GB2442980A - Method and apparatus for determining carbon dioxide with different isotopes in exhaled breath - Google Patents

Method and apparatus for determining carbon dioxide with different isotopes in exhaled breath Download PDF

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GB2442980A
GB2442980A GB0620734A GB0620734A GB2442980A GB 2442980 A GB2442980 A GB 2442980A GB 0620734 A GB0620734 A GB 0620734A GB 0620734 A GB0620734 A GB 0620734A GB 2442980 A GB2442980 A GB 2442980A
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substance
method according
subject
drug
sample
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GB0620734D0 (en
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Bertil Hok
H Kan Pettersson
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Autoliv Development AB
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Autoliv Development AB
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/08Detecting, measuring or recording devices for evaluating the respiratory organs
    • A61B5/083Measuring rate of metabolism by using breath test, e.g. measuring rate of oxygen consumption
    • A61B5/0836Measuring rate of CO2 production
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/01Arrangements or apparatus for facilitating the optical investigation
    • G01N21/03Cuvette constructions
    • G01N21/031Multipass arrangements
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N21/00Investigating or analysing materials by the use of optical means, i.e. using infra-red, visible or ultra-violet light
    • G01N21/17Systems in which incident light is modified in accordance with the properties of the material investigated
    • G01N21/25Colour; Spectral properties, i.e. comparison of effect of material on the light at two or more different wavelengths or wavelength bands
    • G01N21/31Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry
    • G01N21/35Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infra-red light
    • G01N21/3504Investigating relative effect of material at wavelengths characteristic of specific elements or molecules, e.g. atomic absorption spectrometry using infra-red light for analysing gases, e.g. multi-gas analysis
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/0004Gaseous mixtures, e.g. polluted air
    • G01N33/0009General constructional details of gas analysers, e.g. portable test equipment
    • G01N33/0027General constructional details of gas analysers, e.g. portable test equipment concerning the detector
    • G01N33/0036Specially adapted to detect a particular component
    • G01N33/0055Specially adapted to detect a particular component for radionuclides
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483Physical analysis of biological material
    • G01N33/497Physical analysis of biological material of gaseous biological material, e.g. breath
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61BDIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00Detecting, measuring or recording for diagnostic purposes; Identification of persons
    • A61B5/0059Detecting, measuring or recording for diagnostic purposes; Identification of persons using light, e.g. diagnosis by transillumination, diascopy, fluorescence
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00Features of devices classified in G01N21/00
    • G01N2201/06Illumination; Optics
    • G01N2201/061Sources
    • G01N2201/06186Resistance heated; wire sources; lamelle sources
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2201/00Features of devices classified in G01N21/00
    • G01N2201/06Illumination; Optics
    • G01N2201/066Modifiable path; multiple paths in one sample
    • G01N2201/0668Multiple paths; optimisable path length
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/0004Gaseous mixtures, e.g. polluted air
    • G01N33/0009General constructional details of gas analysers, e.g. portable test equipment
    • G01N33/0027General constructional details of gas analysers, e.g. portable test equipment concerning the detector
    • G01N33/0036Specially adapted to detect a particular component
    • G01N33/004Specially adapted to detect a particular component for CO, CO2
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/483Physical analysis of biological material
    • G01N33/497Physical analysis of biological material of gaseous biological material, e.g. breath
    • G01N33/4972Determining alcohol content

Abstract

A breath test to determine the blood concentration of a drug, pharmaceutical or narcotic etc. in a human or animal comprises analysing exhaled breath with respect to carbon dioxide (CO2) with different isotopes, wherein the drug has been labelled with at least one rare isotope of carbon or oxygen. The presence of the drug in the bloodstream of a subject is preferably detected by infrared spectroscopy of a sample of the expired breath of a subject. Also shown is the apparatus for performing the breath test analysis and an application of the apparatus which is incorporated in a vehicle as a safety feature to prevent ignition if the blood concentration of the drug is not as expected.

Description

Improvements in or relating to detection of substances in a subject THE

PRESENT INVENTION relates to the use and misuse of drugs, pharmaceuticals, and other substances. in many situations, it is desirable to determine whether such substances are present in the blood circulation of a person. For example, it is widely known that vehicle drivers may cause considerable damage to life and property under the influence of certain agents.

In fact, a major part of lethal and other serious traffic accidents can be attributed to this problem.

The problems with alcohol-related traffic accidents have been treated with considerable success dunng the last decades. In many countries, a maximum allowed blood alcohol concentration has been stipulated, for the EU region, typically 0.05%. Breath sampling techniques allow the reliable determination of blood alcohol concentration, and are based on the strong correlation between the concentration in blood and expired air. Instruments for breath alcohol measurements are commercially available for screening and evidential purposes. For several decades, these techniques have been used on a large scale, and the use of alcohol interlocks preventing the intoxicated driver from starting the vehicle is increasing. The added effect of this effort is significant both in terms of the number of intoxicated drivers, and the number of alcohol-related accidents.

It could thus be stated that driver impairment due to alcohol represents a large social problem which, however, is decreasing when adequate countermeasures are applied. The problems related to vehicle drivers influenced by drugs are also large, and unfortunately, growing. This is due to the increasing use of medication for various purposes, the growing number of pharmaceuticals with behavioural influence, the existence of an illegal market, and the absence of efficient enforcement methodology.

Antidepressants and other psychopharmacological drugs influencing brain or central nervous system functions may be expected to influence vehicle driving by reduced attention to the task, impaired cognitive functions related to upcoming events including responsiveness, impaired judgement and reaction time etc. Anabolic steroids, sleeping pills, sedatives and pain relieving agents can be expected to have similar effects. Commonly, these drugs exhibit combinational effects with, e.g. alcohol, and between themselves.

It should be considered that the influence of drugs on vehicle driving may not always be negative. In fact, patients suffering from diabetes, epilepsy and other diseases may be allowed to drive a vehicle if and only if their disease is adequately controlled by medication. In these cases, detection of the appropriate pharmaceutical may thus serve the opposite purpose to detection of drugs with deleterious effect: Presence of the drug should be the normal situation, whereas absence could be a signal for driving prevention.

The number of substances with potential impact on driver performance is counted in hundreds. They range from naturally occurring extracts to synthetic products for oral, intravenous or. other means of administration. They may have widely different constitutional and biological interaction mechanisms. A second difficulty when contemplating methods for determination is that the concentration levels in most cases are very low. Thirdly, most substances have low volatility, rendering direct determination from breath samples, such as in the case of alcohol, impractical.

The approach taken by most investigators is to use blood or urine sampling combined with powerful laboratory techniques, such as mass spectroscopy (MS) or quartz crystal microbalance (QCM), commonly in an electronic nose' configuration. This approach has resulted in impressive instrumental performance in terms of resolution and selectivity. Techniques capable of selective detection at ppb (parts per billion) levels of certain drugs have been developed. However, these instruments are very expensive and require highly skilled operating staff. The concurrent development of lab-on-chip' technology may in the future make them less exotic from a practical point of view.

Replacement of blood/urine sampling with e.g. transcutaneous detection will represent a practical improvement but will be difficult to combine with the requirements of short response time and user friendliness.

According to one aspect of the invention there is provided a method of labelling a drug or other substance for human or animal consumption, said substance comprising a metabolisable organic compound, the method comprising constituting said compound with a known enriched content of at least one rare isotope of carbon or oxygen.

According to another aspect of the invention there is provided a method for the determination of substance in the blood of a subject, including the steps of -a priori addition or substitution to said substance at least one rare isotope of carbon or oxygen being element of at least one metabolisable compound -proximity sampling of expired air from said subject with recognition capability -analysing said breath sample by means of infrared spectroscopy with respect to isotopic constitution of exhaled carbon dioxide.

According to another aspect of the invention there is provided a method of detecting the presence, in a human or animal subject, of a drug or other substance labelled by the method of the invention, comprising taking a sample of the expired breath of said subject and determining the relative proportions, in said sample, of two or more of said isotopes.

According to another aspect of the invention there is provided a drug or other substance labelled by the method of the invention.

According to a still further aspect of the invention there is provided apparatus for determining the presence of or concentration in a human or animal subject, of a drug or other substance comprising a metabolisable organic compound, the drug or other substance being labelled by the method of the invention, the apparatus including a sensor unit, including an enclosure for a sample of expired breath from said subject, a source of infrared radiation mounted for emitting infrared radiation into said enclosure, an infrared detector mounted for detecting radiation emitted by said source and which has traversed at least a part of the interior of said enclosure, said infrared detector being capable of detecting selectively infrared radiation within the absorption band of carbon dioxide constituted with a predetermined rare isotope of carbon or oxygen and of discriminating such radiation from infrared radiation within the absorption band of carbon dioxide constituted with the most common isotopes of carbon and oxygen, and means for receiving signals from said detector or detectors and providing output information relating to the presence or concentration of said substance.

The term "enclosure" as used above is not intended to be limited to enclosures which are impermeable or which bound an enclosed space on all sides. The enclosure may take the form, as in the preferred embodiment, of a tube open at both ends or even, if less preferably, an open framework around the volume or space and which framework supports the said infrared source and detectors.

The present invention, in its currently preferred embodiments, is concerned with a method and apparatus for the detection and/or determination of quantity of substances, e.g. drugs or pharmaceuticals, in the blood of a subject, e.g. a vehicle driver. The invention, in this aspect, represents a different approach to the problem of drug detection as compared to the ones mentioned above, It assumes the collaboration between drug manufacturers and manufacturers of detection apparatus, which in practice will exclude the illegal market.

Basically, the preferred method according to the invention involves the steps of: * Adding or substituting to the substance a metabolisable compound enriched with one or several rare isotopes of carbon or oxygen * Proximity sampling of expired air from the subject with recognition capability * Analysing the breath sample by means of infrared spectroscopy with respect to isotopic constitution of exhaled carbon dioxide (C02).

By a metabolisable compound is meant an organic, compound known to be biologically destructible by metabolism, preferably all the way to carbon dioxide and water, involving consumption of atmospheric oxygen, and under the influence of various enzymes for catalysis. The addition/substitution of isotope-labelled compound should, of course, be performed a priori, at the manufacturing stage. If the compound is present within the blood of a subject, it will be gradually metabolised. During this process, CO2 with an increased concentration of rare isotopes will be emitted and detectable in a breath sample from the subject. As will be described in more detail below, the main infrared absorption band of isotope-labelled CO2 is slightly shifted compared to the normal constitution 12C1602, (the superscripts indicating 12 and 16 atomic mass units for normal carbon and oxygen, respectively). After adequate spectroscopic analysis, it is thus possible to determine whether or not CO2 from the metabolisable compound and drug is detectable in the subject's breath. In fact, under certain circumstances which will be described in more detail below, the rare/normal isotopic ratio may be correlated to the absolute blood concentration of the substance.

By proximity sampling of expired air is meant that the point of sampling is located in the near vicinity of the subject's mouth/nose region, but not necessarily in physical contact with the subject. Preferably, such sampling involves the positioning of a multivariable sensing cell, allowing expired air to flow through and past it. Consequently, the breath sample may be somewhat diluted with ambient air when it arrives at the point of measurement. By recognition capability is meant that specific characteristics of expired air, such as time variation profiles of, for example, flow velocity, temperature, humidity, and/or carbon dioxide concentration are analysed, providing categorisation of a certain event as approved or disapproved sample, i.e. to determine whether a particular sample is a valid sample or one of which may provide incorrect results.

Proximity breath sampling may involve instruction of the subject to expire against a specified sensing area. In a cooperative subject, this will result in a forced expiration of 0.5-1.5 liters of expired air which may be sampled at a distance of 20-50 cm. Passive sampling from a non-cooperative subject is also possible but requires closer proximity, typically 10-20 cm, due to the smaller flow velocities and volumes associated with relaxed expiration.

Proximity sampling eliminates the need for a mouthpiece, which is otherwise mandatory in breath sampling equipment. The handling of mouthpieces represents a serious limitation with respect to hygiene, cost and user-friendliness. Nevertheless, an apparatus according to the invention may, if desired, include a mouthpiece communicating with the sample enclosure or sensing unit.

The method according to the invention solves the problem of identification and selectivity between hundreds of substances by isotope labelling. Thus, by arranging for different substances to be labelled using respective difference concentrations of rare isotopes of carbon and oxygen, identification of a particular substance may be made on the basis of the relative concentrations of said isotopes detected. It will be understood that whilst the drug or substance of concern may itself be constituted with rare carbon or oxygen isotopes, in many cases it may be preferable to incorporate, in the formulation of a medicine, for example, a metabolisable organic carbohydrate, such as glucose, which is isotopically labelled in the manner described. The method the invention solves the problem of sampling, by hosting the label in a metabolisable compound resulting in emission of a volatile product (C02), thus making proximity breath sampling practical. In its preferred form, the invention makes use of a reliable physical detection mechanism (infrared spectroscopy), providing adequate sensitivity and specificity. Furthermore, by using different combinations of several isotopes, it is possible to categorise and identify substances by using a coding scheme. Furthermore, the method requires minimal intervention, provides almost immediate response, can be combined with alcohol detection, and can be implemented at low cost.

In one embodiment of the invention, the metabolisable compound is identical with the actual drug to be determined. This implementation has the obvious advantage that the metabolic rate will be closely related to the pharmacological action. After intake and distribution by the blood circulation, its concentration and action is expected to peak and then decay at a similar rate. This solution is, however, only suitable when most of the active substance is metabolised all the way to CO2 and water, which is is not always the case. It may then be more appropriate to use a separate compound as carrier of the isotopic label.

Glucose, (formula C6H1206) may be taken as an example of a metabolisable compound. Its combustion (metabolic conversion) may be described by the following reaction formula: C6H1206 + 602? 6C02 + 6H20; iH=-2.8 MJ/mole (1) The negative and large reaction enthalpy iH indicates that an appreciable amount of energy is released. The metabolic reaction takes place in a fairly large number of steps, each mediated by the catalytic action of enzymes. The oxidation and generation of CO2 is part of a nine-step cyclic process known as the citric acid cycle. This process is common to all carbohydrates but the total length of the reaction chain, and thereby the reaction rate, may vary from one compound to another. For example, polysaccharides, like starch, require much longer time than simple monosaccharides, like glucose.

From the reaction formula (1) it is obvious that labelled carbon atoms after metabolism will appear in the emitted CO2. It is less obvious but follows from more detailed analysis of the reaction kinetics, that oxygen atoms labelled to carbohydrates will also be emitted as CO2 rather than H20.

12C1602 exhibits a distinct infrared absorption peak at approximately 4.26 i.tm wavelength, and a bandwidth of approximately 0.1.tm. This peak is due to a mode of asymmetric stretching vibration within the linear CO2 molecule, in which the central carbon atom vibrates in opposite direction to the two surrounding oxygen atoms. Quantum mechanical calculation based on solving Schrädinger's equation for the potential function of an harmonic oscillator provides the following relation for the allowed vibration energies E: E=!!-=(v+1/2).h.Jii v=1,2,3,... (2) In fact, this expression is very similar to the corresponding expression for resonance frequency of a classical harmonic oscillator with mass M and spring constant k, except for the quantum numbers v. Other denotations are as follows: c=the speed of light =2. 998*1 08 m/s, X = the wavelength at resonance, and h=Planck's constant =6. 6256*1 O Js. The total mass M of the CO2 system at hand is given by M-C 0 (3) M +2M0 Mc and M0 denote the mass of carbon and oxygen atoms respectively.

Substituting 12C with 13C will cause an increase of the effective mass M, and the absorption wavelength will, according to eq. (2), be shifted from 4.26 to 4.38 tm. If, in addition, 160 is replaced by 180 the absorption peak will shift even further to 4.46 j.tm.

Although 3C and 18Q could be categorised as relatively rare isotopes, they are stable and naturally occurring, at ratios of approximately 1.1% and 0.2% respectively, compared to the normal isotopes. The isotope ratios 13C112C and 180,160 are nearly constant in nature, due to the fact that physical and chemical isotope separation mechanisms are relatively weak. Other potentially useful isotopes are 14C which is mildly radioactive with a half-life of 5730 years, and 170 which is stable but rarer than 18Q The method according to the invention also provides the capability of absolute determination of concentration of the substance. This may be performed by applying an algorithm involving the absolute measurement of background and breath sample carbon dioxide concentration, Cco2background, CCo2sarnpIe, and estimated or independently determined alveolar carbon dioxide concentration CCC2aIveoIar. In its simplest form, the following algorithm may be used for the determination of absolute blood concentration C,IOOd of the substance, based on the corresponding sample concentration of the substance, Cxsampie, directly related to the isotope ratio being measured: c xblood -xsample ç CO2sarnpk CO2backgrowid Equation (4) is based on the assumption that the dilution involved in the sampling process is independent of isotopic constitution. This assumption is justified since the dilution primarily involves gas mixing due to turbulent flow.

A normal resting adult person dissipates 100W power and consumes the equivalent of approximately 20 grams glucose per hour. In the method according to the invention, it is possible to resolve variations of isotope ratio of less than 0.1%. Typical dosage of isotope-enriched substance could therefore be a fraction of a gram.

The production of compounds enriched with rare carbon or oxygen isotopes can be performed both as part of a natural extraction process, or a completely synthetic process. In the former case, a culturing plant using e.g. sugar-cane or sugar-beet is arranged for natural photosynthesis in an atmosphere with isotope labelled CO2. This corresponds to running the reaction (1) backwards, using ultraviolet light as the energy source. A completely artificial production line could use other starting isotope enriched material.

The production cost of isotope labelled substances will, of course, increase somewhat compared to its normal cost. However, this cost increase should be marginal in view of the abundance of raw material, modest energy consumption, and the use of automatic processing.

An embodiment of the present invention as applied to a method and system for the determination of a substance in the blood of a vehicle driver, is described below with reference to the accompanying drawings in which: Figure 1 is a schematic view partly a sectional view and partly a block diagram of an apparatus embodying the invention, Figure 2 is an infrared spectrogram showing absorption spectra for normal and isotopically labelled carbon dioxide, and Figure 3 shows a schematic multivariable diagram, for a typical proximity breath sample, and comprises graphs showing several variables which may be measured in an apparatus embodying the invention in order to ascertain whether a valid sample has been secured.

The embodiment of the present invention described below is concerned with a method and a system for the determination of a substance in the blood of a vehicle driver. The basic elements of the method have been described above, and in the following, a more detailed description will be given in relation to the enclosed drawings, Figures 1, 2 and 3.

As already explained, the system, i.e. apparatus, according to the invention is capable of the determination of small quantities of isotope labelled CO2. A block diagram of the system according to a preferred embodiment is depicted in Figure 1. The sensor unit 1 of the system preferably has small physical dimensions, typically 8 x 5 x 2 cm or smaller, and may either be a self-contained unit, or may be built in to other equipment. It may, for example, be integrated in a vehicle in order to prevent a vehicle driver from driving under the influence of certain drugs. In this case, the function of the apparatus may be similar to, or even combined with that of, an alcohol interlock system. The apparatus may also be a stand-alone unit used in or outside vehicles. Another implementation is a handheld instrument which could be used by anyone who may wish to test the presence and concentration of a drug or substance in a subject's blood.

The sensor unit 1 depicted in Figure 1 may be positioned directly in proximity to the subject's nose/mouth region. An alternative is to use a fluid link involving active transport of the breath sample between the sensing point and the system 1, for example a tube connecting a mouthpiece with the sensor unit.

This alternative may be preferable in applications requiring physical protection of the system, but has the disadvantage of higher complexity and risk for clogging of the fluid link.

The sensor unit I includes a source 2 of broadband infrared radiation, such as a filament acting as a black body radiator by Joule heating. Preferably, the source I is packaged with an internal parabolic reflector to collect the emitted infrared beam 3 into a useful aperture. The beam 3 is subjected to multiple reflections against reflecting surfaces 4, 5, which may be concave in order to collimate the beam before it enters a plurality of detectors 6, 7. The detectors 6, 7 include interference filters tuned to specific absorption peaks, as will be described in more detail in relation to Figure 3. By multiple, typically 5-10, reflections, it is possible to obtain relatively long optical paths, 30-50 cm, within a much smaller enclosure. Preferably, the surfaces 4, 5 have reflectance exceeding 0.99 for infrared radiation, e.g. by using polished gold or aluminium surfaces.

An attractive conjugate feature of interference filters may be exploited in the system as indicated in Figure 1. The filter of detector 6 will only transmit a narrow band, whereas the residual part will be reflected, and can be used with no significant signal loss for the detector 7, employing a filter with a different passband.

The sensor unit 1 may also include one or several other sensor elements 8 for measuring variables not easily obtained by infrared spectroscopy. Such variables may include temperature, air flow velocity and relative humidity, all measurable by standard, commercially available, relatively low cost components.

The sensor unit I is physically designed to allow air flow 10 to pass through and past the unit without significant obstruction. It may or may not include a small fan 9 to enhance flow velocity, and thereby to minimise the system response time. A physical shutter mechanism 12a,b is used for opening the sensor unit 1 when a determination is to be made, and keeping it closed at all other times for protection against particle, aerosol and dust contamination of the optical devices. The sensor cell I may also include a heating or cooling element, allowing operation at extreme temperatures.

An electronic unit 11 is included in the apparatus shown. This unit incorporates analog circuitry, mainly amplifiers and filters, for drive and detection of sensor signals. It also includes circuitry for analog/digital conversion, and a digital microprocessor for executing arithmetic and logical operations according to a program stored in a permanent memory. The program will handle the signal communication between different parts of the system and with external units according to an established protocol. It will also implement the necessary calculations according to algorithms which may be both general and specific to the application, such as that represented by eq. (4).

The electronic unit 11 may preferably be implemented as one, or several, application-specific integrated circuits (ASIC). The size of the unit 11 will then be marginal compared to the optical subsystem, and its production will be extremely cost effective.

A display/communication unit 13 is included in the system, and is directly connected to the electronic unit 11. It communicates results of determinations to the user, and also accepts commands e.g. to display information stored in the memory of the electronic unit, or to change from one operational mode to another.

The sensor, electronic and display/communication units 1, 11 and 13 are preferably packaged in one single enclosure, preferably in a polymer material, allowing relatively complex design geometry to be combined with very low production cost.

Figure 2 shows infrared absorption spectra of normal (left curve) and 13C-modified (right curve) CO2. The curves are identical, except for a translation along the wavelength axis. The centre wavelength of normal CO2 is 4.26 jim, and is associated with a dip of the curve, having lobes on each side. For 13C, the centre wavelength is shifted to 4.38 jim, as already explained from the theoretical expression (2). The side-lobes are a result of rotational energy levels, which are actually quantised, although this is, not shown in Figure 2 due to modest resolution.

From Figure 2 it is obvious that by choosing one band-pass filter in the range 4.20-4.30 jtm, and another one at 4.40-4.50 jim, it is possible to select transmission for either one of the isotopic CO2 versions. State of the art interference filters with 0.1 tm bandwidth are readily available, and can be produced at low cost. The same applies to other isotope configurations, making it possible to encode categories of substances into different isotopical combinations. For example, the type of substances having deleterious effect on driving capability could use singular 3C as the isotopic code, whereas disease-controlling substances could use both 13C and 18Q The spectroscopic system built up from the source 1, reflecting surfaces 4, 5 and detectors 6, 7 is easily expanded to include detection of other volatile substances than CO2. Water vapour (humidity) may thus be detected in the wavelength range of 2.6-2.8 tim, and alcohol at 3.4 tm. A neutral band may also be useful, e.g. at 4.0-4.1 tm, with no appreciable absorption from expected gases, as a reference band which allows monitoring of the system performance, allowing specific error signals to be activated in the cases of aging of the source or reduced reflectance of the surfaces 4, 5.

Figure 3 shows schematically the variations in time of a number of quantities associated with a single proximity breath of a subject. The variables are: a) Flow velocity b) temperature C) relative humidity d) CO2 concentration, and e) the expected output from a substance X present in the subject's blood.

Flow velocity (Figure 3 a) will have a background level close to zero in the absence of active pump mechanism. At time = 1 second, the subject is providing a forced expiration, approximately 1.5 seconds in duration. The air velocity promptly rises to more than one or several m/s, then declines. A relaxed expiration would be somewhat shorter in duration, and smaller in magnitude. Each single breath is easily distinguished at a measuring distance of 10-50 cm, since inspired air flow will not affect the recording. The magnitude of the signal declines with distance, and also depends on the size of the orifice'.

Simultaneously with the onset of flow velocity, temperature will rise from the background level (room temperature 23 C in Figure 3b) to a level closer to body temperature. It will not reach body temperature, however, due to dilution of the sample. Furthermore, the downstroke of the temperature recording is expected to be less pronounced than the velocity recording, if there is no active mechanism for air transport.

In a similar manner, relative humidity (RH) will rise from ambient level (35% in Figure 3c) to a level also depending on the dilution. The mucous membranes of the airways are normally effective humidifiers, resulting in almost 100% RH of undiluted expired air. The timing of the temperature and humidity recordings are expected to be nearly equal.

The CO2 curve will start from a background level of almost zero, or 0.04-0.1%, depending on the ambient ventilation, 1000 ppm (0.1%) being accepted as the hygienic upper maximum. Alveolar air has a remarkably constant value of 5.3% in a normal resting subject, and exhibits modest variation with activity level, age, gender, etc. Measuring the absolute 002 concentration, (i.e. the plateau value observed in Fig 3 d), of thesample is thus a preferred method of determining the dilution of the proximity sampling, as already explained in relation to eq. (4). The onset of the 002 curve is somewhat delayed compared to the other curves, due to the effect of the upper airways representing a respiratory dead-space of approximately 150 ml, or 30% of the normal tidal volume (the volume of one relaxed breath) of a resting adult subject.

The signal representing a substance X is shown in Figure 3 e). This recording has equal timing of the CO2 recording, both having alveolar origin. Absolute determination of the X blood concentration involves applying the algorithm (4) to the directly measured value. In order for a breath sample to represent alveolar air, it is required that the CO2 and sample waveforms exhibit a clear plateau. A superficial or uncompleted breath will not be representative of alveolar or blood concentrations.

From the description relating to Figure 3, it should be clear that a number of prerequisites exist for the identification of a breath from a subject, thus providing the system with recognition capability as mentioned above. These criteria can be used in order to make sure that the conditions for the determination are adequate. They may also be tools for avoiding manipulation.

Claims (48)

1. A method of labelling a drug or other substance for human or animal consumption, in order to facilitate the detection or determination of said drug or substance in the blood of a human or animal subject, by analysing the breath of such subject with respect to carbon dioxide with different isotopes, said drug or substance comprising a metabolisable organic compound, the method comprising constituting said compound with a known enriched content of at least one rare isotope of carbon or oxygen.
2. A method according to Claim I in which said compound is constituted with respective known enriched contents of a plurality of rare isotopes of carbon or hydrogen.
3. A method of detecting the presence, or determining the amount, of a drug or other substance labelled by the method of Claim I in the blood of a human or animal subject, comprising taking a sample of the expired breath of said subject and analysing the breath of such subject with respect to carbon dioxide with different isotopes by detecting the presence, in said sample, of said isotope of carbon or oxygen or determining the proportion, in said sample, of said isotope of carbon or oxygen relative to the total carbon or oxygen respectively in the sample.
4. A method of detecting the presence, in the blood of a human or animal subject, of a drug labelled by the method of Claim 2, comprising taking a sample of the expired breath of said subject and determining the relative proportions, in said sample, of two or more of said isotopes.
5. A method according to Claim 4 or claim 5 wherein the presence and proportion of said or the respective said isotope is determined by spectroscopy, for example by infrared spectroscopy.
6. Apparatus for determining the presence of, or concentration in, the blood of a human or animal subject, of a drug or other substance labelled by the method of any of Claims 3 to 5, the apparatus including a sensor unit, including an enclosure for a sample of expired breath from said subject, a source of infrared radiation mounted for emitting infrared radiation into said enclosure, an infrared detector mounted for detecting radiation emitted by said source and which has traversed at least a part of the interior of said enclosure, said infrared detector being capable of detecting selectively infrared radiation within the absorption band of carbon dioxide constituted with a predetermined rare isotope of carbon or oxygen and of discriminating such radiation from infrared radiation within the absorption band of carbon dioxide constituted with the most common isotopes of carbon and oxygen, and means for receiving signals from said detector or detectors and providing output information relating to the presence or concentration of said substance.
7. A method for the determination of a drug or other substance in the blood of a human or animal subject, including the steps of -a priori addition or substitution to said drug or other substance of at least one rare isotope of carbon or oxygen being element of at least one metabolisable compound -proximity sampling of expired air from said subject with recognition capability -analysing said breath sample by means of infrared spectroscopy with respect to carbon dioxide with different isotopes.
8. A method according to claim 1 in which said determination is quantitative, e.g. by relating said constitution to the concentration of said substance.
9. A method according to claim 3, 4 or 8 in which said sampling involves the positioning of a multivariable sensor unit in the vicinity of nose/mouth region of said subject, allowing said sample to flow through and past said sensor unit.
10. A method according to any of claims 1, 2 or 7 in which said substance includes at least one agent known to influence central brain or nervous system functions.
11. A method according to claim 1, 2 or 7 in which said substance and compound are identical.
12. A method according to claim 1, 7, 10 or 11 in which said isotope is 13C or 180.
13. A method according to Claim 2, 7, 10 or 11 in which said compound is constituted with respective enriched contents of 13C and 180
14. A method according to claim 3, 4, 5 or 7 to 9 including, multivanable sensing of specific characteristics of expired air, including time variation profiles of one or more of flow velocity, temperature, humidity, and carbon dioxide concentration, and using the result to determine the validity or otherwise of the sample.
15. A method according to claim 3, 4, 5, 7 to 9 or 14 including determination of concentration of said substance, by applying an algorithm involving absolute measurement of background and breath sample carbon dioxide concentration, and estimated or independently determined alveolar carbon dioxide concentration.
16. A method according to claim 7, 10, 11 or 13 in which a plurality of said isotopes is used in a coding manner for identification or categorisation of said substance.
17. A method according to claim 7 or claim 16 in which said constitution is determined by measuring a ratio of one said isotope to another.
18. A method according to claim 17 in which said ratio is correlated to the concentration of said substance.
19. A method according to claim 1, 7 or 11 to 13 in which said compound comprises a carbohydrate, adapted to said agent with respect to metabolic rate.
20. A method according to claim 3, 4, 7, 8 9 or 14 to 18 including measurement of emitted and background carbon dioxide concentration within said sample.
21. A method according to claim 3, 4, 7 to 9, 14 to 18 or 20 including the instruction of said subject to expire against a specified sensing area.
22. A method according to claim 3, 4, 7 to 9, 14 to 18 or 20 in which said breath sample is acquired passively without cooperation of said subject.
23. Method according to claim 7, 21 or 22 in which said subject is a vehicle driver.
24. A method according to claim 7 or claim 23 in which said taking of breath sample is connected in time to the starting of a vehicle, said connection being physically defined by necessary starting procedure, such as unlocking or activating an ignition mechanism.
25. A method according to claim 24 in which the spectroscopic output corresponding to isotopic constitution is the determining factor of locking/unlocking mechanism.
26. A method according to claim 7, 21 or 22 in which said spectroscopy is combined by direct determination of volatile substance, e.g. alcohol, by detecting absorption specific to said volatile substance.
27. A method according to claim 7 in which said spectroscopy includes the passage of said breath sample through a plurality of beams of infrared radiation enabling the analysis of weak absorption due to low concentration levels of isotope labelled carbon dioxide.
28. A method according to claim 7 in which the spectroscopic output corresponding to isotopic constitution is used as measure of blood concentration of said substance.
29. Apparatus for the determination of a drug or other substance in the blood of a subject, said drug or other substance or an additive to it being enriched with at least one rare isotope of carbon or oxygen, including- -a sensor unit adapted for collection of a proximity breath sample from said subject -said sensor unit including at least one source and one detector of infrared radiation -said detector being specifically adapted to detect infared radiation within the absorption band of carbon dioxide with said isotope -at least one electronic unit for the analysis of signals from said detector, with respect to carbon dioxide with different isotopes, and providing output information relating to the presence of said drug or other substance.
30. Apparatus according to claim 6 or claim 29 in which said sensor unit includes concave surfaces adapted to multiple reflections and collimation of said radiation, having reflectance exceeding 0.99.
31. Apparatus according to claim 6, 29 or 30 including a plurality of detectors being positioned at different path lengths of said radiation, whereby a transmission band of a detector at short path length will reflect said radiation allowing a longer path length for a second detector.
32. Apparatus according to any of claims 6 or 29 to 31 in which said sensor unit includes at least one shutter mechanism allowing, in its opened condition, air flow to pass said radiation.
33. Apparatus according to any of claims 6 or 29 to 32 in which said sensor unit is adapted for positioning in proximity with the mouth/nose region of said subject.
34. Apparatus according to any of claims 6 or 29 to 33 including at least one fan to enhance air flow through said sensor unit.
35. Apparatus according to any of claims 6 or 29 to 34 including at least one sensor for the measurement of temperature, air flow velocity, or relative humidity.
36. Apparatus according to any of claims 29 to 35 in which said electronic unit includes at least one microprocessor.
37. Apparatus according to any of claims 29 to 36 in which said electronic unit includes at least one application specific integrated circuit.
38. Apparatus according to any of claims 29 to 37 including a display/communication unit.
39. A drug or other substance labelled by the method of claim 1 or claim 2.
40. Apparatus as claimed in Claim 6 wherein said sensor unit includes a plurality of infrared detectors mounted for detecting radiation emitted by said source and which has traversed at least a part of the interior of said enclosure, each said infrared detector being capable of detecting infrared radiation within a respective waveband.
41. Apparatus according to Claim 6 or Claim 40 including at least one reflector in said enclosure arranged so that infrared radiation from said source will pass, in said enclosure, to said reflector, to be reflected thereby before reaching said detector.
42. Apparatus according to Claim 41 including a plurality of reflectors in said enclosure arranged so that infrared radiation from said source can undergo multiple reflections in said enclosure before reaching a said detector.
43. Apparatus according to Claim 41 or Claim 42, wherein said reflector includes concave reflectors adapted to collimate said infrared radiation.
44. Apparatus according to any of Claims 41 to 43 wherein a plurality of said detectors is provided, specific to respective IR wavelength bands.
45. Apparatus according to Claim 42 or Claim 43 including a plurality of said detectors specific to respective infrared wavelength bands and at least one said detector being reflective for infrared wavelength bands outside of its specific detection band, the arrangement being such that where infrared radiation originating from said source strikes said one detector, at least a significant part of such radiation which is outside the specific waveband of that detector will be reflected by that detector to reach, directly or after one or more reflections, a further said detector.
46. A method of labelling a drug or other substance for human or animal consumption, substantially as hereinbefore described.
47. A method of identifying the presence, in a human or animal subject, of a drug or other substance substantially as hereinbefore described.
48. Apparatus for determining the presence or concentration in a human or animal subject of a drug or other substance substantially as hereinbefore described with reference to the accompanying drawings.
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