CN105445343B - One breath multi-parameter expiration nitric oxide measurement method and device - Google Patents

One breath multi-parameter expiration nitric oxide measurement method and device Download PDF

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CN105445343B
CN105445343B CN201510782786.1A CN201510782786A CN105445343B CN 105445343 B CN105445343 B CN 105445343B CN 201510782786 A CN201510782786 A CN 201510782786A CN 105445343 B CN105445343 B CN 105445343B
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expiratory
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谢雷
韩杰
曹青
韩益苹
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Wuxi Sunvou Medical Treatment Electronic Co Ltd
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    • G—PHYSICS
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Abstract

The invention proposes a kind of one breath multi-parameter expiration nitric oxide measurement method and devices, subject controls the variation of expiratory gas flow during exhaling without a break, pass through the flow changing curve of setting, realize the flow F (t) on each tiny time point all in quasi-stationary state according to changing rule, pass through integral algorithm, the concentration of exhaled NO Ce (t) of quasi-stationary state corresponding to outflow F (t) can be calculated, obtain the parameters of expiration nitric oxide, including maximum airway flux Jaw, alveolar air NO concentration C a, concentration of exhaled NO under standard expiratory gas flow 50ml/s can be conversed, according to corresponding expiratory gas flow under measurement result and the result, a kind of new method for measuring airway dead space volume Vaw is also provided simultaneously.

Description

One breath multi-parameter expiration nitric oxide measurement method and device
Technical field
The present invention relates to expiration nitric oxide measurement method and equipment.
Background technique
Expiration nitric oxide (eNO) measurement is that respiratory inflammation cell secretes the gaseous signal molecule generated, be can be used as Inflammation of the airway inflammation marker for respiratory disease detects.Currently, eNO measurement mainly follows following generally acknowledged physiological models (as shown in Figure 1):
Ce=Ca+Jaw/F (1)
Wherein, Ce is point rate concentration (ppb) of eNO, and Ca is alveolar or point rate concentration (ppb) of small airway NO, and Jaw is branch The rate (pl/s) that tracheae or big airways NO are generated, F is exhalation flow rate (ml/s).The applicable elements of the model are exhalation flow rates F is constant, and Ce is the stable state concentration unrelated with expiratory duration, and is simply possible to use in by obtaining multiple Ce(F) line of measured value Property return and calculate, return and calculate the qualities of data such as repeatability of Ca and Jaw and depend on the pendulous frequency of CE (F).
It is known as more implication determination techniques on technical literature based on model (1), pertinent literature and patent are related to: two Room models More implication unsteady flow measurement techniques (Tsoukias. J Appl Physiol 85:653-699,1998), more mouthfuls of loudspeaker model Gas unsteady flow measurement technique (US20070282214), instrument used in technology mainly include AM General medical treatment Sievers Nitric Oxide Analyzer (NOA 280i), Ecophysic company of Switzerland 88 sp NO of CLD The chemiluminescent analyzers such as Analyzer and the NIOX of Sweden Aerocrine company.The reliability of these technologies depends on measurement Number, number is more, and the quality of data is better, but the permanent flow rate Fs of 3 implication 3 times is at least needed to measure 3 Ce.
More implication measurements are since the physiological status measured every time is different, and the quality of data is poor, and patient is difficult to cooperate.Cause This, the determination techniques of mainly one breath 50ml/s exhalation flow rate of clinical application at present, including above-mentioned chemiluminescence analysis Instrument and more convenient and fast expiration determination sensor, such as the MINO electrochemical sensor of Sweden Aerocrine are still irrigated with China Company receives the products such as coulomb breath analyzing instrument.It is commonly referred to as FeNO on measured value document under the flow velocity, due under the flow velocity Bronchus NO > > alveolar NO, therefore FeNO main representative bronchus NO, are mainly used for the detection of bronchitis or bronchial asthma, To the disease with alveolar or small airway inflammation highlights correlations, for example, small airway asthma, chronic obstructive pulmonary disease and interstitial lung disease Deng then acting on limited.
To overcome the shortcomings of existing technologies, the present invention proposes and realizes the technology of one breath multi-parameter expiration NO measurement, The multiple parameters such as Ca, Jaw and FeNO can not only be obtained simultaneously without a break, but also there is the automatic self-calibration function for examining calibration Energy；It is not only more convenient patient's test, but also eliminates the error propagation that more implications repeatedly measure.In addition, the present invention is without existing The high-accuracy chemiluminescent analyzer that technology must rely on, but receive a coulomb electrochemical sensor.
Summary of the invention
In order to overcome the drawbacks of the prior art, the present invention is exhaled by the innovation in method and device in subject without a break The variation of automatic intelligent control expiratory gas flow during gas, by the flow changing curve of setting, according to changing rule reality Flow F (t) on present each tiny time point calculates outflow F by integral algorithm all in quasi-stationary state or stable state (t) the concentration of exhaled NO Ce (t) of the quasi-stationary state corresponding to, obtains the parameters of expiration nitric oxide, including Ca, Jaw with FeNO.According to corresponding expiratory gas flow under measurement result and the result, while also providing a kind of measurement airway dead space volume The new method of Vaw.
In the expiration of one breath various flow, expiration dead volume Vaw is the time from t- τ to t in i.e. residence time τ, flow F When (t- τ) changes to F (t), the integral of flow versus time in entire section:
Realization approach of the invention is to be separated sampling and measurement process by gas circuit design, rather than the prior art is adopted simultaneously The method of sample and analysis.The present invention (guarantees that the flowing of gas wherein is when exhaling sampling and analysis measurement using elongated tubular Piston flow, i.e., into elongated tubular expiratory air not along the mixing of tube layer) in exhalation process with fast speed synchronous collection portion Divide the expiration gas under different expiratory durations (flow velocity), it will be thin with the relatively low flow velocity that the sensor response time is adapted in analysis The gas collected in long tube carries out analysis measurement by entering sensor；Gas stream when by gas circuit design and to sampling and measurement The NO concentration curve that the control of amount ratio records sensor is corresponding with expiratory gas flow (time) curve, to realize using slow The electrochemical sensor of response realizes the measurement to fast-changing expiration NO concentration.
It realizes above-mentioned design philosophy, needs to consider and solve on measuring device design, measurement method and algorithm following Several critical issues, specifically:
1) expiratory gas flow controls
Flow sensor and flow controller are combined into a flow automatic feedback control system, subject's sustained exhalation When, flow sensor measures expiratory gas flow, and transfers data to flow controller, and the flow controller is by the data and in advance If target flow be compared, and in time adjust expiration pipeline latus rectum (latus rectum is turned down when flow is excessive, when flow is too small Latus rectum is tuned up), feedback regulation speed is less than 100ms, in this way by the rapid survey to expiratory gas flow and to pipeline latus rectum It is timely adjustment can guarantee that expiratory gas flow is changed by preset changes in flow rate rule substantially, such as in 6 ~ 10 seconds, expiratory flow Amount linearly decreases to 20ml/s from 300ml/s.
In actual application, can control expiratory gas flow, (control expiratory gas flow is linear with expiratory duration linear attenuation One big advantage of variation is that algorithm model is relatively simple), such as linearly decreased to it from 300ml/s within 6 ~ 10 second time The bound of 20ml/s(expiratory gas flow can adjust according to actual needs)；Also it is reciprocal or other with the time to can control expiratory gas flow Any mode changes, and expiratory gas flow changing rule difference does not influence to measure, only different in algorithm process, with linear side The flow of formula rule variation can algorithmically formulate solution, and the expiration curve of variation reciprocal can reduce difference in analysis gas chamber The influence for the axial concentration diffusion that position gas concentration is different and generates, measurement accuracy are higher.When expiratory gas flow variation does not have When regular, it is difficult to obtain analytic solutions, but can solve by numerical integration algorithm.
2) expiration sample mode and expiration sample storage:
Preferred expiration sample mode is in variable-flow exhalation process persistently with the pump of a high flow capacity while exhaling A part of expiratory air is pumped into elongated gas chamber (flowing of the gas in elongated tubular is piston flow), so not using constant flow rate Gas under same expiratory duration (or flow) can be evenly distributed in elongated gas chamber, algorithmically corresponding (synchronization) expiratory gas flow Relationship between expiration NO concentration is relatively simple.Another advantage using the sample mode is that the gas circuit resistance is smaller, Big flow easy to accomplish is exhaled, and on the other hand, chamber volume required by which is smaller, is also beneficial to the miniaturization of instrument, Time of measuring can be saved when analyzing measurement simultaneously.
Gas to be analyzed is stored in gas chamber, and the preferred structure of the gas chamber is an elongate conduit, in order to be guaranteed Flowing of the gas in gas chamber meets the condition of piston flow in sampling and analytic process.To be reduced as far as possible due to gas in gas chamber The influence that gas concentration caused by bulk concentration difference axially diffuses should guarantee that NO concentration is linear change in elongated tubular as far as possible (according to Fick law, gas diffusion velocity is directly proportional to concentration gradient, such as gas concentration linear change in elongated tubular, then one In fixing time, the gas concentration of central portions of long-thin pipes will not change, and give up elongated tubular both ends when data processing is analyzed in measurement in this way Measurement data, can be further improved the accuracy of measurement result.)
Guarantee that the Gas concentration distribution being collected into elongated tubular is not so difficult to accomplish, as long as can control the inverse of expiratory gas flow F Linearly over time variation can, and this point can be realized by aforementioned expiratory gas flow control method.
3) measurement analysis and synchronized algorithm:
By the pipe when exhaling and a part of expiratory air be stored in elongate conduit with high flow velocities when sampling, and analyzing Gas in road carries out analysis measurement to be passed through sensor compared with low flow velocity, in order to play this two relatively independent procedure correlations Come, it is necessary to have a synchronizing time point, the selection of the synchronous point can be designed by gas circuit for realize.
A kind of gas that selection synchronizes point methods for that will analyze to pump and be arranged in elongated gas chamber leading portion, in this way at the end of expiration sampling Body is drawn into sensor first and is analyzed when measuring analysis, the start time point is corresponding be exactly exhale sampling end when Between point.
Another method for choosing synchronous point is one cycle analysis gas circuit of design, and analysis pump is after elongated gas chamber at this time End, gas when analysis measurement in analysis pump driving gas chamber enters after sensor measures, by removing NO with NO filter After return in elongated gas chamber, since the flowing of gas in gas chamber is piston flow, when this portion gas is when returning to sensor, due to NO gas is filtered out by NO filter, and the response of NO sensor can rapidly drop to zero, and it is exactly to exhale that the time point is corresponding Time point at the end of gas sampling.
After synchronous point is chosen, if it is known that when sampling and analysis gas flow ratio, can be bent by the measurement of sensor Line associates with expiratory gas flow experiment curv, makes the relational graph between sensor response and expiratory gas flow.
The flow-rate ratio of gas is bigger when sampling and analysis, and the requirement to the sensor response time is lower, such as the ratio of the two For 10:1, then the sensor measurement that the available response time is 10 seconds is exhaled the situation of change of NO concentration in 1 second.Sampling and measurement point The size selection for analysing gases used flow depends on the response time of sensor and the temporal resolution that measurement is required, to expiration NO Analysis, sampling can be controlled in 5 ~ 20 times with analysis flow-rate ratio.
) Jaw, Ca and FeNO calculation method:
About expiration nitric oxide one breath variable-flow data analysing method, George proposed a kind of numerical value in 2001 The computerized algorithm of simulation, but the algorithm is complex, does not obtain products application so far.
The present invention will consider (anti-by expiratory gas flow adjuster in exhalation process under conditions of expiratory gas flow linear change Feedback adjusts expiratory resistance size and achievees the purpose that the linear change for controlling expiratory gas flow), each expiration is directly calculated by analytic solutions Parameter.
Expiratory gas flow change curve as shown in Figure 2, defines following parameter:
Expiratory gas flow changes the slope of slope a: flow F (t) linear decline；
Air flue residence time τ (F): gas through the time required for air flue exhalation in vivo, and expiratory gas flow and is exhaled by alveolar Die with rage volume correlation；
Air flue dead volume Vaw: air flue volume.
In the expiration of one breath various flow, expiration dead volume Vaw is the time from t- τ to t in i.e. residence time τ, flow F When (t- τ) changes to F (t), the integral of flow versus time in entire section:
(2)
By Fig. 2 (expiratory gas flow linear change), the integral expansion and abbreviation carry out to formula 2 is obtained:
(3)
The quadratic equation with one unknown of formula (3) about τ (F) is solved, is obtained:
(4)
When t is greater than τ (F) between upon exhalation, concentration of exhaled NO Ce, the NO generated for alveolar air NO concentration C a and air flue are dense Spend the sum of Cb, wherein Cb be τ (F) in the time airway walls be diffused into the NO total volume in air flue divided by air flue volume, it may be assumed that
(5)
So: (6)
Formula (3) are substituted into formula (6), are obtained:
(7)
It enables, it obtains:
(8)
Wherein: (9)
Parameter Vaw in formula (9) is related with individual difference, and the Vaw of health adult is between 120 ~ 150ml.
Therefore control expiratory gas flow F (t) measures different flow from the linear transformation that becomes smaller greatly in one breath is exhaled Under expiration NO concentration C e value, if it is known that air flue dead volume Vaw, so that it may be modified and be repaired to flow according to formula (9) Then flow F ' (t) after just maps to Ce-1/F ' (t), obtained slope is Jaw, intercept Ca.And under 50ml/s flow Expiration NO concentration can be calculated according to (6) formula.
It can be seen that control expiratory gas flow linear change can be such that entire data handling procedure greatly simplifies, layman can also be straight It connects and measurement result is analyzed and processed using above-mentioned formula.
It, can also be according to formula (2), (4) using numerical integration if expiratory gas flow change curve is nonlinear certainly Method to calculate Ce (t) corresponding under different expiratory durations and, then right with Ce (t)Mapping, it is obtained Slope is Jaw/Vaw, intercept Ca.
5) calculating of Vaw:
The above method needs to know experimenter's air flue dead volume Vaw when measuring Jaw, Ca, and there are certain individual differences for this (Vaw of health adult is in 120 ~ 150ml), there are two the methods for obtaining Vaw value at present, first is that by it with height, weight or The relationship at age directly calculate (Journal of Applied Physiology: ), second is that passing through expiration CO2Test obtains (Anesthesiology 2006;104:696-700).
Vaw actually on Anatomical significance, pass through CO2Vaw and expiration the NO two Room models of expiration of disperse measurement are fixed There may be certain differences by the Vaw of justice, if the variation that can be directed to expiration NO concentration directly measure Vaw, in addition to can It is clinically perhaps also meaningful outside applied to above-mentioned calculating, such as can be used for the differentiation of airway obstruction degree.
By expiration NO two compartment model it is found that in variable-flow expiratory measurements, expiration NO value is expiratory gas flow (F), alveolar air Concentration (CaNO), maximum airway walls flux (JawNO) and air flue dead volume Vaw function, it is known that air flue dead volume, change exhale Flow can calculate alveolar gas concentration (CaNO), maximum airway walls flux (JawNO).
Under conditions of alveolar concentration and certain maximum airway walls flux, the size and gas of expiration NO concentration are in air flue Residence time τ it is directly proportional, and the residence time is the function of Vaw and expiratory gas flow, and for same subject, Vaw is certain , as long as thus residence time τ it is consistent, the concentration of expiration NO is also consistent.In other words, have due to unsteady flow measurements with Vaw Close, as long as thus carry out independent measurement at least twice, wherein at least once be unsteady flow measurement, a simultaneous equations can be established Calculate Vaw.
Thus we can draw the following method for surveying Vaw:
1.) constant expired flow is combined with change expiratory gas flow
Expiration expiration NO concentration is measured first under constant expired flow rate F 2, then carries out unsteady flow measurement, and record is exhaled NO concentration is with expiratory gas flow change curve, in variable-flow test condition expiration NO concentration and constant expired flow rate F2Lower measurement is exhaled When concentration is equal, the residence time corresponding to the two is consistent, and such as corresponding expiratory gas flow is F at this time1, have:
(10)
In expiratory gas flow linear change, by formula (3) and (10), can obtain:
(11)
Realize that above-mentioned measurement can be there are many method, it will be most readily appreciated that mode be to be exhaled twice by constant flow with variable-flow Gas measurement realizes, without a break a kind of implementation of measurement are as follows: controls the exhalation flow rate and is opened in after exhalation dead space gas the dimension that begins It is constant to hold expiratory gas flow, after being kept for 1 to 2 seconds, then changes in a predetermined manner, expiratory gas flow is under 300ml/s in 6 ~ 10 seconds Drop to 20ml/s.
Realize the another way of above-mentioned measurement are as follows: control the exhalation flow rate first and change in a predetermined manner, such as flow Amount variation range is to drop to 20ml/s from 300ml/s in 6 seconds, then controls expiratory gas flow in 50ml/s ~ 100ml/s model In enclosing and maintain 2 ~ 4 seconds.
2) unsteady flow measurement but expiratory gas flow changing rule is different twice
As previously mentioned, the expiration residence time expiration NO concentration is determined to same subject, and the residence time is dead by air flue The size of volume, expiratory gas flow variation pattern and expiratory gas flow determines, thus theoretically changes expiratory gas flow variation pattern, passes through The measurement of expiratory gas flow and expiration NO concentration can solve air flue dead volume by simultaneous equations.
Realize that a kind of method of above-mentioned measurement for unsteady flow measurement twice, such as controls expiratory measurements flow linear change twice But it is different to change slope, but they all meet formula (9), establishes simultaneous by choosing the identical point of measurement expiration NO concentration twice Equation can solve Vaw.
Realize the another way of foregoing invention method are as follows: it controls the expiratory gas flow and changes in a predetermined manner, flow Variation range is to linearly decrease to 20ml/s from 300ml/s in 6 seconds, will then be exhaled to set changes in flow rate, by 20ml/s Change linear change to 200ml/s, for 4 seconds, the slope of the two stage expiratory gas flows variation is different.It is surveyed twice by choosing The identical point of amount expiration NO concentration, which establishes simultaneous equations, can solve Vaw.
It realizes the another way of foregoing invention method also: being exhaled as described in control within certain time (such as 4 ~ 6 seconds) Throughput changes (such as from 300ml/s to 20ml/s) from big to small, and then control exhales and arrives variation (4 ~ 6 seconds) from small to large, than Expiratory gas flow change curve when equal compared with expiration NO concentration, Vaw can also be acquired by carrying out numerical integration processing.
Therefore by designing specific device and the suitable algorithm of selection, a bite multi-parameter NO can be conveniently realized Measurement.Fig. 3 ~ Fig. 7 show a variety of realization devices for realizing the measurement, although measuring device, analytic process will be different, But its common ground for measuring analytic process can be summarized as follows:
1) exhale: control is exhaled with the variation of preset flow program, and record expiratory gas flow changes over time curve；
2) sample: the gas or part of it that expiration overall process is breathed out are collected in an elongated tubular gas chamber；
3) measure: the gas in elongated tubular is passed through sensor and carried out by the gas flow rate being adapted with the sensor response time Analysis measurement, record sensor response change over time curve；
4) synchronous: synchronous expiration and analytic process find the data corresponding relationship between expiratory gas flow and expiration NO measured value；
5) it corrects: according to pair between airway dead space air volume and exhalation flow rate changing rule amendment expiratory gas flow and expiration NO It should be related to；
6) it calculates: Jaw, Ca and FeNO is calculated according to corresponding relationship between revised expiratory gas flow and expiration NO50。
The following are a variety of devices signals for realizing one breath multi-parameter expiration nitric oxide measurement:
Fig. 3 is a kind of device gas circuit structure schematic diagram for realizing above-mentioned analysis method, and described device gas circuit is by sampling module (100) it is constituted with analysis module (200), it is characterised in that: the sampling module is by flow sensor (101), flow regulator (201), solenoid valve (301) is composed in series, and passes through threeway and analysis module between flow regulator (201) and solenoid valve (301) In gas chamber (401) be connected；The analysis module is successively by gas chamber (401), threeway (501), analysis pump (602), gas humidity Adjuster (701), NO sensor (801), NO filter (901) and triple valve (302) constitute circulation gas circuit；Pump (601) passes through Threeway (501) is connected with gas chamber (401), a triple valve (303) in parallel between NO filter (901) and NO sensor (801).
It can be achieved to follow measurement fast using the slower electrochemical gas sensor of reaction speed using above-mentioned gas circuit structure The concentration of exhaled NO of speed variation, the actually professional person of this field principle design more can realize dress according to the present invention It sets.
Detailed description of the invention
Fig. 1 alveolar and air flue nitric oxide generate and diffusion fixed double chamber bed.
Fig. 2 one breath unsteady flow measurement expiratory gas flow change curve and expiration NO measurement of concetration curve.
Fig. 3 one breath variable-flow expiration nitric oxide measuring device composition schematic diagram.
Fig. 4 expiratory gas flow and expiration NO change over time curve.
Fig. 5 one breath unsteady flow measurements and curve.
Fig. 6 one breath variable-flow CeNO (50ml/s) measures the correlation with standard expiration equation measurement result.
The consistency of Fig. 7 one breath variable-flow CeNO (50ml/s) measurement and standard expiration equation measurement result.
Specific embodiment
Application Example one
A kind of gas circuit structure schematic diagram of Fig. 3 device of method to realize the present invention, described device by sampling module 100 with Analysis module 200 is constituted it is characterized in that the sampling module is by flow sensor 101, flow regulator 201, solenoid valve 301 are composed in series, and pass through the gas chamber 401 in threeway (not indicating) and analysis module between flow regulator 201 and solenoid valve 301 It is connected；The analysis module is successively by gas chamber 401, threeway 501, analysis pump 602, gas humidity adjuster 701(such as Nafion Pipe), NO sensor 801, NO filter 901 and triple valve 302 constitute circulation gas circuit；Pump 601 passes through threeway 501 and gas chamber 401 It is connected, a triple valve 303 in parallel between NO filter 901 and NO sensor 801.
Process is as follows when carrying out one breath variable-flow expiratory measurements using the device:
1) it exhales:
Valve 301 is opened to continue to exhale energetically maintenance 6 ~ 10 seconds, in exhalation process after subject sucks cleaned air Control expiratory gas flow is adjusted by process control flow adjuster, makes it with preset flow velocity change of program (such as linear decline), Flow sensor 101 measures real-time measurement record expiratory gas flow and changes over time curve；
The present invention preferably two kinds of expiratory gas flow variation patterns exist in this way first is that control expiratory gas flow changes linearly over time Subsequent algorithm processing is upper relatively simple；There are also the variations reciprocal one is control expiratory gas flow at any time, can guarantee so elongated The variation of NO concentration is linear in pipe, can greatly reduce the gas concentration caused by gas concentration difference in gas chamber in this way Axially diffuse the influence to measurement result, improve measurement accuracy (according to Fick law, gas diffusion velocity and concentration gradient Directly proportional, such as gas concentration linear change in elongated tubular, then within a certain period of time, the gas concentration of central portions of long-thin pipes will not change Become, can be further improved measurement result by giving up the measurement data at elongated tubular both ends when data processing is analyzed in measurement in this way Accuracy.)
Actually control expiratory gas flow rule variation it is not necessary to, as long as expiratory gas flow be variation and know air flue Jaw and Ca can be also calculated using numerical algorithm in dead space volume Vaw.
2) it samples:
While exhaling, sampling pump 601, analysis pump 602 are opened, adjusts triple valve 302,303 positions, will exhale full mistake A part of the gas of journey exhalation is collected in elongated tubular gas chamber 401, and a part of sample gas is through gas chamber 401, threeway at this time 501 and sampling pump 601 empty；Another part is passed through gas chamber 401, threeway 501, analysis pump 602, gas humidity adjuster 701, NO Sensor 801, triple valve 303 and triple valve 302 empty, and gas overall flow rate is about 10ml/s at this time, and the sampling time 6 ~ 10 seconds；
3) it measures:
Valve 301 and flow regulator 201 are closed after the completion of sampling, closes sampling pump 601, open analysis pump 602, adjustment The position of triple valve 302,303 becomes gas flow direction: gas chamber 401, threeway 501, analysis pump 602, gas humidity are adjusted Device 701, NO sensor 801, NO filter 901, triple valve 302 and gas chamber 401, gas flow rate is about 1ml/s at this time, and entire point Analysing process time is about 120 seconds, changes over time curve in analysis overall process record sensor response；Gas passes through NO filter The steady-state current that sensor measures after 901 is zero current；
4) synchronous:
Expiration gas at the end of exhaling sampling collects the least significant end in elongated gas chamber 401,602 driving of pump in analysis Gas flowing (flowing of the gas in pipeline is piston flow) in circulation gas circuit, gas passes through NO after the measurement of sensor 801 After filter 901 filters, NO concentration is reduced to 0, this portion gas can return in gas chamber 401, in this way when the expiration that gas chamber 401 is collected After all having analyzed, the response current of sensor will mutate (zero current), and the corresponding concentration of this time point is exactly The concentration of expiration NO at the end of expiration sampling；
Due to demarcating sample gas flow (about 10ml/s) and analysis gas flow (about 1ml/s) in advance, it is equivalent to Exhaled gas per second can measure 10 seconds on a sensor, and time of measuring is exaggerated 10 times, and sampling of exhaling from the above mentioned terminates Time and when analysis there is the consistent of the inflection point time of zero current, thus can find expiratory gas flow and expiration NO measured value Between data corresponding relationship；
5) it corrects:
Expiratory gas flow is modified according to aforementioned formula (9).
6) it calculates:
Jaw, Ca and FeNO50 are calculated according to corresponding relationship between revised expiratory gas flow and expiration NO；
7) self-calibration:
It realizes the self-calibration to transducer sensitivity, first has to collect the uniform NO gas of concentration in gas chamber 401 (no Must know specific concentration), this can adjust triple valve 302,303, open pump 601,602 and be directly evacuated by closing valve 301 Sampling realizes that airflow direction is divided into two-way at this time, all the way are as follows: NO gas source, flow sensor 101, flow regulator 201, gas chamber 401, then threeway 501, pump 601 empty, another way are as follows: NO gas source, flow sensor 101, flow regulator 201, gas chamber 401, then threeway 501, pump 602, gas humidity adjusting device 701, NO sensor 801, triple valve 303,302 empty；
Triple valve 302,303 positions are adjusted when self-calibration, by pump 602 make gas in gas chamber 401 by threeway 501, Pump 602, gas humidity adjuster 701, NO sensor 801, triple valve 303,302 return to gas chamber 401, are followed in this way by 2 ~ 3 times Ring measurement analysis, can directly calculate NO gas concentration in gas chamber 401 by method disclosed in patent ZL201210207872.6, And then its sensitivity to NO response is calculated according to the response current of cyclic process NO sensor 801, realize self-calibration.
Below by taking a subject time one breath variable-flow Sampling analysis process as an example, introduce at the data of the method for the present invention Reason process:
Expiratory gas flow V (t), the concentration of exhaled NO Ce (t) obtained after various flow sampling changes over time Fig. 4:
Slope a=- 15.6ml/s is found out according to the curve (square icon) of expiratory gas flow F (t)-t2；
The Vaw volume of subject can be byIt finds out, is 141ml；
By a and Vaw substitute intoIn find out revised expiratory gas flow F ' (t) versus time curve (triangle icon).
By revised expiratory gas flow F ' (t) and expiration NO concentration C e (t) mapping (Fig. 5), which is most Big airways wall flux Jaw, intercept are steady state alveolar gas NO concentration C a, can calculate and work as after substitution standard expiratory gas flow 50ml/s Under mouth expiration NO concentration C e.
Following table is the data processed result of 4 subjects, and the airway walls flux Jaw of four subjects respectively may be about 950pl/ S, 700pl/s, 140pl/s and 480pl/s, as a result repeatability is good.It is dense that subject's alveolar air NO is calculated using the above method Ca is spent, and inverse goes out the concentration C e of the exhaled NO under the expiratory gas flow of 50ml/s, exhalation when testing with standard expiratory gas flow Gas NO concentration is compared to consistent.
Fig. 6 is that 36 volunteers carry out Ce with one breath variable-flow expiration method and standard expiration method respectivelyNO(50ml/ S) result tested compares the consistency of both (every kind of method measures 3 times, takes mean value for comparing) result, as seen from the figure its line Property correlation analysis it is good, Pearson correlation is 0.907 (P=0.000), and the two strong correlation passes through Bland-Altman Figure compares (Fig. 7), and the mean value of two groups of measurement differences is 0.3ppb, standard deviation 2.8ppb, in 95% confidence interval, two The distribution of the difference of secondary kind of method measurement is -4.9 between 5.9ppb.It can recognize on clinical (the +/- 5ppb of clinical application tolerance) Result for two kinds of measurement methods is consistent.
To normal adult's one breath unsteady flow measurement CaNORange be -0.3 ~ 5.3ppb, JawNOFor 273 ~ 1348pl/s, This compares with literature values 1.0 ~ 5.6ppb of alveolar gas concentration, 420 ~ 1280pl/s of maximum airway pressure amount, distribution of results compared with It is reasonable.
Another processing mode to data obtained is by numerical algorithm according to formula (4) according to expiratory gas flow song Line acquires the expiration NO concentration C e(t under different expiratory durations) and its corresponding expiration residence time, then with Ce (t) rightMapping is Jaw/Vaw, intercept Ca according to formula (8) obtained slope.

Claims (7)

1. one breath multi-parameter expiration nitric oxide measurement method, which is characterized in that it realizes that process is as follows:
Exhale: during which sustained exhalation controls expiratory gas flow and changes in a certain range, record expiratory gas flow changes over time song Line；
Sampling: a part of exhaled gas is collected into an elongated tubular gas chamber with the constant sampling flow velocity set in exhalation process In；
Measurement: with the measurement flow velocity adaptable with the sensor response time by the gas collected in elongated tubular gas chamber by entering an oxygen Change nitrogen sensor and carry out analysis measurement, record sensor response changes over time curve；
It is synchronous: according to sampling flow velocity, measurement flow velocity and the expiratory flow-volume curve recorded, sensor to the sound of gas in elongated tubular Answer the corresponding relationship of curve, synchronous expiration sampling process and the time for measuring analytic process；
Amendment: according to airway dead space gas volume and exhalation flow rate changing rule amendment expiratory gas flow and expiration NO concentration measurement Between corresponding relationship；
It calculates: according to the corresponding relationship between revised expiratory gas flow and expiration NO concentration measurement, calculating an oxidation of exhaling Expiratory air under the parameters of nitrogen, including maximum airway flux Jaw, alveolar air NO concentration C a and standard expiratory gas flow 50ml/s NO concentration.
2. one breath multi-parameter expiration nitric oxide measurement method as described in claim 1, when exhaling, control expiratory gas flow exists Change a flow automatic feedback control system being combined by flow sensor and flow controller in a certain range come real It is existing, it is characterized in that: in subject's sustained exhalation, flow sensor real-time measurement expiratory gas flow, and transfer data to flow The data are compared by controller, flow controller with preset target expiratory gas flow, and adjust the logical of expiration pipeline in time Diameter guarantees that expiratory gas flow is changed by preset changes in flow rate rule.
3. one breath multi-parameter expiration nitric oxide measurement method as described in claim 1, it is characterised in that control expiratory gas flow Linearly over time or inverse changes.
4. one breath multi-parameter expiration nitric oxide measurement method as described in claim 1, wherein the sampling, measurement process Be characterized in that: the gas sampling flow velocity is 5 ~ 20 times for measuring flow velocity.
5. it is a kind of measure airway dead space air volume method, it is characterised in that: by control change expiratory gas flow state carry out to Few expiration NO measurement of concetration twice, a constant flow rate measurement, the unsteady flow measurement of once linear variation；In variable-flow test-strips Part expiration NO concentration and constant expired flow rate F2When lower measurement exhalation concentrations are equal, the residence time corresponding to the two is consistent As corresponding expiratory gas flow is F at this time1, according to formula, the airway dead space air volume Vaw is calculated, Middle a is the rate of variable-flow expiration linear change.
6. a kind of method for measuring airway dead space air volume as claimed in claim 5, it is characterized in that: expiration state changes twice Change can be realized during a sustained exhalation by flow controller, expiration leading portion or expiration latter end guarantee have one section it is constant The exhalation process of flow velocity, other time are variable-flow exhalation process.
7. a kind of method for measuring airway dead space air volume as claimed in claim 5, it is characterized in that: expiration state is equal twice For unsteady flow measurement, but the changing rule of expiratory gas flow twice is different.
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