CN105445343A - Method and device for measuring nitric oxide of one-breath multi-parameter expiration - Google Patents
Method and device for measuring nitric oxide of one-breath multi-parameter expiration Download PDFInfo
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Abstract
The invention discloses a method and a device for measuring nitric oxide of one-breath multi-parameter expiration. The method comprises the following steps: controlling the variation of the expiration flow rate in the one-breath expiration process of a subject, enabling the flow rate F(t) at each micro time point to be quasi-steady according to the change rule by setting the flow rate change curve line, and by an integral algorithm, calculating the concentration Ce(t) of the expired gas NO at the quasi-steady corresponding to the flow rate F(t) so as to obtain each parameter of the expired nitric oxide, which comprises the maximal gas passage flux Jaw, and the concentration of alveolar gas NO Ca, and converting into the concentration of expired NO at the standard expiration flow rate 50ml/s. Meanwhile, a novel method for measuring the gas passage dead cavity volume Vaw is also provided according to the measurement result and the expiration flow rate corresponding to the result.
Description
Technical field
The present invention relates to expiration nitric oxide measuring method and equipment.
Background technology
The gaseous signal molecule that respiratory inflammation emiocytosis that what expiration nitric oxide (eNO) measured is produces, can be used as airway inflammation mark and detects for the inflammation of breathing problem.At present, eNO measures and 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 point rate concentration (ppb) of alveolar or small airway NO, and Jaw is the speed (pl/s) that bronchus or big airways NO produce, and F is exhalation flow rate (ml/s).The applicable elements of this model is, exhalation flow rate F is constant, Ce is the stable state concentration irrelevant with expiratory duration, and only can be used for by obtaining multiple Ce(F) linear regression of measured value calculates, and returns the pendulous frequency that the qualities of data such as the repeatability calculating Ca and Jaw depend on CE (F).
Technical literature based on model (1) is called many implications determination techniques, pertinent literature and patent relate to: two Room model many implications variable-flow measuring technique (Tsoukias.JApplPhysiol85:653 – 699,1998), loudspeaker model many implications variable-flow measuring technique (US20070282214), the instrument that technology uses mainly comprises the chemiluminescent analyzers such as the NIOX of the SieversNitricOxideAnalyzer (NOA280i) of AM General medical treatment, the CLD88spNOAnalyzer of Ecophysic company of Switzerland and Aerocrine company of Sweden.The reliability of these technology depends on the number of times of measurement, and number of times is more, and the quality of data is better, but at least needs 3 implication, 3 permanent flow rate F to measure 3 Ce.
The physiological status that many implications measure owing to measuring at every turn is different, and the quality of data is poor, and patient is difficult to coordinate.Therefore, the determination techniques of mainly one breath 50ml/s exhalation flow rate of current clinical practice, comprise above-mentioned chemiluminescent analyzer and determination sensor of exhaling more easily, the MINO electrochemical sensor of such as Sweden Aerocrine and Chinese Shang Wo company receive the products such as coulomb breath analyzing instrument.Measured value document under this flow velocity is commonly referred to FeNO, due to bronchus NO>> alveolar NO under this flow velocity, therefore FeNO main representative bronchus NO, be mainly used in the detection of bronchitis or bronchial astehma, to the disease with alveolar or small airway inflammation highlights correlations, such as, small airway asthma, chronic obstructive pulmonary disease and interstitial lung disease etc., then limited use.
For overcoming the defect of prior art, the present invention proposes and achieves the technology of multiparameter expiration NO mensuration without a break, not only can obtain multiple parameter such as Ca, Jaw and FeNO without a break simultaneously, and have the self calibrating function of automatic gauging calibration; Not only more convenient patient's test, and eliminate the propagation of error of many implications repetitive measurement.In addition, the high-accuracy chemiluminescent analyzer that the present invention must rely on without the need to prior art, but receive a coulomb electrochemical sensor.
Summary of the invention
In order to overcome the defect of prior art, the present invention is by the innovation in method and device, in the process that experimenter exhales without a break, automatic intelligent controls the change of expiratory gas flow, by the flow changing curve of setting, quasi-stationary state or stable state is according to flow F (t) that Changing Pattern realizes on each tiny time point, pass through integral algorithm, calculate the concentration of exhaled NO Ce (t) of the quasi-stationary state corresponding to flow F (t), obtain the parameters of expiration nitric oxide, comprise Ca, Jaw and FeNO.According to expiratory gas flow corresponding under measurement result and this result, also provide a kind of new method measuring airway dead space volume Vaw simultaneously.
One breath various flow exhale in, expiration dead volume Vaw be the time from t-τ to t i.e. residence time τ, when flow F (t-τ) changes to F (t), the integration of flow versus time in whole interval:
Realization approach of the present invention will to be sampled by gas circuit design and measuring process is separated, but not prior art is sampled and the method analyzed simultaneously.The present invention utilizes elongated tubular (to ensure that gas flowing is wherein piston flow when exhaling sampling and analysis to measure, namely enter the expiratory air of elongated tubular not along the mixing of tube layer) in exhalation process with the expiration gas under the different expiratory duration (flow velocity) of fast speed synchronous collection part, when analyzing with the sensor response time adapt compared with low flow velocity, the gas collected in elongated tubular is passed through to carry out analysis to measure into sensor; Designed by gas circuit and make the NO concentration curve of sensor record corresponding with expiratory gas flow (time) curve to the control of gas flow ratio when sampling and measurement, thus realizing utilizing the measurement of the electrochemical sensor of slow-response realization to fast-changing expiration NO concentration.
Realize above-mentioned design philosophy, measurement mechanism design, metering system and algorithm need to consider and solves following key issue, being specially:
1) expiratory gas flow controls
Flow sensor and flow controller are combined into a flow automatic feedback control system, during experimenter's sustained exhalation, expiratory gas flow measured by flow sensor, and transfer data to flow controller, these data and the target flow preset compare by described flow controller, and latus rectum (is turned down when flow is excessive by the latus rectum of the pipeline of adjustment expiration in time, when flow is too small, latus rectum is tuned up), its feedback regulation speed is less than 100ms, substantially can ensure that expiratory gas flow is by the fluctuations in discharge rule change preset by the Quick Measurement to expiratory gas flow and the timely adjustment to pipeline latus rectum like this, as in 6 ~ 10 seconds, expiratory gas flow linearly drops to 20ml/s from 300ml/s.
In actual application, expiratory gas flow can being controlled with expiratory duration linear attenuation (the large advantage controlling expiratory gas flow linear change is that algorithm model is comparatively simple), can adjust according to actual needs as made its bound linearly dropping to 20ml/s(expiratory gas flow from 300ml/s within 6 ~ 10 second time); Also can control expiratory gas flow to change with time inverse or other any mode, expiratory gas flow Changing Pattern difference does not affect measurement, just different in algorithm process, the flow of rule change algorithmically can solve by formulism in a linear fashion, and the impact of the axial concentration diffusion that the expiration curve of change reciprocal can reduce diverse location gas concentration difference in analysis air chamber and produce, measurement accuracy is higher.When expiratory gas flow change does not have rule, be difficult to obtain analytic solution, but solve by numerical integration algorithm.
2) expiration sample mode and expiration sample storage:
Preferred expiration sample mode be continue in variable-flow exhalation process with the pump of a high flow capacity while exhaling by a part for expiratory air with (flowing of gas in elongated tubular is for piston flow) in the elongated air chamber of constant flow rate suction, gas under so different expiratory duration (or flow) can be evenly distributed in elongated air chamber, and the relation algorithmically between corresponding (synchronously) expiratory gas flow and expiration NO concentration is comparatively simple.Adopt another advantage of described sample mode to be that described gas circuit resistance is less, easily realize large discharge and exhale, on the other hand, the chamber volume required by which is less, is also conducive to the miniaturization of instrument, can save Measuring Time when analysis to measure simultaneously.
Atmosphere storage to be analyzed is in air chamber, and the preferred structure of described air chamber is an elongate conduit, and object is to ensure that the flowing of gas in air chamber meets the condition of piston flow in sampling and analytic process.For reducing the impact of the gas concentration axial diffusion caused due to gas concentration difference in air chamber as far as possible, should ensure that in elongated tubular, NO concentration is that linear change is (according to Fick law as far as possible, gas diffusion velocity is directly proportional to concentration gradient, 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 can not change, and gives up the measurement data at elongated tubular two ends like this when Measurement and analysis data processing, can improve the accuracy of measurement result further.）
Ensure to collect that Gas concentration distribution in elongated tubular is not so difficult to be accomplished, as long as the inverse that can control expiratory gas flow F changes just passable linearly over time, and this point realizes by aforementioned expiratory gas flow control method.
3) Measurement and analysis and synchronized algorithm:
Exhale and with high flow velocities, a part for expiratory air is stored in elongate conduit when sampling, and when analyzing, the gas in described pipeline is passed into sensor with comparatively low flow velocity and carry out analysis to measure, in order to these two relatively independent procedure correlations are got up, must have a synchronizing time point, choosing of described synchronous point realizes by gas circuit design.
One chooses synchronous point method for analysis pump is arranged in elongated air chamber leading portion, and first the gas at the end of sampling of exhaling like this be drawn into sensor analysis when Measurement and analysis, and what this start time point was corresponding is exactly the time point of sampling and terminating of exhaling.
The another kind of method choosing synchronous point is design one cycle analysis gas circuit, now analyze pump in the rear end of elongated air chamber, analyzing pump during analysis to measure drives the gas in air chamber to enter after sensor measures, get back in elongated air chamber after removing NO with NO filtrator, flowing due to gas in air chamber is piston flow, when this part gas is when getting back to sensor, because NO gas is fallen by NO metre filter, the response of NO sensor can rapidly drop to zero, and this time point corresponding be exactly exhale sampling at the end of time point.
After synchronous point is chosen, if known sampling and analyze time gas flow ratio, just the experiment curv of sensor can be associated with expiratory gas flow experiment curv, make the graph of a relation between sensor response and expiratory gas flow.
Sampling is larger with the throughput ratio of gas when analyzing, and lower to the requirement of sensor response time, the ratio as the two is 10:1, then the available response time is that the sensor measurement of 10 seconds is exhaled the situation of change of NO concentration in 1 second.Sampling and the size of Measurement and analysis gases used flow select to depend on the response time of sensor and the temporal resolution needed for measuring, analyze expiration NO, sample and analysis throughput ratio can be controlled in 5 ~ 20 times.
) .Jaw, Ca and FeNO computing method:
About expiration nitric oxide variable-flow data analysing method without a break, George proposes a kind of computerized algorithm of numerical simulation in calendar year 2001, but this algorithm is comparatively complicated, does not obtain products application so far.
The present invention (regulates expiratory resistance size to reach the object of the linear change controlling expiratory gas flow in exhalation process by expiratory gas flow regulator feedback) by considering under the condition of expiratory gas flow linear change, directly calculates each expiration parameter by analytic solution.
Expiratory gas flow change curve as shown in Figure 2, defines following parameter:
Expiratory gas flow change slope a: the slope that flow F (t) linearly declines;
Air flue residence time τ (F): the time of gas required for alveolar is in air flue exhalation body, relevant to expiratory gas flow and expiration dead volume;
Air flue dead volume Vaw: air flue volume.
One breath various flow exhale in, expiration dead volume Vaw be the time from t-τ to t i.e. residence time τ, when flow F (t-τ) changes to F (t), the integration of flow versus time in whole interval:
(2)
By Fig. 2 (expiratory gas flow linear change), the integration carried out formula 2 launches and abbreviation obtains:
(3)
Solution formula (3), about the quadratic equation with one unknown of τ (F), obtains:
(4)
When upon exhalation, t is greater than τ (F), concentration of exhaled NO Ce, for the NO concentration C b sum that alveolar air NO concentration C a and air flue produce, wherein Cb be τ (F) in the time airway walls be diffused into NO cumulative volume in air flue divided by air flue volume, that is:
(5)
So:
(6)
Formula (3) is substituted into formula (6):
(7)
Order
:
(8)
Wherein:
(9)
Parameter Vaw in formula (9) is relevant with individual difference, and the Vaw of health adult is between 120 ~ 150ml.
Therefore, expiratory gas flow F (t) is controlled from the linear transformation that diminishes greatly in exhaling without a break, measure the expiration NO concentration C e value under different flow, if know air flue dead volume Vaw, just can carry out correction according to formula (9) to flow to obtain revising rear flow F ' (t), then to Ce-1/F ' (t) mapping, the slope obtained is Jaw, and intercept is Ca.And NO concentration of exhaling under 50ml/s flow can calculate according to (6) formula.
Visible control expiratory gas flow linear change can make whole data handling procedure greatly simplify, and layman also can directly utilize above-mentioned formula to carry out analyzing and processing to measurement result.
If certainly expiratory gas flow change curve is nonlinear, also can according to formula (2), (4) adopt the method for numerical integration to calculate under different expiratory duration corresponding Ce (t) and
, then right with Ce (t)
mapping, the slope obtained is Jaw/Vaw, and intercept is Ca.
5) calculating of Vaw:
Said method needs to know experimenter's air flue dead volume Vaw when measuring Jaw, Ca, there is certain individual difference (Vaw of health adult is at 120 ~ 150ml) in this, the method of current acquisition Vaw value has two, one be by itself and height, body weight or the relation at age directly calculate (JournalofAppliedPhysiology:
), two is by expiration CO
2test obtains (Anesthesiology2006; 104:696 – 700).
In fact the Vaw on Anatomical significance, CO is passed through
2certain difference may be there is in the exhale Vaw of two Room models definition of the Vaw that disperse is measured and expiration NO, if directly can measure Vaw for the change of expiration NO concentration, except can be applicable to above-mentioned calculating, perhaps be also significant clinically, as can be used for the differentiation etc. of airway obstruction degree.
From expiration NO two compartment model, when variable-flow expiratory measurements, expiration NO value is expiratory gas flow (F), alveolar air concentration (Ca
nO), maximum airway walls flux (Jaw
nO) and the function of air flue dead volume Vaw, known air flue dead volume, changes expiratory gas flow and can calculate alveolar air concentration (Ca
nO), maximum airway walls flux (Jaw
nO).
Under alveolar concentration and the certain condition of maximum airway walls flux, the size of expiration NO concentration is directly proportional to the residence time τ of gas in air flue, and the residence time is the function of Vaw and expiratory gas flow, same experimenter, Vaw is certain, as long as thus residence time τ is consistent, the concentration of expiration NO is also consistent.In other words, because variable-flow measurement result is relevant with Vaw, independently measure as long as thus carry out at least twice, wherein at least one times for variable-flow is measured, just can set up simultaneous equations and calculate Vaw.
We can draw the method for following survey Vaw thus:
1.) constant expired flow combines with change expiratory gas flow
First measure expiration expiration NO concentration for 2 times in constant expired flow rate F, then carry out variable-flow measurement, record expiration NO concentration with expiratory gas flow change curve, in variable-flow test condition expiration NO concentration and constant expired flow rate F
2when lower measurement exhalation concentrations is equal, the residence time corresponding to the two is consistent, and the expiratory gas flow as now corresponding is F
1, have:
(10)
When expiratory gas flow linear change, by formula (3) and (10), can obtain:
(11)
Realize above-mentioned measurement and can have multiple method, the mode the most easily expected is realized by constant flow and variable-flow twice expiratory measurements, a kind of implementation measured without a break is: control described exhalation flow rate and open that after exhalation dead space gas, begin to maintain expiratory gas flow constant, keep after 1 to 2 seconds, change in a predetermined manner, in 6 ~ 10 seconds, expiratory gas flow drops to 20ml/s from 300ml/s again.
The another kind of mode realizing above-mentioned measurement is: first control described exhalation flow rate and change in a predetermined manner, if fluctuations in discharge scope for drop to 20ml/s from 300ml/s in 6 seconds, subsequently expiratory gas flow to be controlled within the scope of 50ml/s ~ 100ml/s and to maintain 2 ~ 4 seconds.
2) twice variable-flow is measured but expiratory gas flow Changing Pattern is different
As previously mentioned, residence time of exhaling expiration NO concentration is determined to same experimenter, and the residence time is determined by the size of air flue dead volume, expiratory gas flow variation pattern and expiratory gas flow, thus change expiratory gas flow variation pattern in theory, just solve air flue dead volume by simultaneous equations by the measurement of expiratory gas flow and expiration NO concentration.
A kind of method realizing above-mentioned measurement is that twice variable-flow is measured, as controlled twice expiratory measurements flow linear change but change slope difference, but they all meet formula (9), set up simultaneous equations can solve Vaw by choosing the identical point of twice measurement expiration NO concentration.
The another kind of mode realizing foregoing invention method is: control described expiratory gas flow and change in a predetermined manner, fluctuations in discharge scope for linearly to drop to 20ml/s from 300ml/s in 6 seconds, to exhale to set fluctuations in discharge subsequently, linear change is changed to 200ml/s by 20ml/s, continue 4 seconds, the slope of these two stage expiratory gas flow changes is different.Set up simultaneous equations can solve Vaw by choosing the identical point of twice measurement expiration NO concentration.
Realize foregoing invention method another kind of mode also have: within the scope of certain hour (as 4 ~ 6 seconds) control as described in expiratory gas flow from big to small (as from 300ml/s to 20ml/s) change, controlling subsequently exhales arrives change (4 ~ 6 seconds) from small to large, expiratory gas flow change curve when relatively expiration NO concentration is equal, carries out numerical integration process and also can try to achieve Vaw.
Therefore by designing specific device and selecting suitable algorithm, just can realize a bite multiparameter NO easily and measure.Fig. 3 ~ Figure 7 shows that the multiple implement device realizing described measurement, although measurement mechanism, analytic process can be different, the common ground of its Measurement and analysis process can be summarized as follows:
1) exhale: control to exhale with the flow program preset change, record expiratory gas flow change curve in time;
2) sample: the gas of breathe out expiration overall process or one portion collection are in an elongated tubular air chamber;
3) measure: the gas in elongated tubular is passed into sensor and carries out analysis to measure by the gas flow rate adapted with the sensor response time, record sensor responds change curve in time;
4) synchronous: synchronous expiration and analytic process, find the data corresponding relation between expiratory gas flow and expiration NO measured value;
5) revise: according to airway dead space gas volume and the corresponding relation between exhalation flow rate Changing Pattern correction expiratory gas flow and expiration NO;
6) calculate: calculate Jaw, Ca and FeNO according to corresponding relation between revised expiratory gas flow and expiration NO
50.
Below for realizing the multiple device signal that described one breath multiparameter expiration nitric oxide is measured:
Fig. 3 is a kind of device gas circuit structure schematic diagram realizing above-mentioned analytical approach, described device gas circuit is made up of sampling module (100) and analysis module (200), it is characterized in that: described sampling module is by flow sensor (101), flow regulator (201), solenoid valve (301) is composed in series, and is connected between flow regulator (201) and solenoid valve (301) by threeway with the air chamber (401) in analysis module; Described analysis module forms circulation gas circuit by air chamber (401), threeway (501), analysis pump (602), gas humidity regulator (701), NO sensor (801), NO filtrator (901) and T-valve (302) successively; Pump (601) is connected with air chamber (401) by threeway (501), a T-valve (303) in parallel between NO filtrator (901) with NO sensor (801).
The electrochemical gas sensor utilizing above-mentioned gas circuit structure all can realize utilizing reaction velocity slower is followed and is measured fast-changing concentration of exhaled NO, and in fact the professional person of this area can design more implement device according to the principle of the invention.
Accompanying drawing explanation
Fig. 1. alveolar and air flue nitrogen monoxide produce and diffusion fixed double chamber bed.
Fig. 2. variable-flow measures expiratory gas flow change curve and expiration NO measurement of concetration curve without a break.
Fig. 3. variable-flow expiration nitric oxide measuring equipment composition schematic diagram without a break.
Fig. 4 expiratory gas flow and expiration NO change curve in time.
Fig. 5 is variable-flow measurement result and curve without a break.
Fig. 6 without a break variable-flow CeNO (50ml/s) measures the correlativity with standard expiration equation measurement result.
Fig. 7 without a break variable-flow CeNO (50ml/s) measures the consistance with standard expiration equation measurement result.
Embodiment
Application Example one
Fig. 3 is the gas circuit structure schematic diagram of a kind of device realizing the inventive method, described device is made up of sampling module 100 and analysis module 200, its design feature is that described sampling module is by flow sensor 101, flow regulator 201, solenoid valve 301 is composed in series, and is connected between flow regulator 201 and solenoid valve 301 by threeway (not indicating) with the air chamber 401 in analysis module; Described analysis module successively by air chamber 401, threeway 501, analyze pump 602, gas humidity regulator 701(such as Nafion and manage), NO sensor 801, NO filtrator 901 and T-valve 302 form circulation gas circuit; Pump 601 is connected with air chamber 401 by threeway 501, a T-valve 303 in parallel between NO filtrator 901 with NO sensor 801.
When utilizing this device to carry out one breath variable-flow expiratory measurements, process is as follows:
1) exhale:
Open valve 301, after experimenter sucks cleaned air, continue expiration maintenance energetically 6 ~ 10 seconds, expiratory gas flow is controlled by the adjustment of programmed control flow regulator in exhalation process, make it with the flow velocity change of program (as linear decline) preset, real-time survey record expiratory gas flow change curve in time measured by flow sensor 101;
The present invention is two kinds of expiratory gas flow variation patterns preferably, and one is control expiratory gas flow to change linearly over time, comparatively simple in subsequent algorithm process like this, also having a kind of is control expiratory gas flow inverse change in time, can ensure that the change of NO concentration in elongated tubular is linear like this, the gas concentration axial diffusion that causes due to gas concentration difference in air chamber can be greatly reduced like this on the impact of measurement result, improve the accuracy of measurement (according to Fick law, gas diffusion velocity is directly proportional to concentration gradient, 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 can not change, like this when Measurement and analysis data processing by giving up the measurement data at elongated tubular two ends, the accuracy of measurement result can be improved further.）
In fact it is not necessary for controlling the change of expiratory gas flow rule, as long as expiratory gas flow is change and knows airway dead space volume Vaw, adopts numerical algorithm can calculate Jaw and Ca yet.
2) sample:
While expiration, open sampling pump 601, analyze pump 602, adjustment T-valve 302,303 position, a part for the gas of expiration overall process being breathed out is collected in elongated tubular air chamber 401, and now a part for sample gas is emptying through air chamber 401, threeway 501 and sampling pump 601; Another part through air chamber 401, threeway 501, analyze pump 602, gas humidity regulator 701, NO sensor 801, T-valve 303 and T-valve 302 emptying, now gas overall flow rate is about 10ml/s, 6 ~ 10 seconds sampling times;
3) measure:
To sample rear valve-off 301 and flow regulator 201, close sampling pump 601, open and analyze pump 602, the position of adjustment T-valve 302,303 makes gas flow direction become: air chamber 401, threeway 501, analysis pump 602, gas humidity regulator 701, NO sensor 801, NO filtrator 901, T-valve 302 and air chamber 401, now gas flow rate is about 1ml/s, the whole analytic process time is about 120 seconds, responds change curve in time at analysis overall process record sensor; The steady-state current that gas is recorded by sensor after NO filtrator 901 is zero current;
4) synchronous:
Expiration gas at the end of sampling of exhaling is collected in the least significant end of elongated air chamber 401, when analyzing, pump 602 driving gas flows (flowing of gas in pipeline is piston flow) in circulation gas circuit, after gas is filtered by NO filtrator 901 after sensor 801 is measured, NO concentration reduces to 0, this part gas can be got back in air chamber 401, after the expiration of collecting when air chamber 401 so has all been analyzed, the response current of sensor will be undergone mutation (zero current), and the concentration that this time point is corresponding is exactly the concentration of NO of exhaling at the end of sampling of exhaling;
Owing to demarcating sample gas flow (about 10ml/s) and analytical gas flow (about 1ml/s) in advance, be equivalent to breath per second and can measure 10 seconds on a sensor, Measuring Time has been exaggerated 10 times, there is the consistent of the flex point time of zero current with during analysis in the time that sampling of exhaling from the above mentioned terminates, can find the data corresponding relation between expiratory gas flow and expiration NO measured value thus;
5) revise:
According to aforementioned formula (9), expiratory gas flow is revised.
6) calculate:
Jaw, Ca and FeNO50 is calculated according to corresponding relation between revised expiratory gas flow and expiration NO;
7) self-calibration:
Realize the self-calibration to transducer sensitivity, first the homogeneous NO gas of concentration (concrete concentration need not be known) to be collected in air chamber 401, this is by valve-off 301, adjustment T-valve 302, 303, open pump 601, 602 directly bleed sampling realize, now airflow direction is divided into two-way, one tunnel is: NO source of the gas, flow sensor 101, flow regulator 201, air chamber 401, threeway 501, pump 601 is then emptying, another road is: NO source of the gas, flow sensor 101, flow regulator 201, air chamber 401, threeway 501, pump 602, gas humidity adjusting device 701, NO sensor 801, T-valve 303, 302 is then emptying,
T-valve 302,303 position is adjusted during self-calibration, the gas in air chamber 401 is made to get back to air chamber 401 by threeway 501, pump 602, gas humidity regulator 701, NO sensor 801, T-valve 303,302 by pump 602, like this by 2 ~ 3 circulation Measurement and analysis, just NO gas concentration in air chamber 401 is directly calculated by method disclosed in patent ZL201210207872.6, and then calculate its sensitivity that NO is responded according to the response current of cyclic process NO sensor 801, realize self-calibration.
Below for an experimenter time one breath variable-flow sampling analysis process, introduce the data handling procedure of the inventive method:
Expiratory gas flow V (t), concentration of exhaled NO Ce (t) variation diagram 4 in time that obtain after various flow sampling:
Curve (square icon) according to expiratory gas flow F (t)-t obtains slope a=-15.6ml/s
2;
The Vaw volume of experimenter can be by
obtaining, is 141ml;
By a and Vaw substitute into
in obtain revised expiratory gas flow F ' (t) curve (triangle icon) over time.
(Fig. 5) is mapped in revised expiratory gas flow F ' (t) and expiration NO concentration C e (t), this slope of a curve is maximum airway walls flux Jaw, intercept is steady state alveolar gas NO concentration C a, can calculate mouth expiration NO concentration C e instantly after substituting into standard expiratory gas flow 50ml/s.
Following table is the data processed result of 4 experimenters, and the airway walls flux Jaw of four experimenters is about 950pl/s, 700pl/s, 140pl/s and 480pl/s respectively, and result repeatability is good.Utilize said method to calculate experimenter's alveolar air NO concentration C a, and inverse go out the concentration C e of exhaled NO under the expiratory gas flow of 50ml/s, consistent compared with concentration of exhaled NO when testing with standard expiratory gas flow.
Fig. 6 is that 36 volunteers are respectively with variable-flow expiration method and standard expiration method carry out Ce without a break
nO(50ml/s) (often kind of method measures 3 times to the results contrast tested, get average for comparing) consistance of the two result, its linear dependence analysis is good as seen from the figure, its Pearson correlativity is 0.907 (P=0.000), and the two strong correlation, is compared (Fig. 7) by Bland-Altman figure, two groups of averages measuring difference are 0.3ppb, standard deviation is 2.8ppb, and in 95% fiducial interval, the distribution of the difference of twice kind of method measurement is between-4.9 to 5.9ppb.Clinical (clinical practice permissible variation +/-5ppb) can think that the result of two kinds of measuring methods is consistent.
To adult normal variable-flow measurement Ca without a break
nOscope be-0.3 ~ 5.3ppb, Jaw
nObe 273 ~ 1348pl/s, this and literature values alveolar air concentration 1.0 ~ 5.6ppb, maximum airway pressure amount 420 ~ 1280pl/s compares, and distribution of results is comparatively reasonable.
Be the expiration NO concentration C e(t tried to achieve according to expiratory flow-volume curve by numerical algorithm according to formula (4) under different expiratory duration to the another kind of processing mode of obtained data) and corresponding expiration residence time
, then right with Ce (t)
mapping, be Jaw/Vaw according to the slope that formula (8) obtains, intercept is Ca.
Claims (10)
1. one breath multiparameter expiration nitric oxide measuring method, it is characterized in that: the change controlling expiratory gas flow in the process that experimenter exhales without a break, by the flow changing curve of setting, quasi-stationary state is according to flow F (t) that Changing Pattern realizes on each tiny time point, pass through integral algorithm, the concentration of exhaled NO Ce (t) of the quasi-stationary state corresponding to flow F (t) can be calculated, obtain the parameters of expiration nitric oxide, comprise 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 expiratory gas flow corresponding under measurement result and this result, also provide a kind of new method measuring airway dead space volume Vaw simultaneously.
2. without a break multiparameter expiration nitric oxide measuring method as claimed in claim 1, is characterized in that its implementation procedure:
Exhale: sustained exhalation, period controls expiratory gas flow and changes within the specific limits, record expiratory gas flow change curve in time;
Sampling: in exhalation process, a part for breath is collected in an elongated tubular air chamber with the constant sampling flow velocity of setting;
Measure: passed through to carry out analysis to measure into nitric oxide sensor by the gas collected in elongated tubular air chamber with the measurement flow velocity adapted with the sensor response time, record sensor responds change curve in time;
Data processing: according to sampling flow velocity, measurement flow velocity and the expiratory flow-volume curve recorded, sensor to the corresponding relation of the response curve of gas in elongated tubular, calculate the parameters of expiration nitric oxide, comprise maximum airway flux Jaw, concentration of exhaled NO under alveolar air NO concentration C a and standard expiratory gas flow 50ml/s.
3. without a break multiparameter expiration nitric oxide measuring method as claimed in claim 1, control expiratory gas flow to change the flow automatic feedback control system be combined into by flow sensor and flow controller within the specific limits realize when exhaling, it is characterized by: when experimenter's sustained exhalation, flow sensor measures expiratory gas flow in real time, and transfer data to flow controller, these data and the target expiratory gas flow preset compare by flow controller, and the latus rectum of the pipeline of adjustment expiration in time, ensure that expiratory gas flow is by the fluctuations in discharge rule change preset.
4. without a break multiparameter expiration nitric oxide measuring method as claimed in claim 1, is characterized in that controlling expiratory gas flow linearly over time or change reciprocal.
5. without a break multiparameter expiration nitric oxide measuring method as claimed in claim 1, the feature of wherein said sampling, measuring process is: described gas sampling flow velocity is 5 ~ 20 times that measure flow velocity.
6. measure the method for airway dead space gas volume for one kind, it is characterized in that: carry out at least twice expiration NO measurement of concetration by control break expiratory gas flow state, wherein the measured value of expiration NO concentration is relevant to airway dead space gas volume at least one times, then airway dead space gas volume according to the correlation calculations of the two.
7. a kind of method measuring airway dead space gas volume as claimed in claim 6, is characterized by: twice expiration state is that a constant rate is measured, and one time variable-flow is measured.
8. a kind of method measuring airway dead space gas volume as claimed in claim 6, it is characterized by: the change of twice expiration state realizes in a sustained exhalation process by flow controller, ensuring the exhalation process of one section of constant flow rate at expiration leading portion or expiration latter end, is variable-flow exhalation process At All Other Times.
9. a kind of method measuring airway dead space gas volume as claimed in claim 6, is characterized by: twice expiration state is measured for being variable-flow, but the Changing Pattern of twice expiratory gas flow is different.
10. one breath multiparameter expiration nitric oxide measurement mechanism, be made up of sampling module (100) and analysis module (200), it is characterized in that: described sampling module is by flow sensor (101), flow regulator (201), solenoid valve (301) is composed in series, and is connected between flow regulator (201) and solenoid valve (301) by threeway with the air chamber (401) in analysis module; Described analysis module forms circulation gas circuit by air chamber (401), threeway (501), analysis pump (602), gas humidity regulator (701), NO sensor (801), NO filtrator (901) and T-valve (302) successively; Pump (601) is connected with air chamber (401) by threeway (501), a T-valve (303) in parallel between NO filtrator (901) with NO sensor (801).
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