[0083]Reference is now made to FIG. 1, which is a schematic view of a compact high sensitivity breath analyzer constructed and operative in accordance with a preferred embodiment of the present invention. The breath analysis is performed by a sensitive non-dispersive infra-red spectrophotometer, capable of discriminating between the isotopically labeled CO2 and the natural CO2 in the breath sample being analyzed.
[0084]The patient is connected to the breath analyzer by means of the inlet tube 10, which can be either a nasal cannula or a breathing tube. Such a cannula includes a section of tubing, usually plastic, with two prongs. Each prong is inserted into a nostril and the cannula is then connected to the measuring instrument. As the patient exhales through the nose, a sample of the exhaled air flows through the cannula to the analyzer. A preferred type of breathing tube is constructed of a hollow tube held in the patient's mouth, through which he blows a number of breaths. In the center of the tube is located a small tube whose opening is positioned such that it samples the breath flowing through the main tube, and conveys it through a small flexible plastic inlet tube to the breath analyzer.
[0085]The patient's breath is inputted to the breath inlet conduit 11, which could also incorporate a breath collection chamber for accumulating a number of breaths, from where the breath sample is conveyed to the breath analysis chambers 14, 15 of a non-dispersive infra-red spectrophotometer. The breath analysis chamber could also be part of the breath collection chamber, such that the analysis is performed in the breath collection chamber. The spectrometer preferably uses gas discharge lamp sources 12, 13, such as those provided by Spegas Industries of Jerusalem, Isreal. Such lamps enclose an enriched and nearly pure filling of 12CO2 or 13CO2 respectively. By excitation of an RF field, the gas discharge generates an emission which is typical of the CO2 enclosed within the lamp. The average width of the emission lines from these lamps is only 0.006 cm−1, such that there is little cross-sensitivity. It is possible to detect a change in isotopic gas concentration of the order of a few parts per million.
[0086]In order to obtain the ratio of 13CO2/12CO2 of a breath sample, the absorption of the sample is measured with a 12CO2 lamp and a 13CO2 lamp as light source. Such lamps have been used in a spectro-photometer described in U.S. Pat. No. 5,063,275 incorporated herein by reference. The output signals are measured on an infra-red detector 16. The signals from this detector are processed electronically by the analyzer's electronics unit 17, and the resulting ratio output signal passed to the PC 18 for analysis by the system software according to the requirements of the measurement program.
[0087]FIG. 2A is a schematic view of a patient 20 connected by means of a nasal cannula 22, to a breath test analyzer 21 constructed and operative according to a preferred embodiment of the present invention. A laptop PC 23 is used for controlling the analyzer. The compact size of the analyzer is apparent, when compared with the size of the laptop PC which stands on it. FIG. 2B is similar to FIG. 2A, except that the patient 20 is connected to the breath analyzer 21 by means of a blowing tube 24 which he puts into his mouth whenever sample breaths are required.
[0088]FIGS. 3A to 3D show schematically the various aspects of a complete breath test cycle in the most common mode of operation. The test cycle is shown being performed using a nasal cannula 30 for the breath sampling, but the same procedure can be performed with the samples collected by means of a mouth tube. In the most common mode of operation, the breath test analyzer senses a patient's breath before ingestion of an isotopically labeled substance, analyzes the patient's exhaled breath for the percentage of the isotopically labeled gas in the total exhaled gas of that composition in order to obtain a baseline reading, performs at least one similar analysis after ingestion of an isotopically labeled substance, and provides an indication of the increased presence of the isotopically labeled by-products characteristic of a medical condition, within a time period following the last sensing which is less than the difference in time between the first sensing and the last sensing. The analyses of the patient's exhaled breath may be performed directly, or on samples of exhaled breath collected in a breath collection chamber.
[0089]In FIG. 3A, the patient 31 is shown at time t0 providing the reference breath before taking the isotopically labeled substance suitable for the specific test to be performed. This reference breath enables the analyzer to establish a baseline level for the percentage of the isotopically labeled gas in the breath of the patient without the addition of any products of the isotopically labeled substance ingested.
[0090]FIG. 3B shows the patient at time t1 drinking the isotopically labeled substance 32, shown in this instance in a glass of liquid.
[0091]FIG. 3C is a view of the patient at time t2 providing continuous breath samples for the analyzer through the nasal cannula or breathing tube. The analyzer itself measure the level of the isotopically labeled gas sample at regular intervals, and under the control of the PC, calculates the ratio of the isotopically labeled gas level to that of the naturally occurring gas of the same species foe very breath sample, and subtracts the ratio from the baseline reference breath level. These ratios, known as the delta-over-baseline values, are fitted to a curve of ratio as a function of time, from which the results of the test can be deduced. Each measurement takes a number of seconds, such that the analyses of the exhaled breath are effectively performed on quasi-continuous basis. This is one of the main features which differentiates the procedure possible using a breath analyzer constructed and operative according to the present invention from all prior art procedures.
[0092]The technique proposed here, of performing a multiplicity of analyses or measurements under control of the measurement instrument itself, is applicable to a wide range of medical instrumentation. This technique allows the construction of an analyzer or measurement instrument, wherein the termination point of the test procedure being performed is determined automatically according to the results of the analyses or tests obtained in real time. The termination of the test procedure can refer not only to the termination of the taking of samples form the patient, but also to the termination of the analysis of such samples taken from the patient at an earlier time.
[0093]In the breath analyzer according to a preferred embodiment of the present invention, the multiplicity of analyses on substantially every successive breath, or on frequent samples of collected breaths, allows the analyzer to determine the termination point of the test procedure according to the results obtained in real time. In this most common mode of operation, the measurement system obtains for every breath sample, the ratio of the level of the isotopically labeled gas to that of the naturally occurring gas being analyzed. This ratio is then compared with the baseline ratio obtained at time t0 in order to determine whether a positive result is being obtained. The delta-over-baseline level chosen to define a positive result is dependent on the specific test, and its sensitivity. The method of comparison of the measurement of one breath sample with the previous one can preferably be performed by means of fitting the results to a curve by one of the standard digital curve fitting methods, and determining the derivative of the curve at every new measurement point, or by simple repetitive difference measurements.
[0094]FIG. 3D shows the situation at time t3 when the test has been completed and analysis terminated, either because the desired percentage increase in the level of the isotopically labeled gas has been reached, or because a time limit has been reached without a definitive delta-over-baseline percentage increase of gas having been reached. The display screen of the PC 33 shows the results of the analysis prior to printout. Since the test is complete, the patient 31 has removed the sampling device, and the patient's physician 32 is generally able to give him an immediate diagnosis, or at least the result of the test.
[0095]FIGS. 4A to 4C show the various stages of a complete breath test cycle according to another preferred embodiments of the present invention, where the sampling analyses are performed at times following the ingestion of the isotopically labeled substance, without the need for a baseline measurement. This mode of operation is possible only because of the on-line nature of the measurements which the present invention enables. The method of comparison of the measurement of one breath sample with the previous one, can again be preferably performed by means of fitting the results to a curve by one of the standard digital curve fitting methods, and determining the derivative of the curve at every new measurement point.
[0096]In FIG. 4A, the patient 41 is shown at time t0 ingesting the isotopically labeled substance, in this example in a glass of liquid.
[0097]In FIG. 4B, the patient is shown at time t1 providing continuous breath samples for the analyzer to collect through the nasal cannula or breathing tube. The analyzer itself is measuring the level of the isotopically labeled gas sample at regular intervals, and under the control of the PC, is continuously calculating the ratio of the isotopically labeled gas level as compared to that of the previous measurement, in order to obtain a comparative reading of the change in the percentage level of the isotopically labeled gas from reading to reading as the breath test proceeds. In a preferred embodiment of the present invention, the analyzer program performs digital curve fitting analysis, as described above, in order to monitor the progress of the test.
[0098]FIG. 4C shows the situation at time t2 when the test has been completed and analysis terminated, either because the desired percentage increase in the level of the isotopically labeled gas has been reached, or because a time limit has been reached without a definitive percentage change having been detected. The display screen of the PC 43 shows the results of the analysis prior to printout. Since the test is complete, the patient has removed the sampling device. As previously, the patient's physician 44 is able to advise him immediately of the result of the test.
[0099]The above mentioned operational modes of breath analyzing, and their methods of termination are functionally shown in the flow chart shown in FIG. 5, which is shown for the case when a baseline measurement is made before ingestion by the patient of the isotopically labeled substance. If no baseline measurement is made, the initial stage 1 of the flow chart is omitted, and in place of stage 4, an alternative calculation must be made, such as taking the difference between successive readings.
[0100]FIG. 6 shows graphs of the increase in ratio of the isotopically labeled gas as a function of time as the breath test proceeds, for a number of different patients. The actual results shown were obtained using a breath analyzer constructed and operative according to a preferred embodiment of the present invention, to detect 13CO2 in the breath of patients after ingestion of 13C-labeled urea, for the detection of Helicobacter pylori in the upper gastric tract. In the graphs shown, a value of 5 is chosen as the delta-over-baseline level to define a positive result. Patient number 1 thus has a negative result. Patients 2 and 3 show similar measurement curves, and it can be established after about 3 minutes that both of them have positive results. Patient number 4 has such a strong reaction to the ingest of the isotopically labeled substance that it becomes possible to provide a positive indication about his medical condition within 1 minute, and if the derivative method is used, in even less time.
[0101]The breath analyzer as proposed in the present invention is also operable in a number of different test modes, each with its own software package, for performing any breath test in which the patient ingests an isotopically labeled substance which produce isotopically labeled by-products detectable in th patients breath. Examples of a number of such breath tests are mentioned in the Background to the Invention section above.
[0102]It is clear that in all of the above preferred modes of operation, that the present invention provides a number of significant advantages over measurement procedures using previously available breath analyzers. Firstly, the exhaled breath of the subject can be analyzed in real time, so that there is relatively little delay between the time the specific gastro-intestinal reaction with the isotopically labeled substance takes place, and the time such activity is measured. Secondly, the samples of exhaled breath are obtained rapidly and are analyzed immediately in a manner which substantially increases the accuracy of the results. Thirdly, since multiple samples are obtained, the accuracy of the test is increased. Fourthly, there is less statistical error, since many samples are collected before a positive conclusion is reached. Fifthly, since samples are preferably collected until a preset level of accuracy is reached, ambiguous results can be substantially eliminated, preventing the need for repeat testing. Sixthly, since the analyzer itself makes the decision as to when sufficient samples have been analyzed to provide a clear indication of a medical condition, physiological differences between the response of different people to the various breath tests may be compensated for.
[0103]A further significant advantage of the use of the breath analyzer described in the present invention is that it increases patient compliance to a level that makes preventive medicine test procedures very acceptable. Furthermore, because of the considerably reduced costs of these tests, mass screening programs for a number of common gastro-enterological disorders could become more acceptable to health authorities and hence more widespread.
[0104]It will be appreciated by persons skilled in the art that the present invention is not limited by what has been particularly shown and described hereinabove. Rather the scope of the present invention includes both combinations and sub-combinations of various features described hereinabove as well as variations and modifications thereto which would occur to a person of skill in the art upon reading the above description and which are not in the prior art.
