CN106264533B - A method of measurement expiration nitric oxide air flue diffusion coefficient - Google Patents

A method of measurement expiration nitric oxide air flue diffusion coefficient Download PDF

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CN106264533B
CN106264533B CN201610709920.XA CN201610709920A CN106264533B CN 106264533 B CN106264533 B CN 106264533B CN 201610709920 A CN201610709920 A CN 201610709920A CN 106264533 B CN106264533 B CN 106264533B
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谢雷
韩杰
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Wuxi Sunvou Medical Treatment Electronic Co Ltd
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Abstract

Present invention discloses a kind of methods of expiration nitric oxide air flue diffusion coefficient, it is characterised in that the measurement makes two bites at a cherry, first time measurement method are as follows: does not feel suffocated, obtains maximum airway flux J by changing expiratory gas flow measurementawAnd steady state alveolar NO concentration CalvParameter, second of measurement method are as follows: sustained exhalation after a certain period of time of feeling suffocated will measure obtained maximum airway flux J through the measurement obtained expiration NO total amount of sustained exhalation compared with by the obtained theoretical value of expiration two compartment model for the first timeaw, steady state alveolar NO concentration Calv, sucking air concentration CairParameter substitutes into, and adjusts another parameter air flue diffusion coefficient DawKeep the two result closest.

Description

A method of measurement expiration nitric oxide air flue diffusion coefficient
Technical field
The present invention relates to expiration nitric oxide measurement methods.
Background technique
Expiration nitric oxide has been cured as the detection and analysis that the marker of airway inflammation is used for the respiratory diseases such as asthma Treat boundary's abundant affirmation.Proposed standard was detected with expiration nitric oxide has been formulated within 1999 in 1997 respectively with the U.S. in Europe, and It is formulated in joint in 2005 and discloses this standard (" ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Low Respiratory Nitric Oxide and Nasal Nitric Oxide, 2005 ", ATS is the abbreviation of U.S.'s throat association, and ERC exhales for Europe Inhale association's abbreviation), and expiration nitric oxide clinical application guide (An Official ATS Clinical has been formulated in 2011 Practice Guideline: Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical Applications), for instructing how to carry out expiration nitric oxide detection and how will test result for roaring The diagnosis and therapeutic evaluation of the respiratory diseases such as asthma.
Expiration NO is generated jointly by alveolar region and air flue area, and about NO yield in lung, mainly there are three moulds at present with diffusion Type: two compartment model, three compartment model and loudspeaker model can analyze four parameters unrelated with flow: steady state alveolar NO concentration (Calv), maximum airway walls diffusing capacity (Jaw=Cw*Daw) and air flue diffusion coefficient (Daw).People couple have been deepened in the proposition of the model The understanding of relationship between NO exchanging mechanism and these parameters and physiological and pathological, these three ginseng parameters clinically can be expressed as reduce, Constant, three kinds of possibility of raising, 27 kinds of combinations or pathological state that can be distinguished of corresponding composition.(Steven C. George Etc., J Appl Physiol 96:831-839 2004).
There are many document in terms of in relation to expiration nitric oxide detection method, to existing various measurement methods, Hogman(J. Breath Res. 7 (2013) 017104) and George(J. appl Physiol 104 909,2008) do respectively It introduces comprehensively and objectively relatively, the basis of these methods is all two Room model of expiration nitric oxide.
Generally, the method is divided into two major classes, and one is constant expired flow-measuring method: by least twice The expiratory measurements of different expiratory gas flows calculate various expiration NO parameters as a result, passing through linearly or nonlinearly fitting algorithm formula, right Calv, JawMeasuring expiratory gas flow range used is 100 ~ 500ml/s；To Daw、CwMeasuring expiratory gas flow range used is < 10ml/ s；In order to calculate Daw, when using constant flow rate expiratory measurements technology, since expiratory gas flow is less than 10ml/s, to exhaling, control comes Saying difficulty, larger (4 ~ 10s of sustained exhalation is comparatively easy to accomplish under the exhalation flow rate of 50ml/s, and lower flow velocity is (such as The exhalation flow rate of 10ml/s at least need constant flow rate exhale 20 seconds) and higher expiration under (expiratory resistance is larger) sustained exhalation It will be more difficult).
Secondly for one breath unsteady flow measuring method ((George, J Appl Physiol 91 477-487,2001), By exhaling after feeling suffocated 20 seconds, continuously regulates and controls in exhalation process expiratory gas flow (from 300ml/s to 50ml/s), measure and record The expiration NO concentration curve followed in time with expiratory gas flow adjusts J then according to two Room modelsaw、Calv、 DawDeng ginseng Number fitting expiratory measurements curve determines most suitable parameter by least square method selection.Gas when the method does not consider to feel suffocated Road NO gas axially diffuse and air flue in different parts CwThe inconsistent influence that measurement result is generated.
Airway parameters measurement method instrument described in document is Chemiluminescence Apparatus (Sivers NOA280 or Aerocrine NIOX), the instrument response time fast (t90< 100ms), high resolution (NO Measurement Resolution < 1ppb), be measurement The goldstandard of NO, but the equipment is complex, and applicating maintenance higher cost, in General Clinical using upper gradually by more inexpensive Electrochemical analysis method substituted, but since the electrochemical gas sensor response time is slower, temporal resolution can not expire Sufficient expiration dynamic measurement request above has some limitations in application and is not suitable for the higher dynamic of time resolution requirement Measurement application.
For defect present in the method, still fertile by the improvement to gas circuit, analysis method and algorithm, (China is specially 201510782786.1) temporal resolution of electrochemical sensor has been increased to 0.1 second by benefit, and then realize to exhalation process One breath unsteady flow measurement of NO concentration, can be used for calculating Jaw、Calv、VawEqual airway parameters.But the patented method can't For survey calculation Daw。
It is an object of the invention to be realized by method innovation to airway parameters D on the basis of still fertile foregoing workaw Relatively simple measurement solves the defect of literature method, extends the application range of instrument.
Summary of the invention
Present invention discloses a kind of methods of expiration nitric oxide air flue diffusion coefficient, it is characterised in that the measurement is at least It makes two bites at a cherry, in which:
1) it measures: not feeling suffocated for the first time, by changing expiratory gas flow survey calculation maximum airway flux JawAnd steady state alveolar NO concentration CalvParameter；
2) measure for second: sustained exhalation after a certain period of time of feeling suffocated measures the obtained expiration NO total amount of sustained exhalation；
3) parameter calculates: will measure obtained J for the first timeaw、Calv、CairEtc. parameters substitute into correlation formula, computational theory Expiration NO total amount adjusts another parameter DawParameter keeps it closest with the obtained expiration NO total amount of sustained exhalation.
The first time measures and can be realized by one breath variable-flow method, can also be repeatedly permanent by changing expiratory gas flow Flow expiratory measurements are realized.
In the method, hold your time is typically chosen in 5 ~ 30 seconds, preferably 20 seconds, and sustained exhalation is generally wanted after feeling suffocated Seeking expiratory air volume is 1 ~ 8 times, preferably 2 ~ 4 times of dead space air volume.
There are two types of methods for the measurement of the measurement expiration NO total amount: one is to record full exhalation process expiration NO concentration to become Change curve, expiration NO total amount is calculated by the method that curve integrates；Secondly for exhaled gas to be all collected in an airbag, The gas mean concentration in airbag is measured after expiration, then according to the mean concentration and stereometer of gas in airbag Calculate expiration NO total amount.
The theoretical calculation formula of the obtained expiration NO total amount of two compartment model are as follows:
Wherein:, CwFor the concentration in airway walls, CairTo suck air concentration, CalvFor steady state alveolar NO concentration, τeTo exhale Gas residence time, τinFor air-breathing residence time, τeFor the residence time, t of exhalingholdFor hold your time, teFor expiratory duration air flue, DawFor diffusion coefficient, VawIt is expiratory gas flow for airway dead space air volume, Fex；
Exhale residence time τeIt is found out by the relationship between expiratory gas flow and airway dead space volume:
Air-breathing residence time τinIt is found out by the relationship between inspiratory flow and airway dead space volume:。
The method of the present invention reduces the difficulty of exhalation process control by the design of expiration method, improves the success of measurement Rate and reliability avoid the too simple brought measurement error of two compartment model by the optimization of algorithm, make measurement result more Add reliable.
Detailed description of the invention
Fig. 1 alveolar and air flue nitric oxide generate and diffusion fixed double chamber bed.
Fig. 2 is exhaled between 6 seconds expiration NO measurement of concetration curves and theoretical exhalation NO curve after feeling suffocated 20 seconds with 50ml/s flow Comparison.
Specific embodiment
The theoretical basis of the method for the invention is based on putative two Room mould of Exhaled nitric oxide physiological models --- -- Type (as shown in Figure 1) cuts analysis from simplified physiological models, and it is appropriate then to carry out according to the actual situation to gained calculation formula It corrects and rationally applies, make theoretical more close with experimental result.
It is commonly assumed that when being analyzed using expiration nitric oxide two compartment model:
1) exhaled NO derives from alveolar and air flue (under conditions of closing soft palate, not considering the interference of nasal cavity gas)；
2) in exhalation process, steady state alveolar NO concentration (Calv) concentration is smaller and keeps constant that (generally less than 5ppb, this is Because by alveolar generate or the NO that breathing process is sucked by epithelium healing can be quickly in conjunction with hemoglobin)；
3) when alveolar air flow through air flue and oral cavity discharge before, NO concentration can be gradually increasing, and reason is air flue cortex Concentration (C of the NO that cell generates in airway wallsw) much larger than gas NO concentration (C in air fluea), such NO persistently can be by air flue Wall is spread to air flue, and diffusion velocity meets Fick law；
4) in air flue different anatomic position airway walls NO concentration CwIt is consistent.
Under the premise of herein, expiration NO concentration and airway parameters, especially D under different expiration states are consideredawBetween relationship have:
1) (the expiratory air volume V at this time when expired volume is greater than airway dead space air volumee> airway dead space air volume Vaw, exhale Gas time te> exhale residence time τe)
Concentration of exhaled NO meets relationship at this time:
(1)
Wherein CeFor concentration of exhaled NO, CwFor airway walls NO concentration, CalvFor steady state alveolar NO concentration, DawFor air flue Diffusion coefficient, VawFor airway dead space air volume, τeFor the residence time of exhaling；
Under conditions of constant expired flow Fex, have:
(2)
(1) formula can simplify at this time are as follows:
(3)
It can be seen that by dead space gas exhalation after, expiration NO concentration is unrelated with hold your time, and with steady state alveolar NO concentration (Calv)、 Maximum airway walls diffusing capacity (Jaw), air flue diffusion coefficient DawIt is related, but due to DawTo CeInfluence only in retention time τeFoot Enough long expiratory gas flow in other words (F slow enoughexIt is sufficiently small, τe=Vaw/Fex, wherein VawFor airway dead space air volume) when could show Reveal and, practical application has a difficulty.So document report calculates D using the formulaawWhen expiratory gas flow will generally be less than 10ml/s, and airway dead space gas is exhausted under the flow, it at least will be with the flow sustained exhalation 20 seconds or more, control of exhaling is non- It is often difficult, clinically hardly result in application.
2) (the V when expiration gas volume is less than dead space air producte<Vaw, te<τe)
Expiration NO concentration meets relationship at this time:
(4)
Work as tin >τinShi You:
(5)
By formula (4), (5) it is found that at this time the concentration of expiration NO and sucking air concentration Cair, air-breathing, expiratory duration tin、 teAnd airway parameters Cw、 Daw、Vaw、JawIt is factor-related Deng 7, (define Jaw =Daw*Cw), such as Jaw 、VawIt is known that tin、te、 Ce、CairIt can measure, as long as theoretically taking the C under at least two different times according to the expiration NO curve of this periodeValue composition It can be by D by simultaneous equationsawIt finds out.
When expiratory gas flow is larger, the exponential term numerical value in (4), (5) formula is smaller, to expiration NO concentration CeInfluence not Greatly, the method measured after feeling suffocated is used, expiration NO concentration meets relationship:
(6)
This is visible to be greatly improved exponential term factor pair CeContribution, D at this timeawInfluence to expiration NO also just highlights Come, thus D can be improved using expiratory measurements after feeling suffocatedawThe reliability of calculating.
But when present inventor attempts to use discovery when (6) formula is tested: expiration NO concentration becomes at any time after actually feeling suffocated Gained when changing between curve and theoretical curve that there are biggish differences, and measuring calculating to healthy population using the formula DawDistribution value range is 20 ~ 50ml/s, is much larger than literature values (3.1 ~ 9.2 ml/s), and reproducibility is poor, described in explanation There is also certain defects for method.
Two o'clock may be had by analyzing its reason: first is that physiological models used in the derivation of equation excessively simplify, practical epithelium healing is simultaneously Uniform circular pipe, and air flue each section NO result from diffusion speed be also not necessarily it is uniform, thus with this letter Change model and is difficult accurate simulation expiration NO concentration situation of change；It is higher due to air flue NO concentration second is that during feeling suffocated, Air flue different location, there are biggish concentration gradient, the influence of axial concentration difference diffusion can not neglect the NO between big airways, small airway Slightly.
Due to above-mentioned two compartment model under constant expired flow and expiratory duration be greater than residence time τeWhen demonstrate,proved extensively It is approximate effective (air flue loudspeaker Modifying model can be carried out when necessary) in fact, this illustrates that the two compartment model is anti-to a certain extent The physiological status that air flue NO results from diffusion is reflected, the model has certain reasonability.This is because in constant expired flow Lower and expiratory duration is greater than residence time τeWhen, each parameter D in the modelaw、Cw、Jaw、Calv、VawTo the shadow of expiration NO concentration Sound is in residence time τeInterior accumulation, thus what is reacted is one average as a result, (being exhaled with different by constant flow expiration Throughput repeatedly measures) measure acquired results reflection is also the mean value of an airway parameters.Therefore, a preferred measurement Method should be the relationship analyzed between expiration NO total amount and airway parameters.
Consider the case where NO is axially diffused, such as assume that small airway does not generate not consuming from big airways yet and diffuse through the NO come, NO in the small airway of part then can be also included in integral operation, and then correct the influence that NO axially diffuses generation, in analysis text Discovery when offering middle moisture measurement model, the hypothesis have been adopted and have verified, and illustrate this reasonability for assuming to have certain.Institute It states under hypothesis, is less than τ for exhalingeAnd it is greater than τeTwo parts period, the NO of exhalation all took into account, the total amount Q of expiration NOeIt is full It is enough lower relationship:
(7)
Wherein:
Exhale residence time τeIt is found out by the relationship between expiratory gas flow and airway dead space volume:
(8)
Air-breathing residence time τinIt is found out by the relationship between inspiratory flow and airway dead space volume:
(9)
When being calculated using the algorithm, it is contemplated that the difficulty of long-time expiratory measurements needs to guarantee in certain expiration The gas (to health adult, preferably breathing out the gas of 1 ~ 4 expiration dead volume) of 1~8 expiration dead volume of exhalation in time, Thus there are a most suitable range in expiratory gas flow, time, and expiratory gas flow is too small, then required expiratory duration is too long, expiration difficulty It is larger；Expiratory gas flow is too big, then expiratory duration is too short, and expiration NO concentration is too low, and measurement error is larger, and most suitable condition can It is selected by experiment.
By formula (7) it is found that expiration NO total amount Q after feeling suffocatedeWith maximum airway flux Jaw, air flue diffusion coefficient Daw, air flue Dead space air accumulates Vaw, hold your time thold, air-breathing residence time τin, exhale residence time τe, alveolar NO concentration Calv, inhale, exhale Flow (Fin、Fex, for calculating τin、τe), expiratory duration teIt is factor-related Deng 10, wherein Jaw、、Vaw、CalvDeng 3 parameters (patent 201510782786.1) can be measured by still fertile one breath multiparameter analysis technology, it can also be by reported in the literature more Implication variable-flow expiratory measurements method measures, and thold、τin、τe、Fin、Fex、teAnd expiration NO total amount QeIt can be set Deng 7 parameters The direct survey calculation of suitable device is counted, thus remains next unknown parameter D in formula (7)awThe public affairs can directly be utilized Formula is calculated.
The method of the present invention reduces the difficulty of exhalation process control by the design of expiration method, improves the success of measurement Rate and reliability avoid the too simple brought measurement error of two compartment model by the optimization of algorithm, make measurement result more Add reliable.
Application Example one
Equipment therefor of the present invention is one breath unsteady flow measuring device described in Chinese patent 201510782786.1, Method described in the patent can be used for airway parameters Jaw, Ca, VawMeasurement, and for DawMeasurement, then use institute of the present invention Method is stated, measurement and analytic process are as follows:
1) it measures for the first time: J is measured by one breath variable-flow technology described in patent 201510782786.1aw、Calv、 Vaw；
2) it measures for second: to fix expiratory gas flow sustained exhalation 6 seconds after feeling suffocated 20 seconds, and measuring record overall process and exhale NO concentration curve；
3) it calculates: Daw is calculated by formula (7) according to expiration overall process NO experiment curv and air-breathing, expiration parameter.
Fig. 2 is calculated with 50ml/s flow 6 seconds expiration NO measurement of concetration curves of expiration with according to formula (7) after feeling suffocated 20 seconds The comparison between theoretical exhalation NO curve out, there are biggish differences with measured curve for theoretical curve as seen from the figure.
Table 1 is the airway parameters that a volunteer first passes through that still fertile one breath variable-flow device measuring unsteady flow measurement obtains Value is become after feeling suffocated 20 seconds followed by equipment record with expiratory gas flow sustained exhalation 6 seconds of 50ml/s obtained NO concentration Change curve, then calculate Daw and Cw using formula (7), what table two was listed is morning and afternoon each 5 measurements as a result, it is average The value respectively ml/s of 6.1+/- 2.0, the ml/s of 7.3+/- 2.3, resulting result reproducibility can clinically receive, and measure Mean value and health adult Daw value (3.1 ~ 9.2 ml/s) reported in the literature are close, show that the method is reasonable.
Table one: the volunteer's airway parameters obtained using still fertile one breath variable-flow device measuring
Cair(ppb) Calv(ppb) Jmax(pl/s) Vaw(ml)
3 2.5 644 132
Table two: with 50ml/s flow sustained exhalation 6 seconds after being felt suffocated 20 seconds using still fertile one breath variable-flow device measuring, weight Repetition measurement amount 10 times, and the airway parameters Daw and Cw being calculated using one data of table
In view of the lag that instrument dead volume and sensor respond, appropriate adjustment can be carried out to curve integral domain to obtain More accurate measurement can reduce oral cavity and instrument as a result, if the selection of time of integration point is since 5% or 10% expired volume in this way Influence of the device dead volume to measurement result.
The preferred expiratory gas flow of the present embodiment is 50ml/s, the selection of practical expiratory gas flow and expiratory duration can as needed into Row adjustment, the sustained exhalation time selection generally make expiration total volume reach dead space air product 1 ~ 8 times, preferably 2 ~ 4 times, Too small NO, which is axially diffused, to be affected, DawMeasured value is higher, too big DawThe influence of measurement result is smaller, and as a result reproducibility is poor.
The preferred hold your time of the present embodiment is 20 seconds, too short DawThe reproducibility of measurement is bad, and measurement error is larger, suppresses Gas time too long then subject cooperates difficult.
The first time measures and can be realized by one breath variable-flow method, can also be repeatedly permanent by changing expiratory gas flow Flow expiratory measurements are realized.
Application Example two
Equipment therefor is identical as Application Example one, the difference is that need not constant flow rate exhale, but algorithm is relatively real It is relative complex to apply example one.It is as follows that it measures analytic process:
1) it measures for the first time: J is measured by one breath variable-flow technology described in patent 201510782786.1aw、Calv、Vaw
2) measure for second: after feeling suffocated 20 seconds for a period of time with sustained exhalation, measurement records the expiratory flow of full exhalation process Measure curve and expiration NO concentration curve
3) it calculates: D is calculated by formula (7) ~ (9) according to expiration overall process NO experiment curv and air-breathing, expiration parameteraw。
Application Example three
Equipment therefor is identical as Application Example one, the difference is that the choosing of the measurement method to expiration NO total concentration Select, the present embodiment is that exhaled gas is all collected in an airbag, after expiration to the gas mean concentration in airbag into Row measurement, then calculates expiration NO total amount according to the mean concentration of gas in airbag and volume, logical further according to air-breathing, expiration parameter It crosses formula (7) ~ (9) and calculates Daw。

Claims (9)

1. a kind of method for measuring expiration nitric oxide airway parameters diffusion coefficient, it is characterised in that the measurement is at least in two times It completes, wherein first time measurement method are as follows: do not feel suffocated, obtain maximum airway flux J by changing expiratory gas flow measurementawAnd it is steady State alveolar NO concentration CalvParameter, second of measurement method are as follows: sustained exhalation after a certain period of time of feeling suffocated, by measuring sustained exhalation Obtained expiration NO total amount will measure obtained maximum compared with by the obtained theoretical value of expiration two compartment model for the first time Airway flux Jaw, steady state alveolar NO concentration Calv, sucking air concentration CairParameter substitutes into, and adjusts the diffusion of another parameter air flue Coefficient DawKeep the two result closest.
2. a kind of method for measuring expiration nitric oxide airway parameters diffusion coefficient as described in claim 1, it is characterised in that: institute It states measurement for the first time to realize by one breath variable-flow method, be realized by changing the multiple constant flow expiratory measurements of expiratory gas flow.
3. a kind of method for measuring expiration nitric oxide airway parameters diffusion coefficient as described in claim 1, it is characterised in that suppress The gas time is 5 to 30 seconds.
4. a kind of method for measuring expiration nitric oxide airway parameters diffusion coefficient as described in claim 1, it is characterised in that suppress The gas volume that sustained exhalation certain time is breathed out after gas is 1~8 times of airway dead space air volume.
5. a kind of method for measuring expiration nitric oxide airway parameters diffusion coefficient as described in claim 1, it is characterised in that institute State the measurement method of measurement expiration NO total amount are as follows: record full exhalation process expiration NO concentration curve, integrate by curve Method calculates expiration NO total amount.
6. a kind of method for measuring expiration nitric oxide airway parameters diffusion coefficient as described in claim 1, it is characterised in that institute State the measurement method of expiration NO total amount are as follows: exhaled gas is all collected in an airbag, to the gas in airbag after expiration Body mean concentration measures, and then calculates expiration NO total amount according to the mean concentration of gas in airbag and volume.
7. a kind of method for measuring expiration nitric oxide airway parameters diffusion coefficient as described in claim 1, it is characterised in that institute State the theoretical calculation formula of the obtained expiration NO total amount Qe of two compartment model are as follows:
, wherein CwFor the concentration in airway walls, CairTo suck air concentration, CalvFor steady state alveolar NO concentration, τeWhen being remained to exhale Between, τinFor air-breathing residence time, τeFor the residence time, t of exhalingholdFor hold your time, teFor expiratory duration air flue, DawFor diffusion Coefficient, VawIt is expiratory gas flow for airway dead space air volume, Fex.
8. a kind of method for measuring expiration nitric oxide airway parameters diffusion coefficient as claimed in claim 7, wherein two Room In the theoretical calculation formula of the obtained expiration NO total amount Qe of model, τ the time required to exhalation airway dead space gasePass through expiratory gas flow FexAnd airway dead space volume VawBetween relationship find out:。
9. a kind of method for measuring expiration nitric oxide airway parameters diffusion coefficient as claimed in claim 7, wherein two Room In the theoretical calculation formula of the obtained expiration NO total amount Qe of model, air flue residence time τ when air-breathinginPass through inspiratory flow FexAnd V between airway dead space volumeawRelationship find out:。
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