air, so that the exhaled ammonia detection technology is applied to clinical routine detection. Because the sampling and analyzing scheme of the device is directly used for online breath analysis, certain requirements are placed on the flow and the time of breath, and VOC in the former and later breath may be different, so that the deviation of the final result is caused, and further optimization can be performed.

The other expiratory ammonia detection method adopts an expiratory ammonia detection device which comprises a gas circuit unit (100) and a master control unit (200), wherein the gas circuit unit (100) collects, measures and analyzes an expiratory sample, and the master control unit (200) controls the gas circuit unit and collects, processes, stores and communicates information. The gas path unit (100) consists of an expiratory tube (110), a pressure sensor (190), a first electromagnetic valve (182), a second electromagnetic valve (183), a gas chamber (170), a three-way electromagnetic valve (150), a gas filtering device (120), an analysis pump (162), a detector (130) and a temperature control device (140), wherein the expiratory tube (110), the first electromagnetic valve (182), the second electromagnetic valve (183) and the gas chamber (170) are connected in series, the three-way electromagnetic valve (150), the gas filtering device (120), the analysis pump (162) and the detector (130) are connected in series at two ends of the gas chamber (170), the other interface of the three-way electromagnetic valve (150) is directly communicated with the atmosphere, and the pressure sensor (190) is connected to a pipeline between the expiratory tube (110) and the three-way electromagnetic valve; the temperature control device (140) controls the temperature of the whole air path to ensure that the breath sample is not condensed. The temperature control device (140) can also be started when the three-way electromagnetic valve (150) and the second electromagnetic valve (183) are opened and the analysis pump (162) is started, and the temperature of the gas filtering device (120) is independently controlled to be raised when the air is extracted, the air is swept, and the filtering material is regenerated, so that the desorption of the adsorbed ammonia gas is facilitated.

The general control unit (200) is composed of a control module (210), a screen and visual operation interface (220), a GPRS-4G communication module (230) and a data storage module (240), controls the gas circuit unit, and collects, processes, stores and communicates information.

Above-mentioned expiration ammonia gas detection device's scheme has increased air chamber and circulation gas circuit, and the patient as long as will breath all with one mouthful after holding breath, just can accomplish the sampling, greatly reduced to the requirement of exhaling. And the VOC concentration in the two sections of exhalations is kept consistent, and can be accurately deducted to obtain the ammonia concentration value for eliminating interference.

Drawings

FIG. 1 shows the change of the basic ammonia concentration over time with different antacid administration.

FIG. 2 is a view showing the construction of the ammonia gas detecting device of FIG. 1.

FIG. 3 is a view showing the construction of the ammonia gas detecting device in FIG. 2.

Detailed Description

For the purpose of making the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the accompanying drawings and embodiments, it being understood that the specific embodiments described herein are only for the purpose of illustrating the present invention and are not to be construed as limiting the present invention.