BE1023652B1 - METHOD AND DEVICE FOR DETERMINING A HARMONIC THICKNESS OF A ALVEOLARY MEMBRANE OF A LUNG - Google Patents

Abstract

A method for determining a harmonic thickness of an alveolar membrane of a lung, wherein said lung is supplied with a quantity of a carrier gas carrying a first quantity of particles having a size within a predetermined range, and measured, after a predetermined period during which the carrier gas has been retained in the lung, a second quantity of said particles present in the exhaled gas, a parameter is then determined on the basis of the first and of the second quantity of particles indicating a decrease in the quantity of particles present in the exhaled gas relative to the gas supplied, on the basis of said parameter and a sedimentation rate of said particles in the lung, a dimension of a surface on which sedimentation of the particles through a layer is determined of alveolar gas has taken place, said harmonic thickness being determined from said dimension of this surface.

Description

Method and device for determining a harmonic thickness of an alveolar membrane of a lung

The present invention relates to a method for determining a harmonic thickness of an alveolar membrane of a lung, wherein said lung is provided with a predetermined amount of a carrier gas carrying a first quantity of particles having a size within a predetermined range, and measuring, after a predetermined period during which the carrier gas has been retained in the lung, a second quantity of said particles present in the exhaled gas of the lung, is then determined on the basis of the first and the second quantity of particles a parameter indicating a decrease in the amount of particles present in the exhaled gas relative to the gas supplied.

The application US 2012/0183949 describes a method according to which said lung is provided with a predetermined quantity of a carrier gas carrying a first quantity of particles for determining physiological conditions of the lung. The method is also used for example in respiratory functional tests and is used to measure the lung's ability to diffuse inhaled gas. A patient inhales a predetermined quantity of a gas which he then exhales after holding his breath for a predetermined period of time. Based on the difference in amount of gas exhaled with respect to the amount of inhaled gas, then the amount of gas diffused into the lung can be determined. This quantity of gas diffused then allows a doctor to make a diagnosis on the health of the lung of the patient.

A disadvantage of the known method is that it does not allow accurate measurement of the harmonic thickness of an alveolar lung membrane. It is an object of the invention to provide a method for more accurate measurement for determining the harmonic thickness of an alveolar membrane of a lung. For this purpose, a method according to the invention is characterized in that on the basis of said parameter and a sedimentation rate of said particles in the lung, a dimension of a surface is determined on which a sedimentation of the particles through a layer of alveolar gas in the lung has occurred, said harmonic thickness being then determined from said dimension of this surface. The determination of the size of the surface on which the sedimentation of the particles through a layer of alveolar gas in the lung has taken place gives a more accurate measurement, which in turn allows to determine more precisely the harmonic thickness of the alveolar membrane of the lung considered.

A first embodiment of a method according to the invention is characterized in that a thickness of the alveolar gas layer through which the sedimentation of the particles has occurred is determined, said dimension of the effective surface of the alveolar membrane being then determined on the basis of this thickness of the gas layer and the total capacity of the lung. The thickness of the gas layer can be determined mathematically from the drop in concentration and the rate of sedimentation of the particles.

A second embodiment of a process according to the invention is characterized in that the supply of the carrier gas carrying a first quantity of particles is repeated a number (1/11 n) of times during the execution of the process, the period predetermined (ti) during which the carrier gas is retained in the lung being varied after each supply (i), said second quantity being determined each time at the end of the predetermined period (ti) considered, said parameter being determined on the basis of second quantities determined at the expiry of each of the predetermined periods (ti) of said number. Repeating the supply of carrier gas and particles and varying the period during which the carrier gas is retained in the lung makes the measurement more reliable.

A third embodiment of a process according to the invention is characterized in that the drop in concentration between the first and second quantities of particles evolves according to a mathematical function taking up a decrease over time in the quantity of particles, said parameter being determined from this mathematical function. The use of a mathematical function allows a computer-implemented method.

Preferably, particles having an average geometrical and aerodynamic diameter of less than 5 microns, in particular less than 3 microns and more particularly less than 1 micron, are introduced into the carrier gas. This particle size ensures good sedimentation in the lung and therefore a reliable measurement. The invention will now be described in more detail with the aid of the drawings which illustrate embodiments of the method and device according to the invention. In the drawings:

Figure 1 schematically illustrates a lung;

Figure 2 illustrates a sectional view through an alveolar membrane of a lung;

FIG. 3 illustrates a device for implementing the method according to the invention; and

Figure 4 illustrates a mathematical function showing the decrease in the concentration of particles in the exhaled gas as a function of the retention time in the lung.

In the drawings the same reference has been assigned to the same element or a similar element.

A human or animal lung is used to exchange a gas, usually air, with blood. Figure 1 schematically illustrates such a lung. To achieve this exchange a lung 1 comprises bronchi 2 through which the gas inhaled by a subject, namely a human being or an animal, enters the lung and reaches the bronchioles 3, which have the function of transporting the inhaled gas to The cells 4 correspond to a set of chambers where the inhaled gas passes through an alveolar membrane of the lung to be transferred to the red blood cells contained in the capillaries. In this membrane the gaseous waste contained in the blood pass from red blood cells to the gas present in the cells, in order to then be eliminated during the expiration. The alveolar membrane 5, a sectional view of which is shown in FIG. 2, forms a wall which separates the gas from the blood. This membrane has a surface (S) and a thickness. As this thickness may vary, it is generally referred to a harmonic thickness (μ) of the cellular membrane, which is, as it were, an average thickness of this cellular membrane. The harmonic thickness can be considered as a measure to calculate the exchange resistance of inhaled gas.

In the Weibel model, published for example in Respiration Physiology, 93, 1993, pp. 125-149 and entitled "Morphometric mode! for pulmonary diffusing capacity ", the membrane has a heterogeneous thickness around 1 μm. This model demonstrates that the harmonic thickness must be taken into account in determining the gas conductance in the lung. The present invention is based on the fact that being able to accurately determine the harmonic thickness (μ) of the alveolar membrane makes it possible to use this value to diagnose the health of the lung and to observe possible changes in lung pathology, as example that due to emphysema or alveolar fibrosis.

FIG. 3 illustrates a device for carrying out the method according to the invention. The device comprises an inlet valve 11 having an inlet arranged to be connected to a source 10 of gas and particles. An outlet of the valve 11 is connected by a tube 12 to a first connection of a three-way valve 13. A second connection of the valve 13 is connected, via a coupling part 16, to a pipe which opens on a mouth 18 arranged to be applied to the mouth of a patient 19. A third connection of the valve 13 is connected to a pneumotachometer 14 provided with an outlet 15. The coupling piece 16 is also connected to a sensor 17.

The source of gas and particles contains a carrier gas carrying a first quantity of particles having a size within a predetermined range. This carrier gas is preferably formed by ambient air, but it goes without saying that other gases, such as for example oxygen, helium or a mixture of oxygen with another gas such as nitrogen, CO or NO can be used. The carrier gas can be supplied at room temperature, but it is also possible to heat the carrier gas, for example at the temperature of the human or animal body. In this last embodiment the device comprises a heating element (not included in the drawing) arranged for example between the source of gas 10 and the valve 11. The advantage of heating the carrier gas to the body temperature lies in the that the measured quantities and the particles contained in the carrier gas will not be affected by the difference between the ambient temperature and the body temperature. The carrier gas may also be provided under moisture conditions similar to those present in the human or animal body.

The particles contained in the carrier gas may be of various origins and composition. Thus the particles may be in the form of a liquid suspended in the gas, or formed of solid particles. Particles in the form of a liquid can be droplets of water, alcohol or oil. In the case where the particles are in the form of droplets of alcohol or oil, this alcohol or this oil must of course be such that it does not affect the operation of the lung. The droplets may be in the form of a mist or an aerosol and are present in the liquid phase in the carrier gas. Preferably, an aerosol produced from an isotonic saline solution (NaCl 9 g / l) is used. The particles in solid form can be salt, sugar, lactose or a particle consisting of proteins and / or lipids. The particles are preferably free of a coating layer. Preferably the particles are of the same nature which facilitates their detection, but it will be clear that the invention is not limited to the use of particles of the same nature and a mixture of particles of different nature can also be used .

The size of the particles is chosen such that their geometric and aerodynamic diameter is less than 5 μm, in particular less than 3 μm, more particularly less than 1 μm, and even more particularly less than 0.5 μm. Particles of this size do not affect the structure of the lung and thus do not cause lung damage. It is also possible that the particles are composed of a mixture of particle sizes, the smallest of which have a diameter less than 0.5 μm and the largest have a diameter of less than 5 μm. The advantage of using particles having a diameter of less than 3 μm is that these particles penetrate without problem in the bronchioles of a healthy lung. The particles may optionally be dyed, for example with methylene blue, when the method for measuring the amount of inhaled and exhaled particles requires it. The introduction of the particles into the carrier gas can be done at the supplier of the carrier gas, but it is also possible that the source 10 of gas and particles is formed on the one hand by a carrier gas bottle and on the other hand part by a tank of particles connected to a doser. The latter is then connected to an injector arranged to dose the amount of particles to be injected into the carrier gas.

The concentration of the particles in the first quantity of particles added to the carrier gas is set within a predetermined range of at least 10,000 particles per cm3, in particular at least 100,000 particles per cm3 and more particularly at least 1,000,000 particles per cm3. . When the particle concentration is at least 1,000,000 particles per cm3 this means that the subject inhaling one liter of the carrier gas comprising such a first amount of particles should have on average two or three particles deposited per cell.

The sensor 17 is formed by a particle counter arranged to count the particles in the diameter range corresponding to that of the particles present in the carrier gas. This sensor may be of the electric or optical type. The electric type sensor operates for example by applying an electric field to the particles and the optical sensor operates for example by a color recognition. The sensor is either arranged to count the number of particles present in the carrier gas, or to measure the concentration of the particles present in the carrier gas.

The sensor could also be arranged to analyze the particles present in the exhaled gas. This analysis may include measuring the particle diameter and / or the distribution of different particle sizes in the exhaled gas. Preferably the sensor is arranged to analyze that the particles present in the exhaled gas are of the same kind and of the same size as those present in the inhaled gas.

The method according to the invention comprises providing to the lung of the patient 19 a predetermined amount of carrier gas bearing the first amount of particles having a size within the predetermined range. This carrier gas with its first quantity of particles is supplied from the source 10 via the valve 11 and the three-way valve 12 to the mouth 18 carried by the patient 19. In this phase the valve is connected. in the direction to let the carrier gas and particles flow to the mouth 18. The patient then inhales the carrier gas with the first amount of particles. The patient must then hold his breath for a predetermined period of time to allow the particles time to gravitate into the lung. This predetermined period is for example 4 seconds, but it can however be each value between 4 and 10 seconds. During this predetermined period the particles will sediment by gravitation in the lung and reach the alveolar membrane. Depending on the state of the lung, and in particular the state of the alveolar membrane, and also as a function of the time of the predetermined period, a portion of the inhaled particles will sediment in the lung. If the particles are of the same nature and of comparable size, their sedimentation rate will be essentially the same. The part of the particles that has not sedimented in the lung will be exhaled.

After the expiration of the predetermined period the patient can exhale and the sensor 17 will then measure a second amount of said particles present in the exhaled gas of the lung. In this phase the valve is connected in the direction to let the carrier gas and the exhaled particles from the mouth to circulate towards the sensor. Then, on the basis of the first and second quantity of particles, a parameter is determined indicating a drop in concentration of the particles present in the exhaled gas with respect to the gas supplied.

Then, based on said parameter and a sedimentation rate (v9) of said particles in the lung, a dimension of a surface on which sedimentation through a cellular gas layer of the particles is determined in the lung is determined. Given that the inhaled particles are known, their sedimentation rate is determined using the Stokes law. The harmonic thickness is then determined from said dimension of this surface.

In order to improve the reliability of the measurement of the harmonic thickness of the cellular membrane, the supply of the carrier gas carrying a first quantity of particles is preferably repeated a number (1 * sisn) of times during the execution of the process . Both the predetermined period (ti) during which the carrier gas is retained in the lung, that the first quantity, can be varied during each supply (i), or be the same during each supply. The second quantity being determined each time at the end of the predetermined period (ti) considered. The parameter being determined on the basis of the second quantities determined at the expiry of each of the predetermined periods (fc).

The volume of exhaled gas is preferably determined by integration over time of the gas flow measured by the pneumotachometer 14.

In a simplified model, it is considered at the moment when the patient inhales the carrier gas and its first quantity of particles, that in the mixture of carrier gas and particles, the latter are statistically uniformly distributed in a volume V and form a homogeneous suspension. After inhalation, this mixture of gases and particles will fill a region in the lung which will be delimited by walls on which the particles are likely to be deposited, without possible return to the suspension. Due to gravitation the particles have a vertical movement of sedimentation, at constant speed vs. At the end of the predetermined period (t), during exhalation, the device recovers the shedding mixture of a portion of its particles, ie the second quantity of particles. The device determines the second amount by measuring the fraction F of recovered particles relative to the particles initially present.

In a plane model, that is to say that we consider that the deposition of particles is done on a horizontal flat surface of area S and that the volume occupies a cylinder of height e, we can show that the surface can be expressed by: S = (V / (Vst)) (1 - F)

If we do the test for different predetermined period (ti), the fraction F decreases linearly from 1 to reach 0 at the time (V / (S vs)). In a model of spheres, it is assumed that the volume V is initially filled by a set of N balls of the same radius. In this model we can prove that the surface S can be expressed by: S = ((9 V) / <Vst)) (1- (1 - (8/9) (1- F)) <1/2>)

If one does the test for longer and longer times, the fraction F decreases polynomially.

For the model of spheres, we have considered the whole of the surface, and not just the surface corresponding to the zone that receives particles as is the case for the plane model.

In Heyder's article entitled "Assessment of Airway Geometry with Inert Aerosols" and published in Journal of Aerosol Medicine, 2, 2, 1989, pp. 89-97, it is taught that the second quantity of particles decreases according to an exponential mathematical function with the predetermined period (ti) during which the carrier gas is retained in the lung. Still according to this same literature, considering a set of long cylinders randomly oriented of radius r, the recovery function F can be expressed by: F = exp ((-2 vst) / (π r))

This is illustrated in FIG. 4. In the latter figure, the quantity of particles in the exhaled gas is illustrated as a function of the predetermined period (ti) during which the carrier gas with the first quantity of particles has been retained in the lung.

If the inspiration and expiry breathing modes are kept constant, the previous equation can be written: r = ((-2 vs) / π) (d (In F) / dt)

So that the airway radius can be calculated from the sedimentation rate of the particles and the slope of the logarithm of the recovery function.

According to this same literature, the particle recovery function F can be replaced by the particle concentration function named C. The preceding equation can therefore be written: r = ((-2 vs) / π) (d {In C) / dt) The thickness of the Gas Sheet Thickness (GST) gas layer through which particle sedimentation takes place can be approximated by GST = 2 r. Therefore: GST = ((-4 vs) / π) (d (In (Ct / Co)) / dt) Where Ct is the second quantity of particles measured at time ti, Co the first quantity, dt the period of time elapsed between the time of inhalation and the time when exhalation takes place, vs the rate of sedimentation of the particles in the lung. The surface of the alveolar membrane is then calculated using the geometrical relationship established by Tomkeieff and Hennig (Weibel, "Architecture of the Human Lung", Science, 137, 3530, 1962, pp. 577-585) between the volume of the lung (TLC, Total Lung Capacity) and the thickness of the alveolar gas. A factor of 0.9 is applied to the lung volume to consider only parenchymal volume: S = ((4) (0.9) (TLC)) / (GST)

According to Roughton and Forster (Roughton and Foster, "Relative Importance of Diffusion and Chemical Reaction Rates in the Determination of the Exchange of Gases in the Human Lung", Journal of Applied Physiology, 11, 2, 1957, pp. 290-302), the gas transport in air to blood can be modeled as two serial conductance, a membrane conductance (Dm) and a blood conductance (Db): (1 / DL) = (1 / Dm) + (1 / Db) Where DL is the overall lung conductance, Db is the product of pulmonary capillary volume Vc and Θ, the specific conductance of the gas binding to hemoglobin. Both membrane and blood conductances can be determined by functional assays using tracer gas transfer.

The literature (Martinot, "Lung Membrane Conductance and Capillary Volume Derived from the NO and CO Transfer in High-altitude Newcomers," Journal of Applied Physiology, 115, 2, 2013, pp. 157-166) describes an appropriate method for determining the CO membrane conductance (DmCO) by applying the Roughton and Forster equations for two gas tracers: nitric oxide (NO) and carbon monoxide (CO).

The transfer of gas through the cellular membrane being directly proportional to its surface and inversely proportional to its thickness, the harmonic thickness μ of the cellular membrane can be calculated according to the equation:

μ = (S / DmCO) dCO aC

With dCO and aC being diffusion and solubility for CO gas.

For example, the concept of non-perfused ventilated lung zones can also be introduced into the models in order to take into account the specificities of the lung structure of a subject suffering from a particular pathology.

The deposition of particles in the lung can also be studied using numerical models and numerical simulation tools. From these simulations, the lung surface can be directly deduced from the parameter indicating a decrease in the amount of particles present in the exhaled gas relative to the gas supplied.

Claims (7)

A method for determining a harmonic thickness of an alveolar membrane of a lung, wherein said lung is provided with a predetermined amount of a carrier gas carrying a first quantity of particles having a size within a predetermined range, and after a predetermined period during which the carrier gas has been retained in the lung, a second quantity of said particles present in the exhaled gas of the lung is measured, the first and second quantities of particles are then determined on the basis of the first and second quantities of particles. parameter indicating a decrease in the amount of particles present in the exhaled gas relative to the gas supplied, characterized in that it is determined on the basis of said parameter and a sedimentation rate of said particles in the lung, a dimension of a surface on which a sedimentation of the particles through a layer of alveolar gas in the lung has been bound u, said harmonic thickness being then determined from said dimension of this surface. 2. Method according to claim 1, characterized in that a thickness of the alveolar gas layer through which the sedimentation of the particles has taken place is determined, said dimension of the effective surface of the cellular membrane being then determined on the basis of this thickness of the gas layer and the total capacity of the lung. 3. Process according to claim 1 or 2, characterized in that the supply of the carrier gas carrying a first quantity of particles is repeated a number (1 <iân) of times during the execution of the process, the predetermined period (t). during which the carrier gas is retained in the lung being varied after each supply (i), said second quantity being determined each time at the end of the predetermined period (t,) considered, said parameter being determined on the basis of the second determined quantities at the expiry of each of the predetermined periods (ti) of said number. 4. Method according to claim 3, characterized in that the concentration drop between the first and second quantity of particles evolves according to a mathematical function taking up a decrease in time of the quantity of particles, said parameter being determined from this function mathematical. 5. Process according to any one of Claims 1 to 4, characterized in that particles having an average geometrical and aerodynamic diameter of less than 5 microns, in particular less than 3 microns and more particularly less than 3 microns, are introduced into the carrier gas. at 1 micron. 6. Process according to any one of claims 1 to 5, characterized in that the carrier gas is heated to conditions of temperature and humidity close to those of a human or animal body before its contribution to the lung. A device for determining a harmonic thickness of a lung membrane of a lung, which device comprises a source (10) of carrier gas and a source of particles arranged to supply to said lung a predetermined quantity of the carrier gas carrying a first quantity of particles having a size within a predetermined range, which device also comprises measuring means (17) arranged to measure, after a predetermined period during which the carrier gas has been retained in the lung, a second quantity of said particles present in the gas exhaled from the lung, which measurement means are also arranged to determine on the basis of the first and second quantity of particles a parameter indicating a decrease in the quantity of particles present in the exhaled gas relative to the gas supplied, characterized in that the device comprises processing means arranged to detain to emine, based on a sedimentation rate of a first fraction of the first quantity of the particles as well as on the basis of said parameter, a dimension of a surface on which a sedimentation of the first fraction of the first quantity of the particles through a layer of alveolar gas in the lung has occurred, which processing means are also arranged to determine a harmonic thickness from said dimension of this surface.