CN118050417A - Method for detecting oral exhaled breath ammonia by ion mobility spectrometry - Google Patents
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Abstract
The invention relates to a method for detecting oral exhaled breath ammonia by ion mobility spectrometry, belonging to the technical field of chemical analysis and detection. The method comprises the following specific steps: preparing standard gases of exhaled ammonia with different concentrations, sampling the standard gases into an ion mobility spectrometer, and sequentially detecting the standard gases to obtain quantitative standard curves with different concentrations; directly sampling oral cavity exhaled breath into an ion mobility spectrometry, obtaining an ion mobility spectrometry of a sample to be detected in real time, tracking a change curve of the exhaled breath ammonia signal intensity in real time, judging oral cavity ammonia at the tail end of exhalation to obtain quantitative factors of oral cavity and exhaled breath ammonia, and calculating the ammonia concentration at the tail end of oral cavity according to the quantitative curve of oral cavity exhaled breath ammonia. The invention adopts a direct photoionization single photon ion mobility spectrometry on-line detection technology, has very high sensitivity and specific signal response to low-concentration ppbv ammonia in the exhaled breath of a person, and meanwhile, the ion molecular reaction is not interfered by other components in the exhaled breath, so that the exhaled breath ammonia concentration can be monitored in real time, and an effective detection method is provided for monitoring functions of organs such as liver, kidney and the like, and protecting life health.
Description
Technical Field
The invention belongs to the field of analytical chemistry instrument detection, and particularly relates to an analytical detection method for detecting oral exhaled breath ammonia by using an ion mobility spectrometry.
Background
Ammonia is an important component of human metabolism, participates in a plurality of physiological processes of human body, is closely related to diseases such as renal failure, liver cirrhosis or hepatitis, hepatic encephalopathy, helicobacter pylori infection, halitosis and the like, and is also a potential biomarker for exercise physiology and drug metabolism research. Meanwhile, ammonia has neurotoxicity, and rapid bedside monitoring is important for the identification and early warning of critical diseases. Alveolar ammonia partial pressure and arterial ammonia partial pressure are nearly equal, so a change in expiratory ammonia concentration level may suggest a corresponding pathophysiological change. The human body exhales ammonia concentration low, humidity is big, the background is complicated, and is very high to exhale ammonia sampling and detection requirement. Therefore, development of a detection method with high specificity and sensitivity is required.
In recent years, many studies on online detection of expired ammonia have been made, and Z.H.Endre et al in 2011 use SIFT-MS to continuously monitor expired ammonia for renal dialysis patients, indicating that expired ammonia can well evaluate the efficacy of dialysis; 2016, bayrakli et al, based on spectroscopic detection of exhaled breath from healthy and helicobacter pylori patients, demonstrate the potential advantages of exhaled breath detection in noninvasive diagnosis of helicobacter pylori; in 2020, chen Mingren et al detected respiratory ammonia of 121 chronic kidney disease patients by using semiconductor sensors, and the results showed that there was a good correlation between respiratory ammonia and blood urea nitrogen level, serum creatinine level and glomerular filtration rate; 2021, jinya Ishida et al used chemical sensors to detect exhaled ammonia from chronic liver disease patients, demonstrated a relationship between exhaled ammonia and liver dysfunction, and verified the feasibility of using exhaled ammonia in chronic liver disease diagnosis.
The existing detection method of the exhaled breath ammonia comprises gas chromatography, photometry, a sensor, other methods and the like, wherein the chromatography and chromatography-mass spectrometry technology is most widely applied to the detection of the exhaled breath ammonia, but has the defects of higher cost, large volume, special technician operation and the like, the photometry has simple operation steps, but has poor stability and reproducibility, and the sensor method has the advantages of microminiaturization, short response time and the like, but has inaccurate quantification and the like. The advantages of low concentration of ammonia in human expiration, high humidity, multiple components and adsorption property of ammonia are provided for accurate qualitative identification and high-sensitivity detection of the ammonia in expiration. Han Yiping et al (CN 110780063A) discloses an expired ammonia detection sensor device, which relates to ammonia adsorption and desorption, lacks accuracy, and has no stable and accurate detection technology and real-time analysis detection method so far.
The ion mobility spectrometry has high specificity in the aspect of monitoring trace exhaled breath components, is very suitable for detecting gas phase ammonia in complex matrixes under a high humidity background, and can realize high-sensitivity and high-selectivity detection of exhaled breath ammonia by automatic quantitative correction of humidity without removing water vapor. Aiming at various problems existing in the analysis and detection method, the invention adopts the acetone modified photoionization ion mobility spectrometry to detect the oral exhaled breath ammonia, realizes the accurate quantitative detection of the oral exhaled breath ammonia, and is applied to the detection of the ammonia content in the oral exhaled breath of a human body.
Disclosure of Invention
The technical problems to be solved by the invention are as follows: the method is characterized by comprising the steps of carrying out quantitative detection on the ammonia with different concentrations in a wide range by adopting an acetone modified photoionization migration spectrum, and carrying out quantitative detection on the ammonia with different concentrations in a high-low wide concentration range, and carrying out quantitative detection on the ammonia with the oral cavity exhaled breath, so as to obtain a concentration change curve of the ammonia with the oral cavity exhaled breath, concentration changes of the ammonia with the oral cavity exhaled breath before and after gargling, concentration changes of the ammonia with the oral cavity exhaled breath in the day and concentration distribution of the ammonia with the oral cavity exhaled breath of different people in real time, thereby providing a simple, rapid, noninvasive and noninvasive analysis method for clinical detection of the ammonia with the oral cavity exhaled breath, and providing an analysis detection technology for evaluation of liver and kidney functions of organs and the like.
A method for detecting oral exhaled breath ammonia by ion mobility spectrometry, which comprises the following specific steps:
(1) Establishing a standard curve of the exhaled breath ammonia, selecting standard samples of the exhaled breath ammonia with different concentrations, sampling the standard samples into an ion mobility spectrometry in real time for detection to obtain ion mobility spectrometry of the exhaled breath ammonia standard gas with different concentrations, adopting a photoionization ion mobility spectrometry of an acetone modifier, and performing linear quantitative fitting on a quantitative factor of the exhaled breath ammonia obtained by detection and the concentration of the corresponding exhaled breath ammonia to obtain the standard curve of the exhaled breath ammonia, wherein the quantitative factor of the exhaled breath ammonia is the ratio of the signal intensity of the exhaled breath ammonia in the ion mobility spectrometry to the total ion signal intensity in the ion mobility spectrometry;
Selecting 9 groups of standard ammonia gas samples with 100% RH humidity in a concentration range of 100-2000ppb, wherein the concentration is ：C1(ppb)、C2(ppb)、C3(ppb)、C4(ppb)、C5(ppb)、C6(ppb)、C7(ppb)、C8(ppb)、C9(ppb);, five parallel samples are taken from each group, the 9 groups of ammonia gas standard gases with different concentrations are detected by adopting ion mobility spectrometry to obtain corresponding quantitative factors, namely X 1、X2、X3、X4、X5、X6、X7、X8 and X 9, and a linear equation of a standard curve of the high concentration for quantification of oral exhaled breath ammonia is obtained by fitting: y=a×x+b, fitting to obtain R 2 ≡0.90, wherein Y represents a response quantitative factor of the exhaled breath ammonia, X represents a concentration of the exhaled breath ammonia, and R 2 represents a fitting degree of the exhaled breath ammonia; a and b are constants and are set to be constant,
The quantitative curve of the exhaled breath ammonia is characterized by determining the migration time of the ammonia by an ion mobility spectrometry, determining the detected substance, quantifying by a quantitative factor of ammonia response, and drawing a standard curve of the exhaled breath ammonia concentration relative to the quantitative factor of ammonia response peak.
The ion mobility spectrometer is a photoionization ion mobility spectrometer of an acetone modifier, and experimental conditions adopted are as follows: the electric field strength of the migration tube is: 300-500V/cm, the temperature of a migration tube is 50-200 ℃, the flow rate of acetone carrier gas is 50-200mL/min, the flow rate of bleaching gas is 200-500mL/min, the sampling flow rate is 50-200mL/min, the flow rate of purge gas is 500-3000mL/min, the flow rate of ion migration spectrum sampling by pumping is 50-200mL/min, and the carrier gas and bleaching gas are compressed air treated by silica gel, active carbon and molecular sieve, wherein the water vapor content is lower than 10ppm.
The method comprises the steps of adopting an ion mobility spectrometry to carry out real-time sampling detection on an oral exhaled air sample, wherein an oral cavity is opposite to an air blowing port of a sampling tube of the ion mobility spectrometry to carry out exhaled air sampling, and pumping and sampling the sampled exhaled air sample by a sampling pump to enter an ion mobility spectrometry reaction zone to carry out real-time detection, so as to obtain an ion mobility spectrometry of oral exhaled air and a real-time exhaled air monitoring curve, and continuously tracking a variation curve of an oral exhaled air quantitative factor to obtain the concentration of oral exhaled end ammonia in a single exhalation period;
comparing the detected ion mobility spectrogram of the oral cavity exhaled breath ammonia with the ion mobility spectrogram of the exhaled breath ammonia standard gas, and calculating the actual concentration of the ammonia in the oral cavity exhaled breath according to the standard curve of the exhaled breath ammonia.
The flow rate of the ion mobility spectrometry is 50-200ml/min through pumping sampling, the exhaled gas sample is pumped into a reaction area of the ion mobility spectrometry in real time to react with reagent ions to generate molecular ions, and due to the high selectivity of reagent molecules and the high proton affinity of ammonia molecules in the photoionization ion mobility spectrometry, the high selectivity detection of the exhaled gas ammonia can be realized through the specific and high-sensitivity proton transfer reaction, other components in the exhaled gas cannot react, the interference of the exhaled gas ammonia detection is avoided, and thus the real-time tracking and monitoring of the exhaled gas ammonia concentration can be realized.
Purging the sampling pipeline by using purge gas with different flow rates, wherein the set flow rate ranges from 500ml/min to 3000ml/min to obtain a breathing curve of the exhaled air ammonia at different purge gas flow rates, the breathing cycle of a normal person is about 5 seconds, the residue of the exhaled air ammonia in the pipeline can be reduced by increasing the flow rate of the purge gas, and the breathing curve of the exhaled air ammonia is monitored in real time; in addition, the quantitative factor of the exhaled ammonia remains substantially the same at different purge gas flow rates, which have no effect on the signal response of the exhaled ammonia.
Further, the method is adopted to detect the concentration of the oral exhaled breath ammonia before and after the mouth rinse, and the change of the concentration of the oral exhaled breath ammonia before and after the mouth rinse is obtained.
Further, the method is adopted to continuously monitor the daily oral exhaled breath ammonia concentration change of the person, and a daily change curve of the oral exhaled breath ammonia is obtained.
Further, the concentration of the oral exhaled breath ammonia of different individuals in the morning in the fasting state is detected, and the concentration distribution of the oral exhaled breath ammonia of different individuals is obtained.
Further, the method can be used for real-time tracking and monitoring of the concentration and change of the oral exhaled ammonia, can be used for evaluating the basic metabolism level of a human body, or can be used for evaluating the functions of organs such as liver and kidney, and the like, and the concentration change of the exhaled ammonia can be used for effects such as kidney dialysis, helicobacter pylori infection, and the like.
The technical innovation of the invention is that:
1. the invention is suitable for detecting the exhaled breath ammonia of the human mouth, and the exhaled breath sample does not need complex pretreatment, and can be directly sampled and detected on line in real time.
2. The method can directly sample and detect the exhaled air in real time, widens the application of the ion mobility spectrometry, does not have any influence on people, has the advantages of no wound, no invasion, high detection speed, high sensitivity, strong specificity, low detection limit and low detection cost, can be operated by operators without professional training, and is convenient for the detectors to detect rapidly on site.
3. The method can be used as an index of basic metabolism of human ammonia by detecting the concentration of the exhaled air in the mouth of a human body, and can be used as an auxiliary evaluation index of organ function monitoring.
Drawings
Fig. 1 is a schematic diagram of an ion mobility spectrometry structure for detecting oral exhaled breath ammonia, wherein 1 is a photoionization source, 2 is a high-voltage power supply, 3 is a first mass flowmeter, 4 is an air extraction sampling pump, 5 is a purge gas, 6 is an on-line dilution gas source, 7 is an air inlet, 8 is a carrier gas source of a modifier, 9 is a drift gas source, 10 is a second mass flowmeter, 11 is a third mass flowmeter, 12 is an acetone modifier generating device, and 13 is an ion mobility tube drift gas inlet.
Figure 2 quantification of oral exhaled breath.
Figure 3 shows a real-time trace of the oral exhaled breath ammonia concentration.
Fig. 4 changes in oral exhaled breath ammonia concentration before and after.
Figure 5 is a graph of a box plot of changes in oral exhaled breath ammonia concentration over the day.
Figure 6 concentration profile of oral exhaled breath in different populations.
Detailed Description
The detailed description of the present invention will be described in more detail with reference to the drawings and examples so that the aspects and advantages of the present invention can be better understood.
The ion migration tube adopted by the invention comprises a photoelectric ionization source (vacuum VUV lamplight ionization source) and a Faraday disk which are oppositely arranged at the left end and the right end respectively, and an ion gate positioned between the photoelectric ionization source and the Faraday disk, wherein the area between the photoelectric ionization source and the ion gate is an ionization area, and the area between the ion gate and the Faraday disk is a migration area;
an air outlet is arranged on one side, close to the photoelectric ion source, of the upper wall surface of the ionization region of the ion transfer tube, one end of an air outlet pipeline is connected with the air outlet, the other end of the air outlet pipeline is sequentially connected with a mass flowmeter and an air extraction sampling pump and then is exhausted (connected with the atmosphere), an air inlet is arranged on one side, close to the ion gate, of the upper wall surface of the ionization region of the ion transfer tube, the air inlet is connected with a sampling tube and an online dilution tube, and the air outlet, the air inlet and a floating air inlet arranged on one side, close to the ion detector, of the transfer region on the outer wall surface of the ion transfer tube form an air path circulation system external interface of the ion transfer tube together;
One end of a modifier pipeline is connected with the bleaching gas inlet through a second mass flowmeter and an acetone modifier generating device, the other end of the modifier pipeline is connected with a carrier gas source, one end of the bleaching gas pipeline is connected with the bleaching gas inlet through the second mass flowmeter, and the other end of the bleaching gas pipeline is connected with the bleaching gas source;
a high voltage power supply is provided between an electrode ring on the ionization source side and an electrode ring on the Faraday disk side.
Example 1
9 Groups of standard ammonia gas samples with the RH humidity of 100% are selected in the concentration range of 100-2000ppb, and the concentration X of the standard ammonia gas samples is respectively as follows: five parallel samples of 100ppbv, 200ppbv, 500ppbv, 800ppbv, 1000ppbv, 1200ppbv, 1500ppbv, 1800ppbv and 2000ppbv are taken from each group, and are sampled into an ion mobility spectrometry in real time for quantitative detection to obtain quantitative factors Y of ammonia with different concentrations, namely 0.036, 0.062, 0.146, 0.228, 0.286, 0.338, 0.412, 0.501 and 0.539 respectively, as shown in fig. 2, so as to obtain a quantitative curve of oral cavity exhaled air ammonia, wherein R 2 = 0.999, the concentration of the exhaled air ammonia in a normal healthy human cavity ranges from 100ppbv to 2000ppbv, and the concentration of the exhaled air ammonia has a better linear response. The RSD obtained by correcting each concentration is 1.42% -3.89%, and the method has good repeatability and wide linear dynamic range, can meet the analysis requirement of NH 3 in respiratory gas, and can realize quantitative analysis of oral exhaled ammonia.
The ion mobility spectrometer is a photoionization ion mobility spectrometer of an acetone modifier, and experimental conditions adopted are as follows: the electric field strength of the migration tube is: 500V/cm, the temperature of the migration tube is 130 ℃, the flow rate of acetone carrier gas is 100mL/min, the flow rate of bleaching gas is 500mL/min, the sampling flow rate is 100mL/min, the flow rate of purge gas is 2000mL/min, the flow rate of ion mobility spectrometry sampling by pumping is 700mL/min, and carrier gas, bleaching gas and on-line dilution gas are compressed air treated by silica gel, active carbon and molecular sieve, wherein the water vapor content is lower than 10ppm.
Example 2
The method is applied to detection of oral exhaled breath ammonia of different human bodies, acquires oral exhaled breath ammonia of a human body in real time to detect the oral exhaled breath ammonia in an ion mobility spectrometry, obtains an ion mobility spectrometry of the oral exhaled breath ammonia, tracks quantitative factor change of oral exhaled breath ammonia concentration in real time, and obtains a single breath curve of the oral exhaled breath ammonia, as shown in fig. 3, is a continuous monitoring curve of successive exhaled NH 3 of a healthy volunteer, and shows the characteristics of quick response and real-time analysis of the method. The initial NH 3 concentration during exhalation increases rapidly and the ammonia signal curve drops sharply to baseline at the cessation of exhalation. The single expiration detection only needs 3 seconds, and 5 repeatable breathing curves can be recorded in less than 30 seconds, the response to each expiration is rapid, the corresponding quantitative factors are stable, the reliability and the effectiveness of the method are proved, and the maximum height of the single breathing curve is used as the quantitative factor of oral exhaled breath ammonia for quantifying the oral exhaled breath ammonia.
10 Healthy people 18-60 years old are monitored by the method, and at different times 9;00, 11;00, 14;30 and 17; as shown in fig. 4, the concentration of the oral exhaled breath ammonia is diluted before and after the mouth is rinsed, so that the concentration of the exhaled breath ammonia after the mouth is lower than that before the mouth is rinsed, and the sampling and detection conditions of each person are required to be consistent when the oral exhaled breath ammonia is monitored;
The daily changes in oral ammonia were continuously monitored in 10 healthy persons aged 18-60 using this method, as shown in fig. 5, with a large change in exhaled NH 3 concentration over time, which may be related to an increase in basal metabolic rate, and exhaled NH 3 concentration was reported to be also related to protein intake, exercise load and oral pH levels.
Oral expired air NH 3 from 24 healthy people 18-60 years old was tested by this method (7:30-9:30 on the morning) to minimize the effects of diet and daytime changes. And calculating the concentration of the oral exhaled breath ammonia according to the quantitative curve of the oral exhaled breath ammonia, so as to obtain the concentration distribution of the oral exhaled breath ammonia of different people. As shown in FIG. 5, the histogram of the measurement results shows that the concentration is close to normal distribution, the concentration of all exhaled sample NH 3 (185-1393 ppbv) is in the range of 100-2000ppbv in linear quantitative limit, the average concentration of the crowd is 649ppbv, the 95% confidence interval (95% CI) is 284-1123ppbv, and a reference range is provided for the concentration of exhaled NH 3 in the oral cavity of the healthy crowd.
According to the method, the exhaled breath of different healthy people is detected by monitoring the change of the oral ammonia concentration of the different healthy people, so that an exhaled breath ammonia real-time monitoring curve can be obtained, and a better analysis and detection method is provided for the subsequent exhaled breath ammonia concentration and organ function monitoring.
Claims (4)
1. A method for detecting oral exhaled breath ammonia by ion mobility spectrometry, which is characterized by comprising the following specific steps:
(1) Establishing a standard curve of the exhaled breath ammonia, selecting standard samples of the exhaled breath ammonia with different concentrations, sampling the standard samples into an ion mobility spectrometry in real time for detection to obtain ion mobility spectrometry of the exhaled breath ammonia standard gas with different concentrations, adopting a photoionization ion mobility spectrometry of an acetone modifier, and performing linear quantitative fitting on a quantitative factor of the exhaled breath ammonia obtained by detection and the concentration of the corresponding exhaled breath ammonia to obtain the standard curve of the exhaled breath ammonia, wherein the quantitative factor of the exhaled breath ammonia is the ratio of the signal intensity of the exhaled breath ammonia in the ion mobility spectrometry to the total ion signal intensity in the ion mobility spectrometry;
(2) The method comprises the steps of adopting an ion mobility spectrometry to carry out real-time sampling detection on an oral exhaled air sample, wherein an oral cavity is opposite to an air blowing port of a sampling tube of the ion mobility spectrometry to carry out exhaled air sampling, and pumping and sampling the sampled exhaled air sample by a sampling pump to enter an ion mobility spectrometry reaction zone to carry out real-time detection, so as to obtain an ion mobility spectrometry of oral exhaled air and a real-time exhaled air monitoring curve, and continuously tracking a variation curve of an oral exhaled air quantitative factor to obtain the concentration of oral exhaled end ammonia in a single exhalation period;
(3) Comparing the detected ion mobility spectrogram of the oral cavity exhaled breath ammonia with the ion mobility spectrogram of the exhaled breath ammonia standard gas, and calculating the actual concentration of the ammonia in the oral cavity exhaled breath according to the standard curve of the exhaled breath ammonia.
2. The method according to claim 1, characterized in that: the specific process for establishing the standard curve in the step (1) is as follows:
Selecting 9 groups of standard ammonia gas samples with 100% RH humidity in a concentration range of 100-2000ppb, wherein the concentration is ：C1(ppb)、C2(ppb)、C3(ppb)、C4(ppb)、C5(ppb)、C6(ppb)、C7(ppb)、C8(ppb)、C9(ppb);, five parallel samples are taken from each group, the 9 groups of ammonia gas standard gases with different concentrations are detected by adopting ion mobility spectrometry to obtain corresponding quantitative factors, namely X 1、X2、X3、X4、X5、X6、X7、X8 and X 9, and a linear equation of a standard curve of the high concentration for quantification of oral exhaled breath ammonia is obtained by fitting: y=a×x+b, fitting to obtain R 2 ≡0.90, wherein Y represents a response quantitative factor of the exhaled breath ammonia, X represents a concentration of the exhaled breath ammonia, and R 2 represents a fitting degree of the exhaled breath ammonia; a and b are constants and are set to be constant,
The quantitative curve of the exhaled breath ammonia is characterized by determining the migration time of the ammonia by an ion mobility spectrometry, determining the detected substance, quantifying by a quantitative factor of ammonia response, and drawing a standard curve of the exhaled breath ammonia concentration relative to the quantitative factor of ammonia response peak.
3. The method according to claim 1, characterized in that:
The ion mobility spectrometer is a photoionization ion mobility spectrometer of an acetone modifier, and experimental conditions adopted are as follows: the electric field strength of the migration tube is: 300-500V/cm, the temperature of a migration tube is 50-200 ℃, the flow rate of acetone carrier gas is 50-200mL/min, the flow rate of bleaching gas is 200-500mL/min, the sampling flow rate is 50-200mL/min, the flow rate of purge gas is 500-3000mL/min, the flow rate of ion migration spectrum sampling through a pump is 50-200mL/min, carrier gas bleaching gas and purging gas are compressed air treated by silica gel, active carbon and molecular sieves, and the water vapor content is lower than 10ppm.
4. The method according to claim 1, characterized in that: the method can be used for continuously monitoring the concentration change of the oral exhaled breath ammonia of a person to obtain a change curve of the oral exhaled breath ammonia, and is used for evaluating the basic metabolism level of the person, as an auxiliary evaluation index for organ function monitoring or for evaluating the effect before and after kidney dialysis.
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