Device and method for measuring the total proportion of one or more substances of different volatility in exhaled air for calculating one or more substance concentrations in the blood

Abstract

The invention relates to a measuring system (1) for determining the total proportion of at least one substance in the exhaled air of a living being, comprising: - an air guidance device (2) for directing the exhaled air; - a condensate separation unit (3) through which the exhaled air is passed and which is designed to condense or separate at least a part of the moisture content and the substance content in undissolved form in the exhaled air as condensate; - a substance condensate measuring device (5) designed to determine a substance fraction in the condensate, - a substance detector (9) arranged downstream of the condensate separation unit (3) and designed to measure a substance fraction in the gaseous part of the exhaled air after condensate separation, - an evaluation unit (10) designed to determine a total proportion of the exhaled substance in the exhaled air, depending on the substance content in the condensate and depending on the substance content in the gaseous portion of the exhaled air.

Description

Technical field

[0001] The invention relates generally to the measurement of a proportion of a substance in the blood by measuring the concentration or quantity of the substance in the exhaled air of a living being, i.e. a person or an animal. Technical background

[0002] The effectiveness of a drug typically depends on the concentration or amount of the active ingredient present in a patient's bloodstream. However, the pharmacokinetics of drugs vary considerably between individual patients. This can lead to overdosing or underdosing, resulting in undesirable side effects or insufficient efficacy.

[0003] A well-known method for measuring and monitoring the concentration of a substance, such as a drug, pollutant, poison, or other substance, in the blood of a living being is through the analysis of exhaled air. Exhalation occurs during the expiratory phase of breathing, while gases flow into the lungs during the inspiration phase. Exhaled air is in almost direct contact with the blood via the lungs, so volatile components of a substance enter the gaseous components of the exhaled air, while low-volatility or semi-volatile components can also be exhaled in dissolved form in the moisture content or as aerosols. Substances with particularly low vapor pressure or high boiling points can also occur as particulate organic matter (POM).

[0004] Substances measured in exhaled air vary considerably in their volatility, primarily in their physical properties such as vapor pressure and boiling point. The term "volatility" is used here to generally describe the evaporation behavior or rate of substances, especially liquids, but also solids. For volatile organic compounds (VOCs), the definition used is that of the EPA (United States Environmental Protection Agency) or the World Health Organization (WHO): https: / / www.epa.gov / indoor-air-qualityiaq / technical-overview-volatile-organic-compounds#definition

[0005] It should be noted that the term "substance" used below is not limited exclusively to organic compounds. Rather, it refers to all molecules detectable in exhaled air or in the condensate of exhaled air. Besides VOCs, these substances can also include substances such as ammonia (NH3), acetone, hydrogen sulfide (H2S), etc.

[0006] Sevoflurane (vapor pressure at 21 °C: 21 kPa, boiling point 58.5 °C) is an example of a drug with a volatile active ingredient. Meropenem (vapor pressure approx. 10 kPa) is an example of a drug with a low volatility. -18Examples of drugs with a vapor pressure of 0.4 Pa (boiling point 627 °C, i.e., a POM) and a semi-volatile active ingredient are propofol (vapor pressure at 25 °C: 0.4 Pa, boiling point 256 °C). Volatile substances that are exhaled are present in dissolved form in both the gaseous and moisture components of exhaled air. In this context, "dissolved" means that the volatile substance mixes with the moisture in a homogeneous distribution as atoms, molecules, or ions. An equilibrium is established between the gaseous and liquid components.

[0007] Determining the concentration of semi-volatile and low-volatility substances via exhaled air is particularly difficult, as a portion of the substance may be gaseous, a portion dissolved in the moisture component of the exhaled air, and / or a further portion present as an aerosol / POM in undissolved form in the liquid or solid phase. The ratio of the gaseous, dissolved, and aerosol / POM components varies from person to person. Therefore, simply measuring the concentration of the substance in the gaseous component of exhaled air may only lead to inaccurate conclusions about the substance concentration or the amount of the substance in the blood.

[0008] Currently, volatile substances, such as volatile anesthetics (e.g., sevoflurane, isoflurane, desflurane, nitrous oxide, argon), are measured in exhaled air using detectors such as infrared sensors. The amount dissolved in the moisture content of the exhaled air is neglected in this method. Furthermore, low-volatility drugs, such as meropenem, can be measured in a condensate of exhaled moisture obtained from the breath. See also, for example, Teucke T. et al., “Humidity and measurement of volatile PROPOFOL using MCC-EMS (EDMON)”, Clin. Monit. Comput. 2023 Apr;37(2): Pages 493―500, doi: 10.1007 / 510877-022―00907-0, Epub 2022 Sep 21 for certain substances methods are known which measure concentrations for a volatile fraction and a low-volatility fraction.

[0009] Measuring substance aerosols or POM in exhaled air is currently only carried out, if at all, via complex laboratory analysis.

[0010] However, no devices or methods are known that allow the determination of a total fraction, i.e., a total substance concentration or amount, in exhaled air with an accuracy sufficient to reliably infer the substance concentration or amount in the blood, independent of the chemical properties of the substance being measured. In particular, even with semi-volatile substances, the ratio of the gaseous to dissolved fraction, or the aerosol or POM fraction, depends not only on the substance itself but can also vary from person to person. Furthermore, the total humidity of the exhaled air is individually variable, which significantly influences the ratio between the gaseous and dissolved fractions.

[0011] Furthermore, standard analytical methods in blood or other body fluids do not allow for real-time monitoring of the dosage.

[0012] The object of the present invention is to provide a means of carrying out an improved measurement of the quantity or concentration of a substance in the exhaled air of a living being with high accuracy, even if there is an unknown ratio between the gaseous part and / or dissolved part and / or aerosol / POM part. Disclosure of the invention

[0013] This problem is solved by a measuring system for measuring a total proportion of at least one substance in exhaled air according to claim 1 and a method for determining a total proportion of at least one substance in the exhaled air according to the dependent claim.

[0014] Further details are specified in the dependent claims.

[0015] According to a first aspect, a measuring system for determining the total proportion of at least one substance in the exhaled air of a living being is provided, comprising: - an air guidance device for directing exhaled air; - a condensate separation unit through which the exhaled air is passed and which is designed to condense or separate at least part of the moisture content and the substance content in undissolved form in the exhaled air as condensate; - a substance condensate measuring device designed to determine a substance fraction in the condensate, - a substance detector located downstream of the condensate separation unit and designed to measure the substance content in the gaseous part of the exhaled air after condensate separation, - an evaluation unit designed to determine the total proportion of exhaled substance in the exhaled air, depending on the substance content in the condensate and the substance content in the gaseous portion of the exhaled air.

[0016] In the following, the term "proportion" is understood as indicating the quantity or concentration of the substance in the condensate or exhaled air. This quantity can be related to the mass flow rate of the exhaled air.

[0017] The measuring system according to the invention provides for measuring the specific substance both in the gaseous fraction of the exhaled air and in the condensate of the exhaled air, either as an aqueous solution or as a substance condensate. The condensate consists predominantly of condensed moisture. A substance may be dissolved in it. However, it is also possible that the substance itself condenses and does not form an aqueous solution. In both cases, the substance condensate measuring device measures the fraction, i.e., the quantity or concentration, of the deposited substance.

[0018] The measuring system for determining the total concentration of a specific substance in exhaled air can include an air guide for directing the exhaled air. This air guide incorporates a condensate separator through which all exhaled air is passed. The condensate separator has a cooling surface whose temperature is either fixed, adjustable, or follows a temperature program that may be below the condensation temperatures of the moisture in the exhaled air and the substance itself. For example, a temperature close to 0 °C, i.e., between 0 and 4 °C, can be used. The lower the selected temperature, the more condensate is collected, and the greater the concentration of the substance in the condensate compared to the gas phase.

[0019] The condensate formed, containing the dissolved portion of the substance or the substance itself, is discharged into or fed into a substance condensate measuring device. This device includes a detector capable of determining the substance concentration in the aqueous solution or in the liquid phase of the condensate. The device can also function as a sensor that determines the proportion, i.e., quantity or concentration, of the substance in the condensate.

[0020] The remaining portion of the exhaled air is then fed downstream of the condensate separator to a suitable substance detector to measure the gaseous component of the substance. The substance detector is designed as a gas measuring device, measuring the quantity or concentration of the substance in the gaseous portion of the exhaled air.

[0021] The measuring system may also include one or more of the following devices: - a mass flow sensor, especially upstream of the condensate separator unit, for determining the breathing mass flow of the exhaled air or the breathing volume over a predetermined measuring time; - A separate droplet or aerosol trap to support condensate formation in the condensate separation unit and / or as a barrier downstream of the condensate separation unit to prevent aerosols or POM that have not condensed in the condensate separation unit from reaching the substance detector for the gaseous component. The aerosol trap can be designed, for example, as a semi-permeable membrane or a fine mesh. - a first humidity sensor for determining a first absolute humidity value upstream of the condensate separator unit; - a second humidity sensor for determining a second absolute humidity value downstream of the condensate separator unit. - A pressure sensor to measure the pressure of the exhaled air, in order to determine the proportion of condensate separated together with the temperature of the condensate separator unit, since the boiling point - and thus the volatility - depends on the ambient pressure. - A control unit that controls the temperature or temperature program of the condensate separator unit. In one embodiment (for mechanically ventilated animals), the control unit can also measure the minute volume, respiratory rate, pressure, etc., and transmit these parameters, along with the measurement parameters and the parameters of the condensate separator unit, to an evaluation unit.

[0022] The evaluation unit can be designed to determine, depending on the first absolute humidity value of the exhaled air before condensation and the second absolute humidity value of the moisture-reduced exhaled air after condensation and the mass flow rate of the exhaled air, a proportion of substance in the condensate (including aerosol content) as well as a proportion of the gaseous substance in the exhaled air during the measurement period, and to determine, depending on both proportions, the total proportion, i.e., the total amount of exhaled substance in the exhaled air during the measurement period or the total concentration of the substance in the exhaled air.

[0023] Furthermore, a mass flow sensor can be provided to determine the breathing volume of the exhaled air, particularly over a predetermined measurement period.

[0024] A first humidity sensor is also provided upstream of the condensate separator to determine an initial absolute humidity value. This first humidity sensor can be a dew point sensor, a conductivity sensor, or a capacitive sensor.

[0025] Furthermore, a second humidity sensor can be provided downstream of the condensate separator to determine a second absolute humidity value. This second humidity sensor can be a dew point sensor, a conductivity sensor, or a capacitive sensor.

[0026] Using an evaluation unit, depending on the first absolute humidity value of the exhaled air before condensation and the second absolute humidity value of the at least partially dehumidified exhaled air after condensation, the mass flow rate of the exhaled air or the air volume of the exhaled air, as well as the proportion of separated aqueous condensate, the residual proportion of dissolved substance in the exhaled air after the condensate separation unit can be estimated, and thus, based on the substance proportions in the condensate and in the gaseous part, the total proportion, i.e., the total concentration or the total amount, of the substance in the exhaled air can be determined using a suitable calculation model.

[0027] The condensate separator unit may be provided with a cooling surface with an adjustable temperature, the control unit being further configured to set and / or detect and / or vary the temperature of the cooling surface during the measurement period, so that the condensed moisture content or the proportion of condensate varies, and the evaluation unit being configured to determine a cross-sensitivity of the substance detector to other substances in the exhaled air or to humidity in the exhaled air downstream of the condensate separator unit depending on the varying temperatures and the correspondingly varying measured humidity content, and to take this into account when determining the substance concentration or amount in the gaseous portion of the exhaled air.

[0028] In particular, characteristic curves can be recorded or provided that indicate the proportion as a function of the temperature of the condensate separator. These characteristic curves can be determined without any substance and with various substances and substance concentrations, so that the sensitivity of the substance detector to different moisture concentrations and different substances and substance concentrations can be determined in a manner known per se.

[0029] The evaluation unit allows measurements to be taken at different temperatures of the cooling surface of the condensate separator. This enables the identification of any cross-sensitivity of the substance detector to the moisture content of the exhaled air or to a second substance present in the exhaled air, allowing for correction of the measurement result. In this way, different substance concentrations measured by the substance detector in the exhaled air at various condensate separator temperatures can be used to determine the sensitivity of the substance detector.

[0030] In an evaluation unit, the moisture content before and after the condenser, the exhaled air volume, the gas concentration of the substance in the exhaled air downstream of the condensate separator unit, and the substance concentration in the condensate are evaluated to obtain a total concentration of the substance in the exhaled air.

[0031] To improve the accuracy of the evaluation, the temperature of the condensate separator can be varied according to a temperature profile during the measurement process, i.e., while exhaled air is passed through the device, in order to remove different proportions of moisture and substances from the exhaled air. This allows, in particular, the detection of cross-sensitivity of the substance detector downstream of the condensate separator with respect to moisture content. This cross-sensitivity can then be taken into account when determining the total concentration.

[0032] Furthermore, the evaluation unit can be designed to determine the substance concentration in the condensate as an average value during the measurement period and / or to determine the substance concentration in the gaseous component of the exhaled air as an average value during the measurement period.

[0033] It may be provided that the condensate separation unit is part of a heat exchanger, which reheats the dehumidified exhaled air after measurement by the substance detector in a heating device of the heat exchanger and uses it for the return of breathing air, e.g., from a ventilator, whereby the heat exchanger may, for example, include a Peltier unit.

[0034] The provision of the heat exchanger allows for a combined design between the condensate separation unit and the heating device.

[0035] To perform a measurement, exhaled air can be passed through the device for a predetermined duration. The measurement duration can be determined based on the concentration of the substance in the exhaled air. First, based on the initial humidity sensor, the total amount of water contained in the exhaled air during the measurement period can be calculated from the first absolute humidity measurement and the mass flow rate of the exhaled air.

[0036] Furthermore, the total amount of substance dissolved in the condensate can be calculated from the total amount of exhaled water and the measured concentration of the substance in the condensate.

[0037] Furthermore, the residual amount of dissolved substance remaining in the exhaled air after the condensate separator can be determined from the amount of condensate collected, the two humidity parameters, and the mass flow rate, and used to correct the total substance concentration in the exhaled air, significantly improving the accuracy of the overall setup. Additionally, the total concentration of the substance present in the gaseous portion of the exhaled air can be calculated using the molecular weight and gas constant, taking into account the second absolute humidity parameter.

[0038] Based on the proportion of substance dissolved in the condensate and the proportion of substance present in the gaseous part of the exhaled air, the total proportion of exhaled substance during the measurement period can be calculated as a sum value. If the proportions are given as quantities, they can be added together. If the proportions are given as concentrations, the measured (volume) concentrations must first be converted into quantities and then added together.

[0039] It may be provided that, depending on the total amount of the substance exhaled in the exhaled air during the unit of time or the total concentration of the substance in the exhaled air, the substance concentration in the blood is calculated using a pharmacometric model.

[0040] According to another aspect, a method for operating a measuring system for determining a total proportion of a substance in the exhaled air of a living being is provided, wherein the measuring system comprises: - an air guidance device for directing exhaled air; - a condensate separation unit through which the exhaled air is passed and which is designed to condense at least part of the moisture content in the exhaled air as condensate; - a substance condensate measuring device designed to determine a substance fraction in the condensate, - a substance detector arranged downstream of the condensate separator and configured to measure a substance fraction in the gaseous fraction of the exhaled air, the method comprising the following steps: - Determining a total fraction of the substance depending on the substance fraction in the condensate and depending on the substance fraction in the gaseous fraction of the exhaled air.

[0041] Furthermore, the procedure may include the following additional steps: - Determining the mass flow rate of exhaled air or the volume of breath over a given unit of time; - Determining a first absolute humidity value upstream of the condensate separator; - Determining a second absolute humidity value downstream of the condensate separator; - Determining the proportion of moisture in the exhaled air depending on the first absolute moisture value of the exhaled air before condensation and the second absolute moisture value of the moisture-reduced exhaled air after condensation and the mass flow rate of the exhaled air; - Determining the total proportion of exhaled substance in the exhaled air depending on the proportion of moisture in the exhaled air. Brief description of the drawings

[0042] The embodiments are explained in more detail below with reference to the accompanying drawings. These show: Fig. 1 a schematic representation of a measuring system for measuring the total proportion of a substance in the exhaled air of a living being; Fig. 2. Another embodiment of the measuring system with a heat exchanger; and Fig. 3. A flowchart illustrating a procedure for determining a substance concentration in the exhaled air of a living being. Description of embodiments

[0043] Fig. Figure 1 shows a schematic representation of a measuring system 1 for measuring the concentration of a substance in the exhaled air of a living being. In particular, the measuring system 1 is located in a ventilator that takes in the person's exhaled air, passes it through the measuring system 1, processes it in a manner known per se, and returns it to the person.

[0044] The measuring system 1 has an air guidance device 2, e.g. in the form of a pipe or hose, for defining an unbranched flow path in which a condensate separation unit 3 is arranged.

[0045] The condensate separation unit 3 can be designed with a cooling surface 32 which can be brought to an adjustable temperature by a suitable cooling device 31 and which is suitable for condensing moisture and / or the substance itself from the exhaled air. This allows the flowing exhaled air to be cooled so that condensate is deposited on the cooling surfaces.

[0046] The temperature should be set below the dew point temperature of the exhaled air. If the substance itself is present in the exhaled air as POM or an aerosol and is not directly dissolved in water, the temperature should be set below the condensation temperature of the substance, or the aerosol should be collected by a suitable droplet collector. The condensate, i.e., the condensed moisture containing the substance and / or the substance condensate itself, can then be drained into a sample container 4. For this purpose, the sample container is positioned below the condensate separator 3 so that the condensed and collected droplets can drain away. The cooling surface 32 is preferably arranged vertically so that the separated condensate can flow out of the condensate separator 3 and be collected in the sample container 4 for measuring the substance concentration.

[0047] The sample container 4 is equipped with a substance condensate measuring device 5 for determining the substance concentration in the condensate and can thus determine the concentration of the substance in the liquid condensate. Alternatively, the substance condensate measuring device 5 can also be arranged separately from the measuring system 1. The substance concentration measuring device can be based on an optical (absorption, reflection and / or transmission) measurement method, a conductivity measurement including impedance analysis, a biosensor method with receptors specific to the substance to be measured, a gravimetric or potentiometric method.

[0048] Furthermore, a weighing device 6 can be provided to determine the mass of the condensate in order to determine the amount of moisture extracted from the exhaled air.

[0049] It is also possible to deduce the mass of the condensate by determining its volume.

[0050] Alternatively, the mass of the condensate can also be determined from the difference between the first and second humidity values ​​in conjunction with the mass flow rate. Knowing the first humidity value, the temperature of the condensate separator, and the ambient pressure, the saturation vapor pressure can be calculated. This indicates how much moisture remains in the gas phase; the rest condenses out, and thus the amount of condensate can also be estimated.

[0051] Similarly, the residual moisture content of the exhaled air after the condensate separator is known. Based on the amount of condensate and the determined substance concentration or quantity in the condensate, it is possible to estimate how much of the substance remains in dissolved form after the condensate separator. This allows an evaluation unit to accurately determine the total substance concentration or quantity in the exhaled air using the substance concentration or quantity in the condensate, the substance concentration or quantity in the gas phase, and the estimated substance concentration or quantity dissolved in the residual moisture.

[0052] Upstream of the condensate separator unit 3, a mass flow sensor 6 for determining the breathing mass flow rate and a first humidity sensor 7 for determining a first absolute humidity value in the exhaled air are arranged. The first humidity sensor 7 can be designed as a dew point sensor. Alternatively, capacitive humidity sensors, humidity sensors based on conductivity measurement or thermal conductivity humidity sensors, IR-optical humidity measuring devices, or the like can be used.

[0053] Downstream of the capacitor unit 3, a second humidity sensor 8, e.g., in the form of a dew point sensor, is arranged for determining a second absolute humidity value of the moisture-reduced exhaled air, as well as a substance detector 9 for determining the proportion (concentration or quantity) of the substance in the gaseous portion of the moisture-reduced exhaled air. The substance detector can be configured as a resistive gas sensor, in particular as a (metal oxide) semiconductor gas sensor, as a conductivity sensor, as a gas sensor based on work functions (FETs), as an optical (IR / US / VIS absorption gas sensor), mass-sensitive, capacitive, or electrochemical gas sensor, or as a sensor based on the dosimeter principle or similar.

[0054] The substance condensate measuring device 5, the mass flow sensor 6, the first humidity sensor 7, the second humidity sensor 8 and a substance detector 9 are connected to an evaluation unit 10, which evaluates the measurement data and determines a total proportion, i.e. a total concentration or a total amount during a unit of time.

[0055] In another in Fig. In the embodiment shown in Figure 2, the exhaled air is passed through a heating element 12 in order to reheat it after cooling in the condensate separator unit 3, e.g. to be reprocessed in a ventilator so that it can be supplied to the living being / patient again.

[0056] The condensate separator unit 3 and the heating unit 12 can be configured as parts of a heat exchanger, which may, for example, include a Peltier element 11 or a heat pump. The Peltier element 11 is arranged between the cooling surface 32 of the condensate separator unit 3 and a heating surface 121 of the heating unit 12. During operation of the heat exchanger, energy can thus be saved for reheating the cooler, dehumidified breathing air.

[0057] Furthermore, a CO2 sensor 13 can be arranged upstream of the condensate separator unit 3 to enable detection of whether the air flowing through is indeed exhaled air and / or what the mixing ratio is between the exhaled air and the ambient air. Ambient air dilutes the substance concentration / amount in the exhaled air, so the mixing ratio influences the measurement of the substance concentration / amount (dilution). If the mixing ratio is determined, for example, via a CO2 sensor, this can be used to compensate for the substance measurement.

[0058] Furthermore, a pressure sensor or pressure measuring device can be integrated into the air supply system to precisely measure the pressure and transmit this value to an evaluation unit, which, together with the temperature, determines the saturation vapor pressure of the moisture and the at least one substance in the exhaled air, in order to selectively condense the one substance and to selectively adjust the amount of condensate in order to determine the total substance concentration and / or total substance quantity in the exhaled air.

[0059] Fig. Figure 3 shows a flowchart illustrating a procedure for performing a measurement, which is executed in the evaluation unit 10. The evaluation unit 10 can be configured as a data processing device, such as a computer, FPGA, or microprocessor. The procedure is implemented as a software algorithm in the evaluation unit 10.

[0060] In step S1, it is checked whether the CO2 sensor 13 detects that exhaled air is flowing through the air guide 2. If this is the case, the procedure continues with step S2. Otherwise (alternative: No), the process returns to step S1. Furthermore, in step S1, the pressure of the exhaled air upstream of the condensate separator 3 can be determined.

[0061] In step S2, a timer is started.

[0062] In step S3, the first absolute humidity value of the exhaled air is detected, as well as the temperature.

[0063] In step S4, the temporal profile of the air mass flow or air volume flow is recorded and, by integration, the total amount (volume or mass) of exhaled air since the start of the time measurement is determined.

[0064] In step S5, at a specific time point after the start of the time unit, the substance concentration or the amount of substance is measured in the substance detector 9.

[0065] In step S6, at the specified time after the start of the time unit, the second absolute humidity value is measured with the second humidity sensor 8.

[0066] In step S7, it is checked whether the time unit has ended. If this is the case (alternative: Yes), the procedure continues with step S8. Otherwise (alternative: No), it jumps back to step S3.

[0067] In step S8, the total amount of water exhaled over a given time period is determined from the first absolute humidity measurement and the total amount of exhaled air during that time period. This allows the residual moisture in the exhaled air downstream of the condensate separator to be determined. Alternatively, the residual moisture in the exhaled air can also be determined by measuring a first humidity measurement upstream of the condensate separator and a second humidity measurement downstream. By comparing the amount of condensate to the amount of water in the exhaled air upstream of the separator and measuring the substance content in the condensate, the ratio of dissolved to gaseous substances can be derived. This ratio can then be used as a correction factor for the remaining residual moisture after the condensate separator.

[0068] If the substance is present in its pure form as POM or an aerosol, it can be assumed that it cannot leave the condensate separator. The substance then either dissolves in the aqueous condensate or remains as a solid or liquid phase in the condensate separator.

[0069] In step S9, the total concentration or total amount of substance in the condensate is determined using the substance condensate measuring device. This means the substance can be dissolved in the aqueous condensate or exist as a solid or liquid phase.

[0070] Furthermore, in step S10, the total amount of the volatile substance present in the gaseous fraction of the exhaled air is measured downstream of the condensate separator unit 3 using the substance condensate measuring device. It is assumed that no aerosols or POM are present downstream of the condensate separator unit, so that the substance detector measures only the purely gaseous fraction of the substance.

[0071] In step 11, the evaluation unit calculates the total amount per unit of time or concentration of a substance to be measured in the exhaled air, taking into account the substance concentration or amount in the condensate, the substance fraction dissolved in the residual moisture estimated via the moisture difference, and the concentration or amount of a substance in the gas phase.

[0072] Furthermore, in step S12, the substance concentration in the blood can be calculated from the total amount exhaled per minute using a predefined pharmacometric model.

[0073] The predetermined time unit can be selected depending on the concentration of the substance in the exhaled air and the sensitivity of the substance detection device. For higher accuracy, a longer measurement period may be necessary.

[0074] The duration of the predetermined time unit can be estimated or specified depending on the vapor pressure or boiling point of the substance, also taking into account the properties of the substance detector (detection limit, resolution, sensitivity, and time constant). The method must therefore be adapted and designed for the specific substance and ideally validated and calibrated experimentally.

[0075] Furthermore, a temperature program of the condensate separator can be used to compensate for cross-sensitivities of the (non-specific) substance detector to humidity or other substances contained in the exhaled air. Additionally, a temperature program can be used to selectively condense a specific substance, thus enabling the selective measurement of multiple substances or of a single substance in the background of other substances to which the substance detector exhibits cross-sensitivity.

[0076] Furthermore, a cascade of condensate separation devices can be provided, preferably with different temperatures or temperature programs, for more precise determination of cross-sensitivities and / or for better separation of several substances. QUOTES INCLUDED IN THE DESCRIPTION

[0000] This list of documents cited by the applicant was automatically generated and is included solely for the reader's convenience. The list is not part of the German patent or utility model application. The DPMA accepts no liability for any errors or omissions. Cited non-patent literature

[0000] https: / / www.epa.gov / indoor-air-qualityiaq / technical-overview-volatile-organic-compounds#definition

[0004] Teucke T. et al., “Humidity and measurement of volatile PROPOFOL using MCC-EMS (EDMON)”, Clin. Monit. Comput. 2023 Apr;37(2): Pages 493―500, doi: 10.1007 / 510877-022―00907-0, Epub 2022 Sep 21

[0008]

Claims

[1] Measuring system (1) for determining the total proportion of at least one substance in the exhaled air of a living being, comprising: - an air guidance device (2) for directing the exhaled air; - a condensate separation unit (3) through which the exhaled air is passed and which is designed to condense or separate at least a part of the moisture content and the substance content in undissolved form in the exhaled air as condensate; - a substance condensate measuring device (5) designed to determine a substance fraction in the condensate, - a substance detector (9) arranged downstream of the condensate separation unit (3) and designed to measure a substance fraction in the gaseous part of the exhaled air after condensate separation, - an evaluation unit (10) designed to determine a total proportion of the exhaled substance in the exhaled air, depending on the substance content in the condensate and depending on the substance content in the gaseous portion of the exhaled air. [2] Measuring system (1) according to claim 1, further comprising: - a sensor (6), in particular upstream of the condensate separator unit, for determining a breathing mass flow of exhaled air or a breathing volume over a predetermined unit of time; - a first humidity sensor (7) for determining a first absolute humidity value upstream of the condensate separator; - a second humidity sensor (8) for determining a second absolute humidity value downstream of the condensate separator unit (3), - wherein the evaluation unit (10) is designed to determine a proportion of moisture in the exhaled air depending on the first absolute humidity value of the exhaled air before condensation separation and the second absolute humidity value of the moisture-reduced exhaled air after condensation separation and the mass flow rate of the exhaled air, and to determine the total proportion of at least one exhaled substance in the exhaled air depending on the proportion of moisture in the exhaled air. [3] Measuring system (1) according to claim 1, wherein the condensate separator unit (3) has a cooling surface (32) with adjustable temperature, wherein the evaluation unit (10) is further configured to vary the temperature of the cooling surface (32) during the time unit so that the condensate fraction varies, and wherein the evaluation unit (10) is configured to determine a cross-sensitivity of the substance detector downstream of the condensate separator unit (3) to moisture or another substance in the exhaled air depending on the varying temperatures and to take this into account when determining the substance concentration in the gaseous fraction of the exhaled air. [4] Measuring system (1) according to one of claims 1 to 3, wherein the evaluation unit (10) is designed to determine the substance concentration in the condensate as an average value during the unit of time and / or to determine the substance concentration in the gaseous fraction of the exhaled air as an average value during the unit of time. [5] Measuring system (1) according to one of claims 1 to 4, wherein the condensate separation unit (3) is part of a heat exchanger which reheats the dehumidified exhaled air after measurement by the substance detector in a heating device (12) of the heat exchanger, wherein the heat exchanger in particular comprises a Peltier unit (11). [6] Measuring system (1) according to one of claims 1 to 5, wherein a cascade of several individual condensate separation units (3) with respective substance condensate measuring devices is provided, preferably with different temperatures and / or temperature programs. [7] Measuring system (1) according to one of claims 1 to 5, wherein the measuring devices for measuring the gaseous substance fraction comprise a device for pre-separating substances, in particular in the form of a gas chromatography column (GC column) to improve the selectivity and specificity of the measuring system, so that the influence of cross-sensitivities is reduced. [8] Method for operating a measuring system (1) for determining a total quantity or a total concentration of at least one substance in exhaled air of a living being, wherein the measuring system (1) comprises: - an air guidance device (2) for directing the exhaled air; - a condensate separation unit (3) through which the exhaled air is passed and which is designed to condense at least part of the moisture content in the exhaled air and / or aerosols containing the at least one substance as condensate, - a substance condensate measuring device (5) designed to determine a substance concentration in the condensate, - a substance detector (9) arranged downstream of the condensate separation unit (3) and configured to measure a substance fraction in the gaseous part of the exhaled air, the method comprising the following steps: - Determining the total proportion of exhaled substance in the exhaled air depending on the substance proportion in the condensate and depending on the substance proportion in the gaseous portion of the exhaled air. [9] Method according to claim 8, comprising the further steps: - Determining the mass flow rate of exhaled air or the volume of breath over a given unit of time; - Determining a first absolute humidity value upstream of the condensate separator; - Determining a second absolute humidity value downstream of the condensate separator; - Determining the proportion of moisture in the exhaled air depending on the first absolute moisture value of the exhaled air before condensation and the second absolute moisture value of the dehumidified exhaled air after condensation and the mass flow rate of the exhaled air; - Determining the total proportion of the substance in the exhaled air depending on the proportion of moisture in the exhaled air. [10] Method according to claim 9, with an additional pressure measurement value for determining the breathing phase. [11] Method according to one of claims 8 to 10, wherein the condensate separation device (3) undergoes a temperature profile with varying temperature progression, which is used to determine the concentration of several substances even with limited selectivity of the substance condensate measuring device (5) by means of a calibration. [12] Method according to one of claims 8 to 11, wherein several cascaded condensate separation devices (5) are provided, which in particular have different temperatures and / or each undergo a temperature profile with varying temperature progression in order to determine the concentration of the individual substances in the case of several substances even with limited selectivity of the substance condensate measuring device (5) by means of a calibration. [13] Method according to any one of claims 8 to 12, wherein the substance concentration in the blood is calculated using a pharmacometric model depending on the total amount of the substance exhaled in the exhaled air during the unit of time or the total concentration of the substance in the exhaled air.

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