WO2014140278A1

WO2014140278A1 - Device and method for measuring the concentration of nasal nitric oxide (no) without closing the soft palate

Info

Publication number: WO2014140278A1
Application number: PCT/EP2014/055105
Authority: WO
Inventors: Guy Martinot
Original assignee: Medi-Soft S.A.
Priority date: 2013-03-14
Filing date: 2014-03-14
Publication date: 2014-09-18
Also published as: EP2967433A1

Abstract

The invention concerns a device for measuring the concentration of endogenous NO in the nasal cavities, comprising an analysis circuit (25) for analysing the airflow passing from one nostril to the other and a circuit (26) compensating for the air drawn in by the analysis circuit, said circuits each being provided with a pump (21, 29) and comprising a flow sensor (23).

Description

Device and method for measuring the concentration of nasal nitric oxide (NO) without closure of the soft palate The present invention relates to a method and a device for measuring the concentration of NO in the gas phase in nasal cavities in order to study the bioavailability of endogenous NO in the upper airways.

The gaseous NO origin of nasal fossae is a biological marker whose presence was discovered by Alving et al in 1993. The measurement of nasal NO concentration (nasal NOAE or nNO) is currently being considered and / or used primarily for the detection of primary ciliary dyskinesia (PCD) in children. This condition is associated with a low or even undetectable value of nasal NO concentration. The nasal NO is also a marker of inflammation of the upper respiratory tract (allergic rhinitis or nasolabial polyposis).

The anatomical source of nasal NO is not fully defined, but it is believed that most NO is synthesized by the epithelium lining the walls of nasal cavities and cavities, and diffused by convection to the nostrils. Nasal (sinus) fossils use a primary source of nasal NO. These are cavities filled with air, which communicate with each other and open into the external nasal cavities via an orifice called "ostium". As a consequence, the concentration of nasal FENO is determined by the interaction of several factors such as: the local biosynthetic rate of NO, the level of NO metabolism (bacterial and / or tissue), NO diffusion capacity, air volume in the sinuses and permeability of the ostium. A large amount of nasal NO is detectable in the air aspirated from the nostril. The normal value of nasal FENO is usually between 200 and 2000 ppb. (This value is inversely proportional to the sampling rate, for which reason a standardized flow rate of 250 ml / min is recommended by the ATS).

Since the nasal cavities are in communication with the space of the lower airways (the tracheobronchial space) where the NO is synthesized at a substantially lower concentration (15 to 80 ppb), it is necessary to separate these two compartments (upper and lower) during the measurements to avoid underestimation of nasal NOAEL by the dilution effect.

According to the prior art, this separation is ensured by closure of the soft palate when a positive pressure of 10 cm H ₂ O is generated by oral breathing against resistance, or by voluntary apnea of the subject. A catheter draws a certain amount of air from a nostril at a constant rate and the NO concentration is determined by a known NO analyzer. Generally, this technique consists in adapting a single nosepiece with catheter in a nostril, acting by suction at a flow rate of 50 to 1000ml / min, while the nostril on the other side remains open. A source of air that does not contain NO can also be applied to prevent contamination of the ambient NO.

A measurement of nasal NO with insufflation has been described by Silkoff et al. in American Journal of Rhinology 169-178 Vol 13 No 3 1999 (see Method 5). It also calls for the closure of the veil, considered indispensable. However, in subjects with little or no collaboration, the breathing maneuver against resistance or the maneuver of voluntary apnea is not feasible (ATS J. Respir.Crit Care Med 2005 15; 171 (8): 912 -30) and there is therefore a need for a more suitable method and device, particularly for young children for whom the measurement of nasal NO is particularly important.

For this purpose, the present invention provides a device for measuring nasal NO without closing the veil by creating in the nasal cavities a quasi-constant pressure and practically independent of the variation of the pressure generated by the oral breathing. This object is achieved by injecting a volume of compensation of the purified ambient air of NO with the aid of an injection pump, preferably at a rate automatically controlled. This creates a circulation of air through the nasal cavities. Compensation of the volume sucked by the volume injected ensures a pressure balance inside the nasal cavities allowing a continuous analysis of the nasal NO, while avoiding both the contamination of the ambient NO and the dilution effect by the lower respiratory tract, even when the closure of the soft palate is not assured.

The present invention also provides a method of controlling the sampling rate during measurements. The introduction of a flow sensor at the point of entry of the analysis circuit makes it possible in fact to measure in real time the sampling rate and the visual display of this flow rate. The evaluation of the instantaneous flow rate can be based on the difference measurement ΔΡ between the upstream pressure and the downstream pressure of the circuit. The control of ΔΡ and thus of the flow during the measurement is very useful by allowing to:

- determine the actual value of the actual sampling rate, which may influence the observed value of the nasal NO.

- detect sampling artifacts that are responsible for measurement errors, such as: catheter disconnection, leakage, voluntary nasal ventilation, hyperventilation through the mouth and nasal obstruction.

- monitor the quality of the measurement in real time.

The invention therefore proposes a device for the measurement of endogenous NO in the nasal cavities comprising a circuit for analyzing the air sucked by one nostril and an air compensation circuit injected into the other nostril, each circuit comprising a pump whose flow is independently adjustable and controlled by a

computer connected to a flow sensor of the analysis circuit. Both circuits are airtight with respect to the outside air. The invention will be better understood on examining the accompanying drawings provided by way of example only, in which FIG. 1 illustrates the mechanism of NO biosynthesis in nasal cavities.

Fig.2 illustrates and compares the new method according to the invention and the conventional method of the prior art.

Fig. 3 is a diagrammatic presentation of the frontal and lateral plane of the upper airways of a man, combined with the device according to the invention

The figs. 4a and 4b show schematically the pneumatic circuit according to the invention respectively without and with the computer control and control device.

Fig. 5 illustrates more particularly the components of the respiratory system associated with the analysis circuit according to the invention.

Fig. Figure 6 illustrates the relationship between the NWTF and sampling rate or duration.

Fig. 7 is a graphical representation of nasal flow or nasal FENO over time.

Fig. 8 illustrates the effect of nasal ventilation

Fig. 9 illustrates the effect of an obstruction of the sampling circuit.

The figs. 10 and 11 show the good correlation between the measurements made according to the method of the invention and according to the conventional method of the prior art.

More precisely, FIG. 4b represents a circuit

recording and processing of data by a computer according to the invention. We distinguish in particular:

a computer 34 equipped with dedicated software for recording and processing signals.

an NO analyzer 20 that analyzes the NO concentration and returns the raw signal to the computer 34.

The analyzer 20 is well known per se and may be an electrochemical or fluorescence analyzer (Sievers). Other types of analyzers described in the literature can be used.

the first pump 21a, this pump generates the sampling flow.

- the second pump 29 which generates the air compensation flow in the other nostril, to establish a pressure balance in the nasal cavities) to avoid the mixture of nasal air and bronchoalveolar air. These 2 pumps (21a and 29a) are controlled by the computer via the respective 2 controllers (21b and 29b)

- A suction flow controller (21b) which automatically changes the flow rate of the suction pump (21a) so that its value is equal to that of the flow rate generated by the injection pump (29a).

an injection flow rate controller (29b) which automatically changes the flow rate of the injection pump (29a) so that its value is equal to that of the flow rate generated by the suction pump (21a). This automatic control is generated by the computer 34 which sends the commands to modify the flow rate of each pump via each controller so that their flow values are identical.

- a Permapure 22 dryer: it is a well known drying and / or humidity control device in pneumatic air analysis circuits a barometric flow rate sensor 23 for evaluating the variation of the effective flow rate of the sampling stream. The raw signal of the sampling rate will be recorded by the computer.

a calibration gate 24 intended for the admission of calibration gas in calibration mode or ambient air during a control of the ambient NO.

a sampling gate 25 provides the connection between a nostril and the sampling circuit.

a compensating gate 26 for injecting the purified NO air

a microbial filter 27

two nosepieces ogival type 28a and 28b at the ends of two catheters, to fit tightly to the nostrils.

an ambient air intake with a filter intended to supply the compensation circuit with purified NO air.

a solenoid valve 31 enabling the connection of the analysis circuit (25) to the calibration circuit (24) in the calibration mode or in the ambient NO control mode.

- Solenoid valves 32 and 33 allowing the conversion between the isolation mode of the circuit during measurement "off-set" (determination of the zero level) and the sampling mode (analysis of the nasal NO).

The state of each solenoid valve (SI or SE) is controlled by the computer, depending on the corresponding measurement mode.

When the 2 branches of the circuit are well connected to the two nostrils of the subject (Valve 31 in position SE, valve 32 in the SI position, valve 33 in the SI position), the analysis of the nasal air is performed by an NO analyzer, preferably of the electrochemical type, after a determined time of contact of the flow with the nasal cavities. The electrochemical analyzer actually has a longer response time than a fluorescence analyzer, for which the response is almost instantaneous. Fig. 5 illustrates the components of the physical respiratory system associated with the nasal analysis circuit and the determinants of the sampling rate in a nasal NO measurement. This diagram helps to understand the mechanism of flow variations and justifies the need for flow control during nasal NO measurement.

In this scheme, the respiratory system is divided into two main compartments:

the upper track which comprises the mouth 5; the nasal cavity 3 which is open to the outside via the nostrils 4a and 4b and inside to the nasal cavity 1 via the ostium orifice 2,

- the lower airway which includes the tracheal laryngeal tube 7.1a and the bronchoalveolar shaft in the lungs 8.

Closure of the soft palate 5 allows superior lane separation to the lower lane.

The actual flow rate of sampling is defined as the rate of passage of air from entry point 26 to the upper airway and the analysis circuit 25. The measurement of this flow is provided by the flow sensor 23. Its value is also determined by the ratio between the total pressure gradient ΔΡ and the total resistance Rtot.

Or :

is the actual sampling rate (mL / min)

Pi is the positive pressure generated by the injection pump

Pa is the (negative) pressure generated by the suction pump. Pf is the NO pressure inside the nasal cavity. As the production of NO is permanent and important, the Pf is always positive (relative to the external pressure). As a result, the nasal NO has a tendency to diffuse towards the trachea and the surrounding air. When the analysis circuit is closed, all the NO will be sucked by Pa (more negative).

Pm is the oral pressure, it is determined by the difference between the trans-pulmonary pressure (PI) and the barometric pressure (Pb): Pm = (PI - Pb).

Pn is the pressure inside the nasal cavities. In the normal condition, the Pn is equal to the pressure oral (Pm). The Pn becomes relatively more positive / negative during nasal ventilation generated by the subject. As a result, sampling rate variation can be caused by pressure imbalance and / or resistance change (obstruction in nasal cavities and / or occlusion of catheters). Fig. 6A indicates that the nasal FENO is inversely proportional to the sampling rate. A transient increase in nasal NO flow through biosynthesis and / or an isolated decrease in sampling rate may increase the concentration of nasal NO.

In contrast, a transient decrease in nasal NO biosynthesis and / or an increase in sampling rate may decrease the nasal NOEL.

Fig. 6B shows a typical nasal FENO curve.

The value of nasal FENO varies in 4 phases:

Phase (I): the nasal NOEL gradually increases to a stable value after 10 seconds.

Phase (II): the plateau indicates the equilibrium state of the pressure in the analysis circuit. The FENO value is stabilized for at least 30 seconds.

Phase (III): If sampling is too long (60- 100 seconds): a transient decrease in nasal NAFL may be observed, indicating that sampling exceeded the local production rate of NO.

Phase (IV): Recovery of nasal NO production rate in response to the more negative pressure of the sampling stream.

Figs.7A and 7B are graphical representations of the result of simultaneous measurements of sampling rate (A) and nasal FENO (B) as a function of time.

The trace of the flow 36 presents an oscillation of the VE signal in response to the pressure change in the sampling circuit.

For a correct measurement maneuver, the flow pattern is mono-rhythmic and concentrated at the preset value 39. Continuous and small fluctuations without irregularities in the amplitude are normal.

The flow pattern becomes polyrhythmic if the ventilation rate through the mouth or nostrils is greater than the flow rate generated by the pump.

Flow control involves evaluating changes in the amplitude and frequency of the trace.

The amplitude of the oscillation is proportional to the nasal pressure. The latter varies depending on the connectivity state of the sampling line and the subject's breathing movements. Ideally, the amplitude of the oscillation should be limited in a interval of +/- 25 ml / min. The variation is intolerable if the variation of the amplitude is greater than the limits 50 ml / min (37, 38). The interpretation is also based on the time of onset and duration of the change, as well as its influence on the nasal FENO value. 35 Flow variation is not significant if no change in nasal NOAf is observed ( pressure change and transit time is not sufficient to influence the concentration of NO within the nasal cavities).

The applicant proposed a function to optimize the final result of the nasal NO. For a FENO curve 45 with too many fluctuations (Fig. 7B), the best value of the nasal NO can be determined either instantaneously by an automated algorithm or by manual selection of the user. The software allows an algorithm to automatically and instantly determine the maximum value of the nasal NO during measurement. The algorithm is based on a comparison of the instantaneous values of the concentration of the nasal NO to determine the maximum value.

The establishment of a slider 40 allows a visual appreciation of the best result and a manual optimization of the value of nasal FENO.

Fig. 8 illustrates the change in flow rate and nasal NOEL caused by nasal ventilation. This nasal breakdown increases the nasal pressure (Pn) and therefore the sampling rate. This measurement error is characterized by a large amplitude oscillation on the trace of the flow, associated with a fluctuation on the nasal NO curve.

Fig.9 illustrates the change in flow rate and nasal NOAE caused by obstruction of the sampling circuit. This obstruction may be caused by the presence of nasal polyposis and / or congestion of mucus in the circuit. The nasal obstruction causes an increase in the total resistance and therefore a drop in flow. As the passage of NO is blocked, the concentration of nasal NO is also decreased. The Applicant has verified that the measurements obtained with the device and according to the method of the invention have a good correlation and a high degree of agreement with the standard method as demonstrated by the following data.

Fig. 10 illustrates the significant correlation between nasal FENO values measured in children (5 months-17 years) by the method according to the invention (with electrochemical measurement) and by the conventional method on another apparatus (the measurement at expiration Forced Oral Ecomedics).

Fig. 11 presents a concordance analysis between the two methods by the Bland-Altman diagram and shows that the average difference between the two methods is minimal (13 ppb) for a range of values between 60-1480 ppb. Moreover, the method according to the invention has been compared with the standard method with respect to the response time and the detected values of nasal FENO. The results are shown in Tables 1 to 3:

The new method is characterized by a time

faster response.

With an electrochemical type analyzer the new method allows an improvement of the sensitivity compared to the standard method of the prior art.

The invention therefore relates to a device for the measurement of endogenous NO concentration, or the rate of NO formation, in the nasal cavities comprising a circuit for analyzing the flow of air passing from one nostril to the other and a compensation circuit.

These two circuits each comprise a pump with identical flow rates and automatically controlled to generate trans-nasal flows.

The analysis (or sampling) circuit further comprises a flow sensor at the point of entry and an analyzer for NO.

In the calibration or control mode of the NO in the ambient air, only the analysis circuit that operates is connected to the calibration gate to evaluate the NO in a calibration bag or in the ambient air.

In the in-vivo measurement mode: the 2 circuits are connected to the subject's nasal cavities to create a continuous flow of air passing from one nostril to the other by loading the nasal NO.

The flow sensor assesses the pressure variations between the upstream point and the downstream point of the analysis circuit, and allows sampling flow control during the examination. This check has for main purpose to detect measurement errors.

Sampling flow sensor and nasal FENO signals are displayed in real time. After the test, the best nasal FENO value automatically determined by a software algorithm.

The software makes it possible to optimize the final result, thanks to a movable cursor on the FENO curve. The user can manually change the value of the nasal NO.

Claims

1. Device for measuring the concentration of endogenous NO in the nasal cavities comprising a circuit for analyzing (25) the air sucked via a nostril (4b) and an air compensation circuit (26) injected into the the other nostril (4a), each circuit having a pump (21, 29).

2. Device according to claim 1 wherein for at least one pump the flow is independently adjustable.

3. Device according to the preceding claim wherein the flow rate of the two pumps (21, 29) is independently aj ustable.

4. Apparatus according to any one of the preceding claims wherein the one or more pump rates are controlled by a computer (34) connected to at least one flow sensor (23) of the analysis circuit.

5. Device according to any one of the preceding claims further comprising at least - upstream of the injection circuit (26) - an ambient air intake with a filter (30) for removing the ambient NO.

6. Device according to any one of the preceding claims wherein the analysis circuit comprises in series a solenoid valve (31) allowing the

communication with ambient air or calibration gas in calibration mode.

7. Device according to any one of the preceding claims wherein the analysis circuit comprises solenoid valve (32) which allows to temporarily separate the analysis circuit and the nasal cavities, allowing in conjunction with a valve (33) the measurement of the zero level "off-set" where the analyzer is subjected to purified ambient air NO of the compensation circuit.

8. Device according to any one of the preceding claims wherein the flow sensor (23) is a barometric flow sensor.

9. Device according to any one of the preceding claims wherein the analyzer (20) of the analysis circuit is a chemiluminescent NO sensor.

10. Device according to any of

Claims 1 to 8 wherein the analyzer (20) of the analysis circuit is an electrochemical sensor.

11. Device according to any of

preceding claims wherein the computer controls the flow rate of the pumps by a barometric sensor (23 ') based on the measurement of the pressure difference between a point of the analysis circuit and a point of the compensation circuit.

12. Device according to any of

preceding claims wherein the computer is connected to a monitor display system which includes a movable cursor (40) on the FENO curve to select the best value (the value maximum) of the nasal FENO among all the instantaneous values obtained.

13. Method for determining the endogenous NO concentration of the nostrils by continuously analyzing the NO present in a sampling circuit (25) from one nostril (4b), the other nostril (4a) being supplied with free air NO by an injection circuit (26) in parallel, the sampling circuit being provided with a flow meter.

14. Method for detecting hardware errors of the nasal NO measurement based on an interpretation of the sampling rate signal.

15. The method of claim 13 or 14 applied to a child breathing normally.