WO2008067931A2

WO2008067931A2 - Non-invasive measuring method, apparatus, and use thereof

Info

Publication number: WO2008067931A2
Application number: PCT/EP2007/010279
Authority: WO
Inventors: Yorck Olaf Schumacher; Kai RÖCKER
Original assignee: Universitätsklinikum Freiburg
Priority date: 2006-12-05
Filing date: 2007-11-27
Publication date: 2008-06-12
Also published as: WO2008067931A3; DE102006057185A1

Abstract

Disclosed is a non-invasive method for obtaining measured data suitable for determining the total amount of hemoglobin of a lung breather. In said method, a predefined dose of a breathable tracer is set and is non-invasively fed to the lung breather via one of his or her mucous membranes, and absorption and/or elimination of the breathable tracer is determined at a plurality of points in time by non-invasively measuring a parameter that correlates with the amount of the tracer in the body of the lung breather. Also disclosed are a suitable apparatus as well as CO to be used or the use of CO in a corresponding (e.g. diagnostic) method. Adequate computing rules (illustrated in figure 6, for example) make it possible to automatically determine the total body hemoglobin concentration.

Description

Non-invasive measuring method, device and their use

The invention relates to a method (or method) for obtaining measurement data suitable for determining the total amount of hemoglobin of a lung respirator, in which a predetermined dose of a breathable tracer is adjusted and noninvasively delivered through a body mucosa of the lung respirator; and devices useful in the method, and corresponding uses, and tracers for related applications.

The blood of pulmonary breaths (terrestrial animals like humans) consists of blood cells and plasma. The proportion of blood cells in the total blood volume is also called the volume of erythrocytes because the red blood cells dominate. Closely associated with this size is the total amount of hemoglobin in the organism, which plays a crucial role in the transport of oxygen in the body.

In clinical routine, statements are made about the amount of blood one

Organism mostly taken from the concentrations of hemoglobin and hematocrit. However, since these are purely proportional measures, they are extremely error-prone. Thus, e.g. In acute bleeding, a blood loss of several liters occur without changing hemoglobin concentration or hematocrit.

However, knowledge of the blood volume may facilitate decisions in various aspects for non-curative but at least as often curative purposes, be it to test the performance of athletes or individuals, to determine the general status of the body, or the like. Prophylaxis and therapy decisions can also be simplified. So far, the blood volume or the amount of blood is determined only very rarely. The reason for the low number of measurements is in the past very stressful, difficult or for some purposes impractical and expensive measurement methods.

All known blood volume measurement methods have relied on the invasive introduction of a tracer (which in the present disclosure preferably means a trace substance that can be tracked by measurement), usually a radioactive material (eg, ⁵¹ chromium, ¹²⁵ iodine, radiolabelled iron) or a staining or fluorescent dye (eg Evans Blue) into the bloodstream, eg by injection or infusion. The concentration of this material in a subsequently taken blood sample is, after complete distribution in the blood, inversely proportional to the height of the blood volume. Practically mainly radioactive methods are used so far. The disadvantages are, in addition to the radioactivity, which requires special measures and expensive radioactive substances in the invasiveness: As a rule, blood is removed, radioactively labeled and reinfused. This procedure is expensive, complex in terms of equipment and personnel and time-consuming, so that it is used only in radiological departments. For the patient, it is very stressful and involves not insignificant risks as a result of radioactive radiation and infections in the puncture through the skin.

An alternative method uses carbon monoxide as a tracer and is based on a so-called carbon monoxide rebreathing maneuver (Schmidt et al., Eur. J. Appl. Physiol 95 (5-69, 486-95, 2005)) Inhaled amount of carbon monoxide (CO) over a short period of time, which completely binds to the hemoglobin (as CO-Hb = carboxyhemoglobin) in the blood The amount of CO used is extremely low (it corresponds to the amount of CO emitted when smoking) As a rule, a two-minute respiratory procedure is sufficient to bind the majority of the CO introduced in the experiment in the blood before and immediately after the breathing procedure becomes too accurate Blood is withdrawn at defined times and the CO-Hb content determined laboratory-chemically.The determination of the total body hemoglobin amount is then carried out taking into account the amount of CO inhaled and physi cal factors, such as air pressure and temperature, via the measurement of the rise CO-Hb content caused by CO inhalation. The partial volumes of the blood (erythrocyte volume, plasma volume) and the total blood volume can then be calculated. The error of the measurement method is 0.4 to 2.8%.

The big weakness of the method is the need for blood sampling, which must also be done at precisely defined times in order to achieve a valid result. This also requires the operation of a reliably calibrated CO-Hb meter.

As early as 1948 (see Acta physiologica Scandinavia, Vol. 16, 211-231 (1948)) a method was published in which an estimate of the amount of CO-Hb in the blood by analysis of the CO concentration of the "alveolar" air after inhalation of a The amount of CO during 15 minutes is described here, but at most from the subsequent equilibrium concentration, which is reached after prolonged respiration after the CO supply, the amount of CO-Hb in the blood can be deduced in such a way that a statement about the total amount Since the rebreathing system has to be pre-exhaled for more than 22 minutes, the method of measurement is very time-consuming and has not been established in practice A respiration-dependent determination of the CO concentration does not take place Taken from the entire system.

Recently non-invasive measurement methods with so-called pulse oximeters have also become known. Such devices have not yet been able to detect CO-Hb, but in the meantime (for example, the company Masimo Corp., Irvine, California, USA) there are such devices that non-invasively permit the CO-Hb level in the blood determine. This is done by using electromagnetic radiation of several different wavelengths in the range of UV, IR and / or visible light, which make it possible to determine a number of forms of hemoglobin (oxy-, deoxy-, carboxy- and methemoglobin) and the blood To determine hemoglobin CO saturation level.

Against this background, the object of the invention is to find a method and devices for determining measured values in a simple manner and for Determination of the total body hemoglobin amount can be used. One or more of the following features should be realized: the least possible expenditure on equipment, the lowest possible burden on the organism to be tested (for example, by avoiding radioactivity and repeated blood withdrawals), sufficient accuracy, simple feasibility, even in the case of injured or weakened subjects , and / or largely automatic detection of whole body hemoglobin, as well as rapid feasibility.

The object is achieved by a method mentioned at the outset or corresponding devices which are characterized or make it possible to record and / or (preferably) eliminate the abatemable tracer by non-invasive measurement of a parameter correlated with the amount of tracer in the body of the lung respirator a plurality of points in time during a breath is determined and preferably one or more of the further method steps mentioned below are performed.

By means of the method according to the invention, based on the CO-rebreathing method, the hemoglobin mass can be non-invasively, i. without blood collection, to be determined.

CO binds to hemoglobin (Hb) 300 times better than oxygen and diffuses slowly after binding. The half-life for the diffusion of Hb for CO is 4 hours. The CO diffusing away from the Hb is exhaled via the lungs. Thus, it is known that the end-alveolar CO concentration correlates directly with the CO-Hb concentration in the blood (see, for example, Heinemann et al., J. Clin. Chem. Clin. Biochem 22 (3): 229-35, 1984; Vremann et al., Clin. Chem. 42 (1), 50-56, 1996).

In a first aspect, the invention relates to a noninvasive method for obtaining measurement data suitable for determining the total hemoglobin amount of a lung respirator in which a predetermined dose of a breathable tracer is adjusted and noninvasively delivered through a body mucosa of the lung respirator and the uptake and / or Preferably, the elimination of the breathable tracer is determined by non-invasive measurement of a parameter correlated with the amount of tracer in the body of the lung respirator at a plurality of times.

This method is preferably used using appropriate computerized methods for the automatic determination of whole body hemoglobin to achieve automation.

Methods according to the invention can be used for the pure acquisition of measurement data, from pure measurement signals via parameters correlated for example with the concentration of the tracer to the preferred determination of total body hemoglobin (total body hemoglobin mass) or other measurement data as defined below. The measurement data can be used in further steps for various purposes: for example, for the mere determination of the general physical status with respect to the Gesamtkörperhogoglobinmasse without curative purposes or in the context of a diagnostic procedure, especially for medical purposes, then in particular in a first process step, a dose amount of the tracer (preferably without presence of the subject).

Knowledge of total hemoglobin mass may be useful in various aspects for non-cure, but also for curative (= curative) purposes (then it is a diagnostic procedure in the strict sense), be it e.g. for testing the performance of athletes (for example as part of an examination of their training condition) or of persons, e.g. before traveling in

Areas with higher altitudes or before air travel or for general determination of the status of the body, for example, to determine whether it is possible to further increase its performance (including healthy) (increased total body hemoglobin means better oxygen transport and thus more efficiency) Suitability for specific tasks or situations or fitness check or the like. Optionally, the values obtained can also be used for diagnostic purposes in the sense of a diagnostic procedure (eg for healing purposes), also for therapeutic decisions (eg in dialysis, oncology, intensive care, emergency care or the like). The invention therefore also relates, as a special case to be emphasized, to a method according to the invention (in particular one in which the dosage can be made by adjusting or providing a suitable tracer dose to a used rebreathing device in the absence of the subject), the further reduction phase (In particular, assessment of the total body hemoglobin mass found and decision on another possible therapeutic approach by suitable persons, such as doctors).

In a further aspect, the invention relates to a rebreathing device for the noninvasive determination of the hemoglobin mass which comprises a tracer sensor, in particular a CO sensor, having a t ₉₀ of 500 ms or less, preferably of 250 ms or less, in particular of 150 ms or less ( For example, an IR sensor, a mass spectrometer (MS), a gas chromatograph (GC) or a GC-MS combination (each suitable for the analysis of respiratory gases), or equipped for the measurement of CO-Hb pulse oximeter (suitable for determining the CO- Hb concentration in blood), or two or more of the same or different ones of these sensor devices) or included as accessories. This can be used in a method according to the invention.

Preferably, it is specially set up by appropriate programming (as exemplified below) and equipment.

The invention also relates to at least one TracerGnsbesondere CO) sensor (eg as an IR sensor, as a mass spectrometer (MS), as a gas chromatograph (GC) and / or GC-MS combination) (each for measuring the tracer eg CO concentration in breathing gas) or a pulse oximeter (in particular for measuring the Hb-tracer, eg Hb-CO concentration), which / which is equipped with an evaluation unit that is programmed to determine the total body hemoglobin, in particular on the elimination of a in a tracers described above and described below. Preferably, the steps and calculation methods of the evaluation are implemented as in the examples (when using at least one pulse oximeter, preferably only starting from the description of the measurement data in FIGS. 5 and without consideration of a lung compartment, but optionally with consideration of other tracer or CO distribution compartments).

Finally, the invention also relates to carbon monoxide for use as tracer gas in the context of a non-invasive, in particular one mentioned in one of the following claims diagnostic method for determining the total body hemoglobin content of a pulmonary.

The terms used above and below preferably have the meanings corresponding to the following definitions, unless stated otherwise, where in each case individual, several or all more general terms can be replaced by more specific (also from the example), which results in preferred embodiments of the invention:

Non-invasive means, in particular, that in a method according to the invention, no procedures are performed in violation of a surface (eg skin, mucosa) of a lung respirator by means of medical instruments or apparatus such as lancets, catheters, infusion or injection needles or the like, in particular that no blood collection takes place , The mere uptake of a mouthpiece or insertion of a tube into the respiratory tract is preferably not excluded, as well as slight pressure by pulse oximeter on the skin.

Under pulmonary breathing (hereinafter also partially referred to as a subject, which stands for test person or subject) are in particular birds, amphibians, reptiles or primarily mammals, especially humans to understand.

A defined dose is to be understood as meaning an amount of a tracer which does not or only to a tolerable extent have a harmful effect on the subject - for example, in the case of carbon monoxide, an amount ranging from 0.2 to 5, preferably from 0.5 to 2, in particular from 0.7 to 1, 0 ml of carbon monoxide per kg of body weight of the subject. This dose is preferably provided such that accidental overdosing is not possible, for example (preferably in advance) in the form of pre-fillable and then as Supply reservoir connectable or already connected chambers, pre-filled cartridges, bags, bottles or syringes or similar containers, which allow the supply of a clearly determined dose of the tracer and can be connected, for example via an open and lockable valve with a rebreathing device. Preferably, in particular if the method according to the invention takes place in the context of a diagnostic method, in particular for medical purposes, the evaluation of the data can be carried out without the presence of the subject. Knowledge of the exact administered dose is required for subsequent measurement and calculation.

A abatembarer tracer is a gaseous at temperatures in the range of 0 to 50 ⁰ C trace substance or a precursor thereof which releases a abatembaren tracer, preferably a gas, in particular a gas, which enters with hemoglobin, a complex bond, particularly carbon monoxide (CO).

Non-invasive delivery via a body mucosa means, in particular, delivery via a mucous membrane of the respiratory and / or gastrointestinal tract, in particular of the lung, either by means of a dispersion or solution or preferably in gaseous form, in particular via a respiratory gas (this term includes there are also mixtures of gases). The supply preferably takes place by means of a rebreathing device, since a correction for CO still present in the lungs can then be carried out in the exhaled air due to the steep initial phase of the CO decrease.

The noninvasive determination of the elimination of the abatembaren tracer by means of a correlated with the amount of tracer in the body of the lung breather parameter is preferably carried out (which should not exclude the removal of breathing gas from the mouth, eg via a mouthpiece or a tube) and / or on the Outside of the body of the lung respirator, in particular via a measurement of the concentration reduction of the tracer (as such) in

(preferably exhaled, ie Aus-) breathing gas (concentration of the tracer directly as a parameter) by means of one or more specific sensors (preferred variant), and / or by measurement by absorption measurement in the visible, UV and / or IR range on the intact body, for example by means of a pulse oximeter equipped to detect a parameter associated with the tracer (for example the concentration of the tracer hemoglobin complex).

"Breathing gas" is preferably the breathing gas in a closed system near the mouth, or alternatively or additionally the exhalation gas near the mouth of the subject, in one possible preferred embodiment of the invention the end-alveolar exhalation gas may be meant, in another the inhaling and exhaling gas in one closed system near the mouth, wherein the amount of CO is then preferably integrated as shown below, so that even without consideration of the tracer concentrations only in end-alveolar expiratory gas good results can be achieved, which is a particular advantage of the process in question.

"Determination of elimination at a plurality of times" means that during each breath, at least 2 measurements, preferably 3 or more measurements, in particular 6 or more measurements, are taken The advantage of such a variety of measurements is that single measurement errors can be better averaged out Preferably, this can be achieved by means of a sensor for the content of tracer in the respiratory gas or a pulse oximeter having a tgo of 500 ms or less, in particular of 250 ms or less, above all of 150 ms or less (tgo is as defines the time required to register 10% to 90% of a step change in gas concentration.) Time thus also means period, so preferably 2 or more measurements per second are possible, for example 4 or more measurements per second possible measurements may be due to the t90 values of the sensors or measuring instruments used borders.

"Measured data" are direct sensor signals and / or pulse oximeter signals or measurements derived therefrom, such as tracer concentration, CO-Hb concentration, rate of tracer leaching (eg ΔCO-Hb = change in carboxyhemoglobin concentration) and / or total body hemoglobin mass. The computer-aided (at least largely automated) determination of the total hemoglobin amount of a lung respirator from the data obtained, which represents a step of a further preferred embodiment of the invention, and which likewise falls under the term "measurement data", takes place, if desired, advantageously with computer-aided smoothing of raw data, but preferably, for example, according to a "moving average" method in which, for example, the mean value is formed sequentially for a specific number of measured values (eg 10 or 20) before and / or after a measured value to be smoothed), integration (in particular eg breathable integration, wherein the respiratory tract detection is preferably carried out by means of the data of a flow meter (flow meter).

Meter), for example, the tracer concentration, determining the time course of the tracer concentration (preferably with the aid of prior calibration, especially when eliminating the tracer) based on the integral values and application of known in principle Umrechvorschriften (for example, linear dependence of the CO concentration and the CO-Hb saturation according to equation I below) for determining the carboxyhemoglobin (CO-Hb) saturation and / or (preferably and) adaptation of curve functions (in particular also for determining distribution compartments of the tracer and their separation) and their use in arithmetic instructions for Determination of total CO-Hb (eg, including the use of the equation shown below

V), for example by means of the methods and equations mentioned below in the examples.

Preferred embodiments of the present invention have one or more of the following features:

The rebreathing device according to the invention preferably includes a calibration function for the CO content. For example, the zero signal (ambient air or special breathing gas without CO) and the signal for a gas with a defined CO content (for example 50 ppm) can be determined and the difference of the resulting measured values used for calibration.

The rebreathing device according to the invention preferably has ports or chambers which allow the tracer to be used (in particular CO) quantity from chambers or containers with a clearly metered amount of tracer, eg with tracer or tracer-containing gas mixtures pre-filled individual cartridges, prepare and administer, which increases the safety for the subjects.

In a method according to the invention takes place between a Rückatemphase (preferably about 2 minutes) and a Auswaschphase (for example, 5 to 60 minutes, eg about 10 minutes) of the abatembaren tracer preferably the automatic switching of the proband mouthpiece between Rückatemreservoir and room air or O ₂ supply an automatically switchable valve, eg an electronic solenoid valve.

In a possible preferred variant of the invention (method and rebreathing device) is the mouthpiece with the sensor unit for the tracer (in particular with a CO sensor for CO measurement), preferably with the above-preferred tgo values, from the rest of the unit removable, so that the subject is given more freedom of movement. In this case, the above-mentioned automatically switchable valve between Ü ₂ supply and room air can be dispensed with in the corresponding rebreathing device.

Preferably, the respective phases of the measurement procedure are e.g. displayed on a display for the subject and / or operator of the rebreathing device, so that accordingly a preferred rebreathing device according to the invention is equipped with a corresponding evaluation module (eg in the form of a computer) with display (eg computer monitor) or used in the method according to the invention becomes.

In a preferred embodiment of the invention, the rebreathing device according to the invention (which is then also used in the method according to the invention) contains protection mechanisms to protect against unfavorable gas conditions (for example, the oxygen concentration should not be too low, the carbon dioxide concentration should not rise too high). Therefore, it is preferably provided that when exceeding thresholds in an emergency even during the rebreathing phase, a valve for Room air is automatically opened.

When using the respiratory gas concentration of the tracer, the measurement of its concentration is preferably breathable (for example, by integration of several measured values during a breath) .This enables accurate automatic analysis of the washout kinetics.

A further preferred embodiment of the invention relates to the computational (computer-aided) implementation of an integration of the determined tracerderi fourth measurement signals (sensor signals) of Auswaschkinetiken and (which is particularly necessary when measuring the CO concentration via a CO sensor of exhaled CO) a computational separation the proportion of different CO binding compartments, in particular the lung and blood portion of the applied CO, preferably by finding adapted functions (fitting) and decomposition of superimposed functions in individual functions. As a result, an accurate distribution of CO in the system can be calculated. Only the blood-bound amount of CO is relevant for the calculation of total body hemoglobin, but the CO levels of other compartments (such as CO still present in the lung or CO bound in other compartments such as myoglobin) can be determined by fitting the abatmoid kinetics (fitting) and are corresponding Corrections are possible, but can be excluded, if desired or required, to obtain more accurate readings. This procedure increases the accuracy and reproducibility of the new measurement method.

Recording and delivery process can be used alternatively or together, with the release (= washout) -Kinetik (elimination) is preferred.

Further preferred embodiments of the invention can be found in the claims, preferably in the subclaims, which are incorporated herein by reference, and in the following example.

The following example is illustrative of the invention without limiting its scope (with individual features or more specific definitions taken from the Examples can also be used for a more precise definition of more general subject matters, individually or in groups, which leads to preferred embodiments of the invention):

It shows:

Fig. 1: Schematic representation (in cross section) of an inventively applicable and inventive rebreathing device. The arrow indicates the direction of the airflow when inhaling a subject. Fig. 2: Graphic representation (detail) of the CO signal at the mouth as a function of time in the washout phase (elimination phase of the CO in open system). The abscissa (x-axis) is the time (min), the ordinate (y-axis) is the CO signal (V).

Fig. 3: Graphical representation (detail) of the CO signal as a function of time in the washout phase with curve for breath-integrated CO signal. Values on abscissa and ordinate as in FIG. 2.

4: Graphical representation of the CO concentrations determined from integrated CO signals (as shown in FIG. 3) with the aid of a calibration as a function of time. Periods are shown as bars. Each point corresponds to one breath. X-axis time (min), y-axis CO concentration in respiratory gas (ppm).

FIG. 5: Graphical representation of the CO-hemoglobin (CO-Hb) saturation (% of Hb ₁ present as CO-Hb) determined from the CO concentrations in FIG. 4 over time. FIG. x-axis time (min), y-axis CO-Hb saturation in%. FIG. 6: Graphical representation of the adaptation (fitting) to falling exponential functions for the CO elimination from the two main compartments. FIG

Blood and lung, as well as the reference (zero) value for CO-Hb before CO application (measured by the CO concentration in the respiratory air before CO administration) and the initial curve (also resulting from addition of the derived components) Dependence on time. X-axis = time (min), y-axis = CO-Hb saturation in%.

Fig. 7: Schematic representation of another Rückatmungsvorichtung according to the invention with fixed or removable unit mouthpiece and measuring sensors (if this unit is removable, the rebreathing device can also be designed without the valve 10 shown, the Clippings A and B show the path of the air when opening the way to the room air (A) or the Rückatemreservoir (B)).

1 shows an exemplary rebreathing device 1 for noninvasive determination of the hemoglobin mass. A mouthpiece 2 is adjoined by an area with measuring sensors and / or devices 3 (in particular a CO sensor and a flow meter, also other sensors or measuring devices such as oxygen or CO ₂ sensors or measuring devices are possible here), followed by a CO ₂ - Absorption chamber 4. An attachment 5 allows the connection to a CO applicator (for example, a cartridge or a syringe with a defined CO-

Amount). The CO supply is controlled by a valve 6, which is opened for CO supply, while another valve 7, the connection to a Rückatemreservoir 8, for example in the form of a so-called Douglassack, which may have, for example, an internal volume of 3 I. The valves 6 and 7 may be embodied, for example, coupled, so that the valve 7 can be opened with a time delay after the valve 6, for example as a coupled, automated vacuum valve system 9 with flow / volume meter. Another valve 10 may allow the supply of fresh air or oxygen. The data of the measuring sensors and / or devices in the area 3 and the control of the valves can via a (multi-component executable) evaluation module 11 (which may include a control, for example, the CO dosage, the valves and other relevant components of the rebreathing device 1 and For example, as a connectable computer can be executed and preferably the necessary programs, in particular for the implementation of the following calculation rules (eg, the formulas and algorithms, as given below), includes) collected and evaluated or made.

The alternative embodiment shown in Fig. 7 shows a variant in which instead of the Douglassackes as Rückatemreservoir 8 (here accordion-like expandable) bellows is provided, allowing a simpler determination of the volume (for example, by measuring the height of the bellows or a parallel calibrated display) in the rebreathing reservoir, thus allowing easier correction for uninflated CO in the rebreathing device. In one possible embodiment, here the valve 10 can be omitted, namely, if a separation area 24 (eg, as aufsteckbares on or in the remaining area of the connector with the mouthpiece 2) is provided - then the mouthpiece with the measuring sensors and devices 3 can be separated from the rest of the rebreathing device after inhaling the CO 5 and CO exhalation can be performed without these other components, which can allow high mobility for a subject. In another embodiment, the separation region 24 may be provided and yet a valve 10, or the separation region 24 may be omitted entirely and then a valve 10 may be provided to switch between room air and air in the rest of the rebreathing device. A computer 23 (corresponding to the evaluation module 11 in FIG. 1) enables the collection and evaluation of the data.

Otherwise, for the device shown in Fig. 7, the above and below 5 descriptions made to Fig. 1 apply.

As the CO sensor, one having a tgo of 500 ms or less, for example, 250 or, preferably, 125 ms, is used, or is provided in the device, to allow a plurality of measured values to be obtained, for example advantageously a correspondingly equipped IR -Sensor. This can for example be equipped so that an aliquot of the gas flowing through the device is branched off and supplied to the actual sensor.

5 In the procedure can first be a 2-point calibration of the CO sensor with

Standard gas (eg, 50 ppm CO) and against the blank (room air or CO-free standard gas (0 ppm) can be carried out (even without subjects), as in this example .. 0 Also without subjects can (and will in the present example) based on Knowing its body weight, the rebreathing device 1 can be set up to dose a certain amount of CO, for example by attaching a cartridge, bottle, syringe, bag, chamber or other containing a suitable predetermined amount of CO Container, pumping of such an amount or the like. Suitable amounts of CO are 0.7 to 1.0 ml per kilogram body weight of the subject. The rebreathing device is filled with a suitable breathing gas, such as pure oxygen. This filling can also be done without the presence of the subject.

Subsequently, a subject is connected via the mouthpiece 2 (alternatively, for example, a tube would be possible) connected (if he is not already connected in the previous steps).

In a first step, the subject breathes through the area with measuring sensors and / or devices 3 with the valve 10 open (or, if a separation area 24 is present, with mouthpiece 2 and measuring sensors and devices 3 and 2 connected to the rest of the rebreathing device) open) valve 10), for example, 10 breaths quietly on and off. Here are the following

Sizes are collected as references:

Flow rate in l / s Fractional CO ₂ concentration (%) (optional) Fractional O ₂ concentration (%) (optional) Fractional CO concentration (ppm)

In a next step, via the rebreathing device 1, which is previously filled, for example, with pure oxygen or air, the previously set body weight-adapted amount of CO, via e.g. about 2 minutes in the closed

Condition of the system (valve 10, if present, closed) blown back. Because of its high affinity for hemoglobin, CO is bound extensively by hemoglobin during this phase. Another essential part of the CO bolus, which could not be bound to Hb in this way, is in the completion of the rebreathing phase in the lung compartment.

After the end of the approximately 2-minute rebreathing phase with the system closed, for example, in the subsequent wash-out phase, the continuous registration of the breaths over, for example, 10 minutes, takes place analogously to the measurement before Application of the carbon monoxide with the valve 10 open and / or with the use of a possibly existing separation region 24 removed unit mouthpiece 2 and measuring sensors and devices 3. The necessary (CO concentration, flow) and possibly optional data are collected (for example if only the end-alveolar concentration of CO is to be measured, this is determined by parallel determination of the CO ₂ concentration (for example by gas chromatography), which is also highest in the end-alveolar gas, and by the corresponding CO concentration measurements be correlated). In the example described further below not only the end-alveolar, but the CO concentration is used during the entire breath.

In the wash-out phase, raw data (signals) 12 are obtained (FIG. 2) which, as shown here, can advantageously be smoothed by a so-called "moving-averaging" method (for example, by in each case one data window of 20 values each) The measurement signal (hereinafter also referred to as V) of the sensor is applied.) From the resulting smoothed (or unsmoothed) curve 13 or the corresponding numerical values, the CO concentration can now be determined automatically by computer-aided breathing (FIG Signals (V) are here integrated (Fig. 3) in the device itself Breathable ("Breath-by-Breath") computer-aided.

Curve 14 corresponds to the uncalibrated, breath-integrated CO signal. The breath detection is based, for example, on the analysis of the signal, not shown here, for the flow of breathing gas (Flow, l / s).

From the integrated signal and the application of the calibration (zero point, 50 ppm), the values for the breath-by-breath course of the expiratory CO concentration [CO] are determined computer-assisted (FIG. 4). Here every data point represented corresponds to one breath over time (time (min)). Shown are some reference values from a period 15 before the period of the rebreathing maneuver 16 and measurement data in the period 17 after the end of the rebreathing phase. In the experiment shown here no respiratory gas analysis takes place during the phase of rebreathing, but such can also be carried out in this time interval (in order, for example, to observe the absorption phase instead of or in addition to the elimination phase), which is especially true 3 is possible when using pulse oximeters instead of or in addition to the CO sensor).

By means of the values determined in this way, and since there is a linear relationship between the CO concentration [CO] in the respiratory air (preferably exhaled air) and the CO-Hb saturation, the CO-Hb saturation in% is computer-assisted from the CO concentrations. calculated using a suitable formula, eg by Equation I (from Vreman et al., Clin. Chem. 42 (1), 50-56 (1996)):

CO-Hb (%) = 0.25 x [CO] Exhaled air (ppm) - 0.01 (I)

[CO] = volume concentration of CO

Based on these values (or alternatively using a pulse oximeter directly), CO-Hb saturation can be graphically (or computationally) represented

(Ed. 5).

The leaching of CO from the organism after the rebreathing phase when measuring the CO in the respiratory gas is mainly made up of two compartments:

1) "Faster" compartment: The CO remaining in the lungs after the rebreathing phase At a breath depth of, for example, approx. 300 ml per breath, it can be assumed that an average test person with, for example, 5 liters of intrathoracic gas volume (ITGV) will do so after about 15 breaths 1 to 2 minutes), the exchange is faster because the subject hyperventilates after the rebreathing phase.

2) "slower" compartment: the CO bound to the blood after the rebreathing phase.

The leaching from the two compartments is computer-aided from the values for the CO-Hb concentration / time dependency via decreasing exponential functions mapped or automatically analyzed ("fitted") Fig. 6 illustrates the non-linear modeling of leaching two compartments according to the general equation II, obtained here using eg the Levenberg-Marquardt algorithm (other adaptation algorithms would also be usable, such as the Gauss-Newton algorithm or the method of gradient descent) ):

CO-Hb (%) = Asiut ^' e ^{"λBlood ■ ι} + A _Lungθ ^■ e ^{" ALunge ι} + s (II)

Where t is the time after completion of the rebreathing phase and s is the reference value for the CO-Hb (%) fraction of total Hb before CO administration. A and λ are the respective macro parameters of the blood and lung washout functions.

In Fig. 6 can be clearly distinguished between the two main compartments of the CO distribution in the rebreathing phase (blood compartment, fitted curve 18, lung compartment: fitted curve 19), the straight line 20 stands for the reference value for CO-Hb (%) before the beginning of CO application. A generally valid reference for the calculation of the Hb mass represents the size A _B iut 21.

Alternatively, it is also possible to fit and disassemble into a lung and

Already at the level of the integrated CO signals or the CO concentrations and to use only the data for the derived function for the blood values directly for the determination of the (linearly dependent) CO-Hb.

The values thus obtained permit a calculation of the hemoglobin mass: Based on the increase in CO-Hb saturation during the rebreathing phase, which can be determined by the measurement data, at an optimized time, the amount of hemoglobin mass is determined from the administered CO amount, for example, according to equation III (Schmidt et al., Eur. J. Physiol. 95 (5-6): 486-95, 2005, and Bürge et al., J. Med.

Appl. Physiol. 79: 623-631, 1995).

Hb mass (g) = K ^■ D _co '100 ^• (ΔHbCO% ^■ 1, 39) ^"1 (III) Barometric pressure (mm Hg) ^• 273 ⁰ K)

Where K =

(760 mmHg ^• Ambient temperature (° C) + 273)

Dco is the applied CO dose, ΔHbCO% is the increase in HbCO (%) (increase in absolute%) by the rebreathing phase and 1, 39 is the Hüfner number (measure how much ml of oxygen or carbon monoxide can bind a gHb ).

Due to a dynamic change, the selection of the window for ΔHbCO% is relevant for the quality of the Hb mass calculation. Ideally, this should be the moment of maximum binding and distribution of the amount of CO inhaled in the rebreathing phase. However, this time varies due to individual CO kinetics from subject to subject. The method shown for exact numerical detection of the dynamic change is therefore suitable i.a. also for the optimization of this value.

On the other hand, as a standard and to automate the system, the time 0 (zero) can also be used as the moment of maximum HB-CO saturation. In mathematical terms, this value results from the nonlinear modeling shown after transformation from the washout term for blood from Equation II:

, (- λ 0)

Hb-CO (%) zero point = AsIUt = Aßlut (IV)

Furthermore, D _C o can be corrected according to the model shown with the amount of CO "lost" via the lung compartment according to equation V:

(V)

COsystem is the remaining amount of CO in the rebreathing system at the end of the experiment - this value is determined by the measured CO concentration and the (known and when using eg a bellows as Rückatemreservoir 8 as shown in Fig. 7 very easily determinable) volume of System determines. For example, this can be done by means of a shown in Fig. 1, for example, only 22, an aliquot part of the gas in the rebreathing system is directed to the measuring sensors or devices 3, where the CO concentration is determined. Other arrangements (also separate sensors for CO concentration in the rebreathing device) may alternatively be used.

From the above example (FIG. 6), the total body hemoglobin mass can be calculated by way of example: The relevant CO-dose is given by Equation V with A _Lung e = 14.916, λ _Lu length = 3.395, A _B iut = 6.412, λ _B iut = 0.0362:

Dco (ml) = 87.7 = (92.9-3.32) ^• (1-0.02099) (VI)

K is calculated according to C. Bürge et al., J. Appl. Physiol. 79 (2), 623-631, 1995) at a temperature of 26.8 ° C and a barometric pressure of 735.5 mm Hg as:

K = 0.88108 (VII)

After substitution in Equation III, the result for the Hb mass is obtained via Equation VIII:

Hb mass (g) = 866.9 g = (0.88108-87.7-100) / A _B iut- 1, 39 (VIII)

Corresponding computing steps are computer implemented via suitable computer software in the evaluation unit 11 or the computer 24 (evaluation unit and computer are used interchangeably in the present application), so that the total body hemoglobin can be determined automatically.

Alternatively or in addition to the measurement of exhaled CO concentrations, the determination of the decrease in CO-Hb concentration can also be carried out by other noninvasive methods, for example by means of a pulse oximeter, which is also equipped for the measurement of CO-Hb. These measurements can be used, for example, to determine the general body status or for diagnostic purposes for healing purposes.

The summary following the claims is hereby incorporated by reference for the purpose of further illustrating the invention.

/ Claims

Claims

claims

A non-invasive method for obtaining measurement data suitable for determining the total amount of hemoglobin of a pulmonary artefact in which a predetermined dose of a breathable tracer is adjusted and delivered non-invasively through a body mucosa of the lung respirator and the recording and / or elimination of the breathable tracer by noninvasive measurement a parameter correlated with the amount of tracer in the body of the pulmonary at a plurality of times such that two or more per breath of the subject

Measurements of the tracer corresponding parameters are determined is determined.

2. The method of claim 1, wherein as a tracer carbon monoxide is used.

3. The method according to any one of claims 1 or 2, wherein the acquisition of the measurement data for the elimination of the tracer outside of and / or on the outside of the body of the lung respirator is made.

4. The method according to any one of claims 1 to 3, wherein the measurement of the tracer takes place in the respiratory gas, preferably by means of at least one tracer sensor, in particular a CO sensor, preferably an IR sensor, a mass spectrometer (MS), a gas chromatograph (GC ) or a GC-MS combination, or two or more of the same or different ones of these sensor devices.

5. The method according to any one of claims 1 to 3, wherein the measurement of the decrease of the tracer by measuring the absorbance of electromagnetic waves in the UV, IR and / or visible range is made on the outside of the human body.

6. The method of claim 5, wherein the measurement of the decrease of the tracer takes place by means of a pulse oximeter.

7. The method according to any one of claims 1 to 6, wherein computer-assisted the total hemoglobin content of the organism is determined using the data obtained for the elimination of the abatembaren tracer.

B

8. The method of claim 7, wherein with or without prior, subsequent and / or simultaneous calibration with respect to the tracer on the measuring device or instruments used in a first step pre-metered amount of tracer, preferably with carbon monoxide as a tracer, in a io second step a subject by means a rebreathing device is supplied via the respiratory air, and already during the delivery or in particular subsequently in a third step, the decrease of the amount of the tracer by noninvasive determination by means of data from a pulse oximeter, and / or the amount of exhaled tracer,

1 5 zugsweise by means of a corresponding meter as part of

Rebreathing device or a unit of mouthpiece and Messenseonsoren or devices in synchronization with the respiratory flow, and / or a corresponding parameter is determined, a breathtaking automatic integration of directly or determined by a smoothing

20 measuring signals or derived parameters like the

Tracer concentration values or the calculated relative tracer Hb saturation is performed to determine the decrease of the tracer concentration in the body and / or the tracer concentration in the air of the subject with continuous time, a suitable

25 falling exponential function is adjusted by fitting to the available smoothed values, wherein in particular in the case of determining the concentration in the respiratory air, an adaptation to two or more compartments is made and with or without correction to the functions found for other compartments

30 and / or the reference value for tracer Hb before starting the tracer application with the help of the found function for the blood compartment calculated the total body hemoglobin amount of the subject is determined.

9. The method of claim 8, wherein with or without previous, subsequent and / or simultaneous calibration with respect to the tracer on the measuring device (s) used in a first step supplied with carbon monoxide tracer Tracer, in a second step to a subject by means of a rebreathing device on the breathing air 5, and already during the supply or in particular subsequently in a third step, decreasing the amount of carbon monoxide bound to hemoglobin by non-invasively detecting the CO-Hb concentration over the amount of exhaled carbon monoxide by means of a CO meter as part of the oe-respiratory device or a mouthpiece and unit

Messenseonsoren or devices is determined in synchronization with the respiratory flow by means of the data from a flow meter and / or a corresponding parameter, the data obtained are smoothed, for example, by a moving average method, a 5 breaths automatic integration of directly or determined by smoothing Measured signals or derived parameters such as the CO concentration values or the computationally derived relative CO-Hb saturation is carried out, preferably after adjustment by means of the previously performed calibration, to decrease the CO-Hb-0 concentration in the body and / or the CO Concentration in the breathing air of the

To determine probands with continuous time, fit a suitable decaying exponential function to the available smoothed values by fitting, also adapting to two or more compartments, especially blood and lung, by determining and superimposing the functions for two or more

Compartments, and corrected for the functions found for other compartments and / or the reference value for CO-Hb before starting the CO application with the help of the found function for the blood compartment calculated the total body hemoglobin amount of0 subjects.

10. The method according to any one of claims 8 or 9, characterized in that the measurement in the third step of decreasing the amount of bound to hemoglobin carbon monoxide in a period of 10 or less, preferably 5 or less, in particular 3 or less minutes is performed.

11. The method according to any one of claims 1 to 10, wherein the determination of the tracer or the CO with a tgo of 1 s or less, preferably from

500 ms or less, in particular of 250 ms or less, in particular of 150 ms or less, is performed.

12. The method according to any one of claims 1 to 11, wherein in a first step, a rebreathing device (1) in the absence of

Lungenatmers prepared as subjects for the administration of a predetermined amount of tracers.

13. The method according to any one of claims 1 to 7, 11 or 12, characterized in that the measurement of the decrease in the tracer concentration after the completion of the supply of the tracer in a period of 10 or less minutes, preferably 5 or less, in particular of 3 or less minutes, for example, of 2 minutes.

14. A rebreathing device (1) for the non-invasive determination of the hemoglobin mass comprising a tracer sensor with a t ₉₀ of 500 ms or less, preferably of 250 ms or less, in particular of 150 ms or less for the non-invasive acquisition of signals which is a determination of Whole body hemoglobin includes.

15. rebreathing device according to claim 14, characterized in that the tracer sensor is a CO sensor.

16. A rebreathing device (1) according to claim 15, wherein the CO sensor is an infrared sensor.

17. A rebreathing device (1) according to claim 15 or 16, wherein the CO sensor is designed for non-dispersive infrared absorption.

18. rebreathing device (1) according to any one of claims 14 to 17, characterized in that it comprises a via a separating device (24) removable unit from a mouthpiece (2) and Messensoren- and / or devices (3).

19. A rebreathing device (1) according to any one of claims 14 to 18, characterized in that it comprises a valve (10) for switching between room air and the interior of the rebreathing device (1).

20. rebreathing device according to one of claims 14 to 19, characterized in that it comprises an evaluation unit (11) or a computer (23) which is programmed for the evaluation and optionally also the control of a method according to one of claims 1 to 13.

21. A rebreathing device according to any one of claims 14 to 20, which in addition to the components mentioned in each claim a CO ₂ - absorption chamber (4), a Rückatemreservoir (8), a valve (6) for CO supply and a valve (7) for Rückatemreservoir (8) or a corresponding valve combination and an evaluation module (11) or a computer comprises.

22. A rebreathing device according to any one of claims 14 to 21, which further comprises a CO ₂ sensor among the measuring sensors and / or devices (3), in particular to determine the final phase of the respiration during which alveolar air is exhaled.

23. A rebreathing device according to any one of claims 14 to 22, which further comprises securing mechanisms for protection against unfavorable gas conditions.

24. rebreathing device according to one of claims 14 to 23, which has an evaluation unit (11) or a computer (23), the or so is programmed to allow determination of the total body hemoglobin level by reducing the amount of hemoglobin-bound carbon monoxide by noninvasive determination of the CO-Hb concentration over the amount of exhaled carbon monoxide by means of a CO meter as part of the

Rebreathing device or a unit of mouthpiece and Messenseonsoren or devices is determined in synchronization with the respiratory flow by means of the data from a flow meter and / or a corresponding parameter, the data obtained are smoothed o, a breathtaking automatic integration of directly or by

Smoothing determined measurement signals or derived parameters such as the CO concentration values or the mathematically derived relative CO-Hb saturation is performed, preferably after adjustment by means of the previously made calibration to the decrease in CO-Hb concentration in the body and / or the CO concentration in the breathing air of the

To determine subjects with continuous time, fit a suitable decaying exponential function by fitting to the available smoothed values, also adapting to two or more compartments, in particular blood and lung, by 0 determining and superimposing the functions for two or more

Compartments, and corrected for the functions found for other compartments and / or the reference value for CO-Hb before starting the CO application with the help of the found function for the blood compartment calculated the total body hemoglobin amount of the 5 subjects.

25. A rebreathing device according to one of claims 14 to 24 for determining the total hemoglobin content of a lung respirator, which has an evaluation unit (11) or a computer (23) which is so programmed that the determination of the total amount of hemoglobin is the

Using the equation (V)

includes.

26. rebreathing device or pulse oximeter, characterized in that it contains an evaluation module which is used to determine the

Whole body hemoglobin is programmed. / Summary