U.S. patent number RE38,728 [Application Number 10/122,341] was granted by the patent office on 2005-04-19 for breath test analyzer.
This patent grant is currently assigned to Oridion Medical, LTD. Invention is credited to Ephraim Carlebach, Daniel E. Katzman.
United States Patent |
RE38,728 |
Katzman , et al. |
April 19, 2005 |
Breath test analyzer
Abstract
A breath test analyzer, which analyzes exhaled breadths of a
patient for isotope labeled products generated in the patient's
body after ingestion by the patient of an isotope labeled
substance, where the presence of these isotope labeled products
provide an indication of a medical condition in the patient. The
analyzer uses a very sensitive infra-red spectrophotometer, which
enables it to continuously collect and analyze multiple samples of
the patient's breath, and process the outputs in real time, while
the patient is still connected to the analyzer, such that a
definitive result is obtained within a short time, such as the
order of a few minutes. The breath test analyzer is sufficiently
small in that it can be easily accommodated in the office of a
physician. The breath test analyzer can be utilized for a number of
diagnostic breath tests, according to the isotope labeled substance
ingested by the patient and the gases detected in the patient's
breath.
Inventors: |
Katzman; Daniel E. (Kfar Bin
Nun, IL), Carlebach; Ephraim (Ra'anana,
IL) |
Assignee: |
Oridion Medical, LTD
(Jerusalem, IL)
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Family
ID: |
34437579 |
Appl.
No.: |
10/122,341 |
Filed: |
April 16, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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805415 |
Feb 26, 1997 |
6067989 |
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Reissue of: |
151135 |
Sep 10, 1998 |
06186958 |
Feb 13, 2001 |
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Foreign Application Priority Data
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Sep 11, 1997 [IL] |
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121751 |
Sep 17, 1997 [IL] |
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121793 |
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Current U.S.
Class: |
600/532; 128/898;
424/84; 436/811; 600/529 |
Current CPC
Class: |
A61B
5/0836 (20130101); G01N 21/3504 (20130101); G01N
33/0006 (20130101); A61B 5/7239 (20130101) |
Current International
Class: |
A61B
5/083 (20060101); A61B 5/08 (20060101); G01N
21/31 (20060101); G01N 21/35 (20060101); G01N
33/00 (20060101); A61B 005/08 () |
Field of
Search: |
;600/529-538,500-504
;128/897-898 ;436/181,811 ;422/83-84 ;250/339.03,345,343-344 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0 204 438 |
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Oct 1986 |
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EP |
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0 206 625 |
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Aug 1988 |
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EP |
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0 206 626 |
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Aug 1988 |
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EP |
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0 584 897 |
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Mar 1994 |
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EP |
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0 672 383 |
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Sep 1995 |
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EP |
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WO 95/11672 |
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May 1995 |
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WO |
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WO 97/14029 |
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Apr 1997 |
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WO |
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|
Primary Examiner: Hindenburg; Max F.
Assistant Examiner: Astorino; Michael
Attorney, Agent or Firm: Morgan & Finnegan, LLP
Parent Case Text
CROSS REFERENCE TO RELATED APPLICATION
This is a continuation-in-part of commonly-assigned U.S. patent
application Ser. No. 08/805,415, filed Feb. 26, 1997 now U.S. Pat.
No. 6,067,989.
Claims
We claim:
1. A method of breath testing in which samples collected from
exhaled breaths of a subject are analyzed by means of an analyzer,
for a product of an isotopically labeled substance ingested by said
subject, and comprising the steps of: performing a first analyzing
of a first sample collected from at least a first exhaled breath of
said subject; performing a second analyzing of a second sample
collected from at least a second exhaled breath of said subject, at
least said second sample being collected following the subject's
ingestion of said substance; and providing an indication of a
change in the level of said isotope labeled product in said second
sample, while said subject is coupled to said analyzer.
2. The method of claim 1 wherein at least one of said first sample
collected from at least a first exhaled breath of a subject and
said sample collected from at least a second exhaled breath of said
subject is at least one essentially complete exhaled breath of said
subject.
3. The method of claim 1, wherein the first sample is collected
prior to the subject's ingestion of the isotopically labeled
substance, and the second sample is collected following the
subject's ingestion of said isotopically labeled substance.
4. The method of claim 1, wherein both the first and second samples
are collected following the subject's ingestion of said
isotopically labeled substance.
5. The method of claim 1, wherein said second sample is exhaled
following analysis of said first sample.
6. The method of claim 1, and further comprising the step of
coupling the subject to the analyzer substantially continuously
from the analyzing of said first sample to the analyzing of said
second sample.
7. The method of claim 1, and further comprising the step of
coupling the subject to the analyzer substantially continuously
from the collection of said first sample to the collection of said
second sample.
8. The method of claim 1, wherein the subject is coupled to said
analyzer by means of a nasal cannula.
9. The method of claim 1, wherein the first analyzing of said
subject's exhaled breath takes place prior to said product being
detectable in said subject's breath and the second analyzing of
said subject's exhaled breath takes place once said product could
be detectable in said subject's breath.
10. The method of claim 1, and further comprising the step of
determining that said test has a clinically significant outcome in
accordance with the results of the ongoing analyses of said
samples.
11. The method of claim 1, characterized in that said samples are
collected by means of a nasal cannula.
12. The method of claim 1 and further comprising the steps of:
fitting the results of the analyzing of successive samples to a
curve; and determining from said curve whether said test has a
clinically significant outcome.
13. The method of claim 12 wherein the derivative of said curve is
used for said determining.
14. The method of claim 1, wherein the collection of said samples
is discontinued according to the results of the ongoing analyses of
said samples.
15. The method of claim 1, wherein the analyzing of said samples is
discontinued according to the results of the ongoing analyses of
said samples.
16. A method of breath testing comprising the steps of: collecting
samples of a subject's exhaled breath substantially continually;
analyzing said samples of a subject's exhaled breath for a product
of an isotope labeled substance ingested by said subject; and
providing an indication of the outcome of said analyzing in
accordance with the results of the ongoing analyses of said
breaths.
17. The method of claim 16 wherein said analyzing is performed
substantially continually.
18. The method of claim 17, wherein the step of providing an
indication of the outcome of said analyzing comprises the step of
determining changes in an isotopic ratio in said samples of exhaled
breath.
19. The method of claim 17, wherein said samples of exhaled breath
are substantially every successive breath.
20. The method of claim 17, wherein said samples of exhaled breath
are frequent samples of collected breath.
21. The method of claim 17, and further comprising the step of
coupling the subject to the analyzer.
22. The method of claim 21, wherein the step of coupling the
subject to said analyzer comprises the step of coupling the subject
to said analyzer by means of a nasal cannula.
23. The method of claim 17 and further comprising the steps of:
fitting the results of the analyzing of successive samples to a
curve; and determining from said curve whether said test has a
clinically significant outcome.
24. The method of claim 17, wherein the collection of said samples
is discontinued according to the results of the ongoing analyses of
said samples.
25. The method of claim 17, wherein the analyzing of said samples
is discontinued according to the results of the ongoing analyses of
said samples.
26. The method of claim 16, wherein the step of providing an
indication of the outcome of said analyzing comprises the step of
determining changes in an isotopic ratio in said samples of exhaled
breath.
27. The method of claim 16, wherein said samples of exhaled breath
are substantially every successive breath.
28. The method of claim 16, wherein said samples of exhaled breath
are frequent samples of collected breath.
29. The method of claim 16, and further comprising the step of
coupling the subject to the analyzer.
30. The method of claim 29, wherein the step of coupling the
subject to said analyzer comprises the step of coupling the subject
to said analyzer by means of a nasal cannula.
31. The method of claim 16 and further comprising the steps of:
fitting the results of the analyzing of successive samples to a
curve; and determining from said curve whether said test has a
clinically significant outcome.
32. The method of claim 31 wherein the derivative of said curve is
used for said determining.
33. The method of claim 16, wherein the collection of said samples
is discontinued according to the results of the ongoing analyses of
said samples.
34. The method of claim 16, wherein the analyzing of said samples
is discontinued according to the results of the ongoing analyses of
said samples.
35. A breath test analyzer which substantially continually collects
samples of a subject's exhaled breath for analysis for a product of
an isotope labeled substance ingested by said subject, and
determines that said test has a clinically significant outcome in
accordance with the results of the ongoing analyses of said
samples.
36. A breath test analyzer according to claim 35 and comprising: a
breath analysis chamber; a breath inlet conduit for conveying said
exhaled breath from said subject to said breath analysis chamber;
and a gas analyzer operative to analyze gas in said breath analysis
chamber and to conduct a first analyzing of a first sample
collected from at least a first exhaled breath of said subject, and
a second analyzing of a second sample collected from at least a
second exhaled breath of said subject, at least said second breath
being collected following ingestion by the subject of said isotope
labeled substance.
37. A breath test analyzer according to claim 36, wherein at least
one of said first sample collected from at least first exhaled
breath of a subject and said second sample collected from at least
a second exhaled breath of said subject is at least one essentially
complete exhaled breath of said subject.
38. A breath test analyzer according to claim 36, wherein the first
sample is collected prior to the subject's ingestion of the
isotopically labeled substance, and the second sample is collected
following the subject's ingestion of said isotopically labeled
substance.
39. A breath test analyzer according to claim 36, wherein both the
first and the second samples are collected following the subject's
ingestion of said isotopically labeled substance.
40. A breath test analyzer according to claim 36, wherein said
second sample is exhaled following analysis of said first
sample.
41. A breath test analyzer according to claim 36 and further
comprising a breath collection chamber and a gas conduit for
conveying a sample of gas from said breath collection chamber to
said breath analysis chamber.
42. A breath test analyzer according to claim 41, wherein said
breath analysis chamber and said breath collection chamber are
combined, such that the analyzing of said samples takes place
within said breath collection chamber.
43. A breath test analyzer according to claim 36, and wherein said
gas analyzer comprises a gas discharge tube gas analyzer.
44. A breath test analyzer according to claim 36, and wherein said
gas analyzer comprises an infra-red source which emits a
discontinuous spectrum.
45. A breath test analyzer which analyzes a first sample collected
from at least a first exhaled breath of a subject and a second
sample collected from at least a second exhaled breath of said
subject for a product of an isotope labeled substance ingested by
said subject, while the subject is coupled to the breath test
analyzer.
46. A breath test analyzer according to claim 45, and comprising: a
breath collection chamber; a breath analysis chamber; a breath
inlet conduit for conveying said exhaled breath from said subject
to said breath collection chamber; a gas chamber for conveying a
sample of gas from said breath collection chamber to said breath
analysis chamber; and a gas analyzer to analyze gas in said breath
analysis chamber for said product of said isotope labeled substance
ingested by said subject.
47. A breath test analyzer according to claim 46, wherein at least
one of said first sample collected from at least a first exhaled
breath of a subject and said second sample collected from at least
a second exhaled breath of said subject is at least one essentially
complete exhaled breath of said subject.
48. A breath test analyzer according to claim 46, wherein the first
sample is collected prior to the subject's ingestion of the
isotopically labeled substance, and the second sample is collected
following the subject's ingestion of said isotopically labeled
substance.
49. A breath test analyzer according to claim 46, wherein both the
first and the second samples are collected following the subject's
ingestion of said isotopically labeled substance.
50. A breath test analyzer according to claim 46, wherein said
second sample is exhaled following analysis of said first
sample.
51. A breath test analyzer according to claim 46, wherein said
breath analysis chamber and said breath collection chamber are
combined, such that the analyzing of said sample of gas takes place
within said breath collection chamber.
52. A breath test analyzer according to claim 46, and wherein said
gas analyzer comprises a gas discharge tube gas analyzer.
53. A breath test analyzer according to claim 46, and wherein said
gas analyzer comprises an infra-red source which emits a
discontinuous spectrum.
Description
FIELD OF THE INVENTION
The invention relates to the field of analyzers of the breath of
patients to detect the gastric by-products of various diseases and
infections.
BACKGROUND OF THE INVENTION
Since the early 1950's, it has been known that the presence of
bacterial organisms in the gastro-intestinal tract is accompanied
by a high concentration of urease, which hydrolyses urea to form
carbon dioxide and ammonia. These gases are detected in the
subject's blood stream and ultimately, in the subject's breath, if
he had been administered isotopically labeled urea. Such early
results appear in reviews published by R. W. VonKorff et al. in Am.
J. Physiol., Vol. 165, pp. 688-694, 1951, and by H. L. Kornberg and
R. E. Davies in Physiol. Rev., Vol. 35, pp. 169-177, 1955.
Since these early experiments, it has been found that there exist,
in addition to the bacterial infections initially studied, a
significant number of medical conditions associated with disorders
of the gastro-intestinal tract or metabolic or organ malfunctions,
which are capable of detection by means of such simple breath
tests. These breath tests are based on the ingestion of an
isotopically labeled sample, which is cleaved by the specific
bacteria or enzyme action being sought, or as a result of the
metabolic function being tested, to produce labeled gaseous
by-products. These by-products are absorbed in the blood stream,
and are exhaled in the patient's breath, where they are detected by
means of external instrumentation.
Though the early experiments were performed using the radioactive
carbon-14 atom, the most commonly used atom in such test procedures
today is the carbon-13 atom, which is a stable, non-radioactive
isotope, present in a proportion of about 1.1% of naturally
occurring carbon. The labeled substance contains the functional
compound to be used in the test, with almost all of its .sup.12 C
atoms replaced by .sup.13 C atoms. Enrichments of up to 99% of
.sup.13 C are typically used. This compound is cleaved
enzymatically under the specific conditions being tested for,
either during gastric absorption, or during gastro-intestinal
transit, or during its metabolisation in other organs of the body.
The cleavage product produced is .sup.13 CO.sub.2, which is
absorbed in the bloodstream and exhaled in the patient's breath
together with the CO.sub.2 naturally present. The breath sample is
then analyzed, usually in a mass spectrometer or a non-dispersive
infra-red spectrometer. The increased presence of .sup.13 CO.sub.2
is determined, as compared with the expected 1.1% of total CO.sub.2
in healthy patient's breath, resulting from the metabolism of
carbon compounds with the naturally occurring level of
approximately 1.1% of carbon-13.
Though carbon-13 is the most commonly used isotropic replacement
atom in such breath tests, other atoms which have been used include
nitrogen-15 and oxygen-18. In addition, carbon-14 is still used in
some procedures, but being radioactive, there are severe
disadvantages both to its ingestion by the patient, and because of
the storage, handling and disposal precautions required at the test
site.
There are an increasing number of metabolic disorders, bacterial
infections and organ malfunctions which can be diagnosed using such
labeled substances for enabling breath tests. New applications are
being proposed continuously, but among the more common currently in
use are: (a) The detection of Helicobacter pylori infections
gastric and duodenal tracts, by means of the ingestion of .sup.13
C-labeled urea and breath detection of an increased level of
.sup.13 CO.sub.2. It is also feasible to use .sup.15 N-labeled
urea, and to detect nitrogen-15 ammonia .sup.15 NH.sub.3 in the
breath, but this test format is not currently in use. Gastric and
duodenal ulcers, non-ulcer dyspepsia and gastritis have been shown
to be related to the presence of Helicobacter pylori infections.
(b) The detection of fat malabsorption, such as is present in
steatorrhea and Crohn's disease, by means of the ingestion of
.sup.13 C-labeled triolein or tripalmitin, and breath detection of
an increased level of .sup.13 CO.sub.2. (c) Liver function
evaluation (by monitoring the P450 enzyme activity), liver disease
severity and detoxification activity by means of the ingestion of
.sup.13 C-labeled aminopyrin, methacitin or caffeine citrate
(depending on the specific function being tested) and breath
detection of an increased level of .sup.13 CO.sub.2. (d) The
measurement of hepatic mitochondrial activity by means of the
ingestion of .sup.13 C-labeled octanoic acid, and breath detection
of an increased level of .sup.13 CO.sub.2. (e) A check of hepatic
mitochondrial function efficiency by means of the ingestion of
.sup.13 C-labeled ketoisocaproic acid, and breath detection of an
increased level of .sup.13 CO.sub.2. (f) The quantification of
functional liver mass by means of the ingestion of .sup.13
C-labeled galactose, and breath detection of an increased level of
.sup.13 CO.sub.2. (g) The testing of gastric emptying function by
means of the ingestion of .sup.13 C-labeled octanoic acid for the
emptying rate of solids, or .sup.13 C-labeled sodium acetate for
the emptying rate of liquids, and breath detection of an increased
level of .sup.13 CO.sub.2. (h) The determination of exocrine
pancreatic insufficiency by means of the ingestion of a .sup.13
C-labeled mixed triglyceride sample such as octanoil-1,3-distearin
for checking the lipase function, or a .sup.13 C-labeled sample of
corn starch for checking the amylase function, and breath detection
of an increased level of .sup.13 CO.sub.2. The mixed triglyceride
test is one of the tests used for detecting cystic fibrosis. For
the evaluation of the digestion and absorption of medium-chain
fatty acid triglycerides, .sup.13 C-labeled trioctanoin is used in
preference to the mixed triglyceride. (i) The detection of
bacterial overgrowth in the small intestine by means of the
ingestion of .sup.13 C-labeled glycolic acid or xylose, and breath
detection of an increased level of .sup.13 CO.sub.2. (j) The
testing of lactose or glucose intolerance, by means of the
ingestion of .sup.13 C-labeled lactose or glucose, and measurement
of the speed of appearance of an increased level of .sup.13
CO.sub.2 in the breath.
Previously available tests for these illnesses generally involve
drastically more invasive procedures, and are therefore much less
patient compliant than the simple breath tests described above.
Such procedures include gastro-endoscopy, with or without the
removal of a tissue biopsy, biopsies or organs suspected of
malfunction, blood tests to detect antibodies to suspected
bacteria, blood biochemistry tests following ingestion of suitable
compounds, and radiological tests, whether by gamma imaging of the
organ function following ingestion or injection of a suitable gamma
emitter, or by direct X-ray imaging or CT scanning. Furthermore,
there are other disadvantages to the previously used tests, such as
the fact that they rarely give real time information about the
organ function or status being observed. In some cases, such as in
the case of blood tests for antibodies of bacterial infections,
they give historic results which may have no therapeutic relevance
currently, since antibodies to a particular bacterium can remain in
the body for up to 2 years from the date that the infection has
been eradicated.
The above mentioned breath tests are completely non-invasive, and
are executed in comparative real time, so that they have a great
advantage over previously available tests, and their use is gaining
popularity in the medical community, as evidenced by the fact that
suitable isotopically labeled substances are currently available
commercially from a number of sources.
However, in spite of the advantages of isotopically labeled breath
tests, current instrumentation and procedures for performing it
sill have a number of serious drawbacks, which continue to limit
its usefulness. The major disadvantage, which becomes apparent when
a review of prior art breath test performance techniques and
instrumentation is performed, is that none of the currently used
techniques are sufficiently rapid to permit immediate measurement
of the requested parameter, allowing a diagnosis for the patient in
a single short visit to the physicians office.
One of the early breath tests to be proposed is that for detecting
the presence of the Helicobacter pylori bacterium in the upper
gastro-intestinal tract, by means of the oral administration of
isotopically labeled urea, and the detection of the presence of
isotopically labeled carbon dioxide or ammonia in the patient's
breath resulting from the hydrolysis of the urea by the urease
which always accompanies H. pyroli infections. This method is
described by Marshall in U.S. Pat. No. 4,830,010. In this
implementation of the test, the breath of the subject is collected,
preferably from 10 to 120 minutes after administration of the
substance, in a balloon inflated by the subject, and from there is
transferred to a storage and transport container, such as a
Vacutainer.RTM. sold by Becton-Dickenson Inc.
According to a method proposed by Marshall, the sample is then
analysed by mass spectrometry or by infra-red or nuclear magnetic
resonance spectroscopy, for the presence of isotopically labelled
CO.sub.2 resulting from the hydrolysis of the urea. If the
radioactive carbon-4 is used to label the urea, then the breath
sample is analysed by bubbling it through a scintillation solution,
which is transferred to a scintillation counter to determine the
presence of beta radiation in the exhaled breath specimen. Because
of the cost and complexity of the analysis instrumentation, in none
of the preferred methods described by Marshall is it suggested that
the analysis of the breath may be performed on site at the point
where the sample is taken from the patient. The subject must thus
wait at least ten minutes to give the sample, and must then wait
for the laboratory to return the results. Clearly this method
cannot be used to provide the results of the test within the
context of a single visit to the office of the physician.
In a recent article entitled "Minimum Analysis Requirements for the
Detection of Helicobacter pylori Infection by the .sup.13 C-Urea
Breath Test" by P. D. Klieg and D. Y. Graham, published in Am. J.
Gastroenterol., Vol. 88, pp. 1865-1869, 1993, a statistical study
of the reliability and minimum criteria for conducting this test is
presented. The breath analyses were again performed by gas isotope
ratio mass spectrometry at a remote site. Amongst their findings
are that breath sampling at 30 minutes after urea ingestion is
likely to lead to significantly less false-positive and
false-negative results, than sampling after 20 minutes, and that
sampling after 30 minutes is therefore their proposed protocol
time. They also conclude that "In the current environments of
clinical research and patient care, the costs and turnaround times
of CO.sub.2 isotropic abundance measurements continue as the major
barriers to commercial propagation of the .sup.13 C-urea breath
test."
In another described prior art method of executing the urea breath
test, Koletzko and co-workers describe the analysis of the exhaled
breath by means of an isotope-selective non-dispersive infrared
spectrometer [Koletzko et al., Lancet, 345:961-2, 1995]. Even using
such a sophisticated instrument, the subjects are still required to
wait 15 and 30 minutes for successive breath samples to be taken.
Such a long delay to obtain breath samples, as well as the long
wait between samples, is inconvenient and potentially reduces
patient compliance.
Furthermore, as in the previously mentioned prior art, the sample
or samples are collected from the patient and then sent to a
laboratory for analysis, causing a delay in the determination of
the results and forcing the subject to return to the office of the
physician to obtain the results. If the test does not yield
meaningful results, the entire process must be repeated again. The
requirement for multiple office visits potentially further reduces
patient compliance. The potential reduction in patient compliance
can have serious consequences, since Helicobacter pylori is
implicated by the World Health Organisation as a possible cause of
stomach cancer, in addition to its role in gastric and duodenal
ulcers.
The most rapid breath test currently proposed, the "Pytest" from
Tri-Med Specialities, Charlottesville, N.C., USA, takes about 10-15
minutes to perform but uses radioactive carbon-14
isotopically-labeled urea [D. A. Peura, et al., Am. J. Gastro.,
91:233-238, 1996]. The presence of .sup.14 CO.sub.2 in the
subject's exhaled breath is detected by direct beta counting. This
test thus has all the disadvantages of the use of radioactive
materials. Not only is the ingestion of radioactive materials
potentially hazardous, but it also restricts the test to large
testing centers which can handle such materials. Thus, the test
cannot be performed in the office of the average physician, so that
multiple office visits are again required.
Another recent prior art method which discusses implementations of
the .sup.13 C-urea breath test, is shown in PCT Application No.
WO97/14029, entitled "Method for Spectrometrically Measuring
Isotopic Gas and Apparatus thereof", applied for by the Otsuka
Pharmaceutical Company of Tokyo, Japan. In this application too,
the exhaled breath sample is transferred in sample bags from the
patient to the spectrometer, which, because of its cost, complexity
and size, has perforce to be installed in a central sample
collection laboratory, and not in the doctor's office or near the
patient's bed. The inventors in fact state that "The measurement of
such breath samples is typically performed in a professional manner
in a measurement organisation, which manipulates a large amount of
samples in a short time." This prior art proposes the use of one
breath sample before the administration of the urea, and another
after a lapse of 10 to 15 minutes.
Other prior art which describe sensitive analyzer systems for
measuring the isotopic ratios of .sup.13 CO.sub.2 to .sup.12
CO.sub.2 in a gaseous sample, such as is required in an exhaled
breath analyzer for performing the above mentioned breath tests,
includes U.S. Pat. No. 5,077,469, granted to W. Fabinski and g.
Bernhardt, which describes a double reference path non-dispersive
infra-red gas analyzer. A further development of such an instrument
described in European Patent Application No. EP 0 584 897 A1 can be
used to compare the two isotopic CO.sub.2 concentrations in the
exhaled breath by means of infra-red absorption measurements on two
IR-cells filled with gas from the same breath sample.
In U.S. Pat. Nos. 4,684,805 and RE 33493, granted to P. S. Lee, R.
F. Majkowski and D. L. Partin, an infra-red absorption spectrometer
is described for discriminating between the two isotopic CO.sub.2
molecules for the breath tests. Their spectrometer design uses lead
salt laser diodes as the source of radiation. Such laser diodes
have emission lines in the 4 .mu.m to 5 .mu.m wavelength region of
the infra-red spectrum, where the strongest CO.sub.2 absorption
lines are located. As a consequence, despite the lack of
temperature stability of such laser diodes, and the fact that they
must be operated at liquid nitrogen temperatures, their use enables
the spectrometer to achieve the high selectivity and sensitivity
required for breath test analysis.
U.S. Pat. No. 5,317,156, granted to D. E. Cooper, C. B. Carlisle
and H. Riris, describes an FMS (Frequency Modulation Spectroscopy)
laser absorption spectrometer for distinguishing between the week
.sup.12 CO.sub.2 and .sup.13 CO.sub.2 absorption lines in the 1.6
.mu.m infra-red region, where highly stable laser diodes are
available. Even though the CO.sub.2 lines are very weak in this
region, the stability of the GaAs laser diodes used as the source
in this range, and the sophisticated TTFMS (two-tone Frequency
Modulation Spectroscopy) technique used enables the inventors to
provide sufficient differentiation between the two isotopes of
CO.sub.2 that the spectrometer can be used in breath test
analysis.
In U.S. Pat. No. 5,394,236, granted to D. E. Murnick, an apparatus
for isotopic analysis of CO.sub.2 is described by means of laser
excited spectroscopy, utilising the optogalvanic effect to
differentiate between the light of different wavelengths.
Because of the need to provide high sensitivity and good mass
discrimination, all of the above described analysis systems are
complex in nature. They are therefore, costly to manufacture and
generally of large dimensions, making them suitable for commercial
exploitation only for large and high sample volume
installations.
A number of commercial companies offer complete systems for
performing breath tests for the detection and study of the various
gastro-enterologic conditions mentioned previously, using the
isotopically labeled substances commercially available.
The Alimenterics Company of Morris Plains, N.J., markets the
Pylori-Chek .sup.13 C-Urea breath test kit for use with its
LARA.TM. System, for detecting the presence of H. Pylori in the
gastro-intestinal tract. The company is developing kits for the
clinical use of the other breath tests mentioned above. Breath is
collected in a uniquely designed breath collection device, that
also serves to transport the sample to the LARA.TM. System. This
system, which stands for Laser Assisted Ratio Analyzer, is a
sophisticated infra-red spectrometer designed to provide the
sensitivity required to detect tiny percentage changes in the level
of .sup.13 CO.sub.2 in the patient's exhaled breath. Because of the
complexity of the LARA.TM. System, it is a large piece of
equipment, weighing over 300 kg, and very costly. Consequently,
this system too is only feasible for very large institutions and
central laboratories, where the large number of tests performed can
justify the cost.
Meretek Diagnostics Incorporated of Nashville, Tenn., has also
developed such a .sup.13 C-Urea breath test diagnostic system, and
use an isotopic ratio mass spectrometer called the ABCA (Automated
Breath .sup.13 C Analyzer) manufactured by Europa Scientific
Limited, of Crewe, Cheshire, U.K. for analyzing the breath samples.
In this system too, the analyzer unit is large, costly and
sophisticated, and therefore is usually located remote from the
collection point.
Wagner Analysen Technik GmbH of Worpswede, Germany, offers an
infra-red non-dispersive spectrophotometer-based system called the
IRIS.RTM.--Infra Red Isotope Analyser, which is based on the
above-mentioned European Patent Application No. EP 0 584 897 A1.
Though the main useage mode is by means of transport of the breath
samples from the collection point to the analyzer in sample bags,
this system, according to the manufacturer's sales literature, also
has a sample port whereby connection can be made directly to a
breathing mask, an incubator, or a breathing machine. No details of
such a connection tube accessory are however given in the technical
manual accompanying the analyzer, nor does the manufacturer provide
any programs with the system's operational software to enable such
an accessory to be used for performing on-line analyses. This
analyzer has dimensions of 510.times.500.times.280 mm and weighs 12
kg., and in addition, a PC is required for control. Though smaller
and less costly than those mentioned above, it is still too large
and heavy to be described as a truly portable device. Furthermore,
its reported cost of several tens of thousands of U.S. Dollars,
though considerably less than that of the two above-mentioned
commercial systems, still makes it unsuitable for point-of-care or
physician's office use.
In the preferred procedures described in all of the above mentioned
prior art, the patient must wait typically 20-30 minutes before the
active sample is collected, mainly because only one sample is taken
beyond a background sample. This time is necessary to allow the
level of isotopically labeled exhaled gas to reach a relatively
high value, close to its end value, to enable the analyzer to
measure the gas with a sufficient confidence level. However, such a
single point determination potentially decreases the accuracy of
the test, as well as increasing the risk of ambiguous results.
To the best of our knowledge, no breath test analyzer system has
been described in the prior art which is sufficiently small, fast
in producing reliable results, low in production cost, portable and
sensitive, to enable it to be used as for executing tests in real
time in the physician's office or at another point of care.
SUMMARY OF THE INVENTION
The present invention seeks to provide an improved breath test
analyzer which overcomes disadvantages and drawbacks of existing
analyzers, which provides accurate results on-site in times of the
order of minutes, and which is capable of implementation as a low
cost, low volume and weight, portable instrument. The breath
analyzer of the present invention is sufficiently sensitive to
enable it to continuously collect and analyze multiple samples of
the patient's breath from the beginning of the test, and process
the outputs in real time, such that a definitive result is obtained
within a short period of time, such as of the order of a few
minutes.
Such a breath test analyzer is suitable for the detection of
various disorders or infections of the gastro-intestinal tract, or
metabolic or organ malfunctions, and since it can provide results
in real time without the need to send the sample away to a special
center or central laboratory, can be used to provide diagnostic
information to the patient in the context of a single visit to a
physician's office, or at any other point of care in a health care
facility.
In accordance with a preferred embodiment of the present invention,
there is provided a breath test analyzer, including a very
sensitive gas analyzer, capable of measuring the ratio of two
chemically identical gases but with different molecular weights,
resulting from the replacement of at least one of the atoms of the
gas with the same atom but of different isotopic value. Since the
isotopically labeled gas to be measured in the patient's breath may
be present only in very tiny quantities, and since, in general, it
has an infra-red absorption spectrum very close to that of the
non-isotopically labeled gas, the gas analyzer must be capable of
very high selectivity and sensitivity, to detect and measure down
to the order of a few parts per million of the hot gas.
The breath test analyzer is also sufficiently small that it can
easily be accommodated in the office of a physician, such as a
gastro-enterologist, and its cost is also sufficiently low that its
use in such an environment can be economically justified.
There are a number of different operational modes for each type of
test for such a breath analyzer, the common denometer being that
the analysis is performed in real time whilst the patient is
continuing to provide breath for subsequent analyses. In the most
common mode of operation, the breath test analyzer senses a
patient's exhaled 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 a medical
condition within a time period following the last sensing which is
less than the difference in time between the first sensing of the
patient's exhaled breath and the second sensing. This delineates it
from previous breath analyzers, which, because of the generally
remote location of the analyzer from the point at which the samples
are given, cannot provide this indication within such a time
limit.
In an alternative mode of operation, the analyzes are made
successively at times after ingestion of an isotopically labeled
substance, and before the end of production of the isotopically
labeled by-products of the substance, and the analyzer performs
comparisons of the change from sample to sample of the percentage
of the isotopically labeled gas in the total exhaled gas of that
composition, and thereby provides an indication of a medical
condition as soon as the detected change in gas composition
percentage permits it, and before the end of production of the
isotopically labeled by-products of the substance.
There are also two modes of analyzing the breath samples. The
analyser can either perform its analysis on individual exhaled
breaths, or, as stated above, it can perform its analysis on
multiple samples of the patient's breath, continuously collected
from the patient. The method of collection and subsequent analysis
of multiple samples of the patient's breath has been described in
co-pending Isreal Patent Application No. 121793, which is hereby
incorporated by reference. That application described an analyzer
wherein the patient's breaths are exhaled into a reservoir for
collection, in this application called a breath collection chamber,
and transferred from there by one of various methods to the sample
measurement chamber. One of the advantages of the method described
therein, is that the analyzer draws an averaged sample of breath
for measurement, instead of individual breaths, thereby increasing
accuracy. Another advantage is that it is possible, by suitable
valving means, to collect only the plateau parts of multiple
breaths for analysis.
In accordance with a further preferred embodiment of the present
invention, there is provided a breath test analyzer, which analyzes
a first exhaled breath of a patient and a second exhaled breath of
the patient for isotope labeled products generated in the patient's
body after ingestion by the patient of an isotope labeled
substance, by performing a first analyzing of the patient's first
breath and a second analyzing of the patient's second breath, at
least the second breath being exhaled following patient's ingesting
the substance, the analyzer providing an indication of a medical
condition within a time period following the exhalation of the
second breath which is less than the difference in time between the
exhalation of the first breath and the exhalation of the second
breath.
There is further provided in accordance with yet another preferred
embodiment of the present invention, a breath test analyzer as
described above and including a breath analysis chamber, a breath
inlet conduit for conveying exhaled gas from a patient to the
breath analysis chamber; and a gas analyzer operative to analyze
gas in the breath analysis chamber and to conduct the first
analyzing of gas exhaled by the patient's first breath and the
second analyzing of the patient's second breath, at least the
second breath being exhaled following ingestion by the patient of
an isotope labeled substance.
Furthermore, for those preferred embodiments which analyze samples
collected from exhaled breaths of a patient, instead of individual
breaths, it is understood that the analyzer also incorporates a
breath collection chamber, which may be a separate chamber, or part
of the breath inlet conduit, or part of the breath analysis
chamber. In the latter case, the analysis of the gas sample
effectively takes place in the breath collection chamber.
In accordance with another preferred embodiment of the present
invention, there is provided a breath test analyzer as described
above, and wherein the patient's first breath is exhaled prior to
ingestion of an isotopically labeled substance, and the patient's
second breath is exhaled following ingestation of the isotopically
labeled substance.
In accordance with yet another preferred embodiment of the present
invention, there is provided a breath test analyzer as described
above, and wherein both of the patient's first and second breaths
are exhaled following patient's ingestation of the isotopically
labeled substance.
There is further provided in accordance with another preferred
embodiment of the present invention, a breath test analyzer which
analyzes a patient's breath for isotope labeled products generated
in the patient's body after ingestion by the patient of an isotope
labeled substance, the analyzer providing an indication of a
medical condition existent in the patient by analyzing at least two
successive samples of the patient's breath, wherein the at least
two successive samples of the patient's breath include at least one
later sample exhaled following analysis of at least one earlier
sample.
There is still further provided in accordance with another
preferred embodiment of the present invention, a breath test
analyzer as described above and including a breath analysis
chamber, a breath inlet conduit for conveying exhaled gas from a
patient to the breath analysis chamber, and a gas analyzer
operative to analyze gas in the breath analysis chamber and to
conduct analyses of the at least two successive samples of the
patient's breath, wherein the at least two successive samples of
the patient's breath include at least one later sample exhaled
following analysis of at least one earlier sample.
In accordance with still another preferred embodiment of the
present invention, there is provided a breath test analyzer which
analyzes a patient's exhaled breath before and after a product of
an isotope labeled substance ingested by the patient could be
detected in the patient's breath, a first analyzing of the
patient's exhaled breath taking place prior to the product being
detectable in the patient's breath and a second analyzing of the
patient's exhaled breath taking place once the product could be
detectable in the patient's breath, the analyzer providing an
indication of a medical condition within a time period following
the exhalation of the second breath which is less than the
difference in time between the exhalation of the first breath and
the exhalation of the second breath.
There is further provided in accordance with other preferred
embodiments of the present invention, a breath test analyzer which
analyzes a first exhaled breath of a patient and a second exhaled
breath of the patient for the products of an isotope labeled
substance ingested by the patient while the patient is coupled to
the device, or analyzes the above mentioned exhaled breath and
provides an indication of a medical condition while the patient is
coupled to the device, or is breathing into the device. The patient
whose breath is being analyzed can be coupled to the device
continuously from the analyzing of the first exhaled breath to the
analyzing of the second exhaled breath.
There is still further provided in accordance with another
preferred embodiment of the present invention, a breath test
analyzer as described above and including a breath analysis
chamber, a breath inlet conduit for conveying exhaled gas from a
patient to the breath analysis chamber, and a gas analyzer
operative to analyze gas in the breath analysis chamber while the
patient is coupled to the device.
There is even further provided in accordance with still another
preferred embodiment of the present invention, a breath test
analyzer as described above and including a breath analyzer
chamber, a breath inlet conduit for conveying exhaled gas from a
patient to the breath analysis chamber, and a gas analyzer
operative to analyze gas in the breath analysis chamber and to
provide an indication of a medical condition while the patient is
coupled to the device.
There is provided in accordance with another preferred embodiment
of the present invention, a breath test analyzer as described above
and including a breath analysis chamber, a breath inlet conduit for
conveying exhaled gas from a patient to the breath analysis
chamber; and a gas analyzer operative to analyze gas in the breath
analysis chamber and to provide an indication of a medical
condition while the patient is breathing into the device.
In accordance with still another preferred embodiment of the
present invention, there is provided a breath test analyzer as
described above and wherein the patient is coupled to a disposable
breath input device.
In accordance with yet another preferred embodiment of the present
invention, there is provided a medical sample analyzer which
analyzes samples taken from a patient, and wherein either the
taking or the analyzing of the samples is terminated automatically
at a point in time determined by the results of the analyzing of
the samples.
In accordance with even another preferred embodiment of the present
invention, there is further provided a breath test analyzer which
analyzes samples of a patient's breath for isotope labeled products
generated in the patient's body after ingestion by the patient of
an isotope labeled substance, and wherein either the taking or the
analyzing of the samples is terminated automatically at a point in
time determined by the results of the analyzing of samples.
There is also provided in accordance with another preferred
embodiment of the present invention, a medical sample analyzer as
described above, which analyzes samples taken from a patient and
including a sample input port for receiving samples taken from the
patient and an analyzing apparatus for analyzing the samples, and
wherein the analyzing is terminated automatically at a point in
time determined by the results of the analyzing of the samples.
There is further provided in accordance with another preferred
embodiment of the present invention, a breath test analyzer as
described above and including a breath analysis chamber, a breath
inlet conduit for conveying exhaled gas from a patient to the
breath analysis chamber; and a gas analyzer operative to analyze
gas in the breath analysis chamber and wherein the analyzing of
samples from the patient is terminated automatically at a point in
time determined by the results of the analyzing of the samples.
In accordance with another preferred embodiment of the present
invention, there is further provided a breath test analyzer as
described above, and wherein the gas analyzer includes a gas
discharge tube gas analyzer, or an infra-red source which emits a
discontinuous spectrum.
In accordance with yet another preferred embodiment of the present
invention, there is provided a breath test analyzer as described
above, and wherein the results of the analyzing of successive
samples are fitted to a curve, and an indication of a medical
condition in a patient is determined by inspecting the derivative
of the curve.
In accordance with even another preferred embodiment of the present
invention, there is further provided a method of breath testing
which analyzes a first exhaled breath of a patient and a second
exhaled breath of the patient for isotope labeled products
generated in the patient's body after ingestion by the patient of
an isotope labeled substance, and comprising the steps of
performing a first analyzing of the patient's first breath,
subsequently performing a second analyzing of the patient's second
breath, at least the second breath being exhaled following the
patient's ingesting the substance, and providing an indication of a
medical condition within a time period following exhalation of the
second breath which is less than the difference in time between
exhalation of the first breath and exhalation of the second
breath.
There is further provided in accordance with another preferred
embodiment of the present invention, a method of breath testing
which analyzes a patient's exhaled breath for the product of an
isotope labeled substance ingested by the patient, and comprising
the steps of performing a first analyzing of the patient's exhaled
breath prior to the product being detectable in the patient's
breath, performing a second analyzing of the patient's exhaled
breath once the product is detectable in the patient's breath, and
providing an indication of a medical condition within a time period
following the exhalation of the second breath which is less than
the difference in time between the exhalation of th first breath
and the exhalation of the second breath.
Furthermore, whereas all of the above mentioned preferred
embodiments have been described for breath analyzers which analyze
a first exhaled breath of a patient and a second exhaled breath of
the patient, it is understood that the operation of these preferred
embodiments are equally valid for breath analyzer which analyze a
first sample collected from at least a first exhaled breath of a
patient, and a second sample collected from at least a second
exhaled breath of a patient.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will be understood and appreciated more fully
from the following detailed description, taken in conjunction with
the drawings, in which:
FIG. 1 is a schematic view of a breath analyzer constructed and
operative in accordance with a preferred embodiment of the present
invention, showing its main component parts including the breath
inlet conduit and the breath analysis chamber.
FIG. 2A is a schematic view of a patient connected to the breath
test analyzer by means of a nasal cannula, and shows the compact
size of the analyzer, together with its associated laptop PC used
for controlling the analyzer.
FIG. 2B is similar to FIG. 2A, except that the patient is connected
to the analyzer by means of a blowing tube which he puts into his
mouth when a sample breath is required.
FIGS. 3A to 3D show schematically the various steps of a complete
breath test cycle. The test cycle is shown being performed using a
nasal cannula for the breath sampling, but the same procedure can
be performed with the samples collected by means of a mouth
tube.
In FIG. 3A, the patient is shown at time t.sub.0 providing the
reference breath before taking the isotopically labeled substance
suitable for the specific test to be performed.
FIG. 3B shows the patient at time t.sub.1 integrating the
isotopically labeled substance, shown in this instance in a glass
of liquid.
FIG. 3C is a view of the patient at time t.sub.2 providing
continuous breath samples for the analyzer to collect through the
nasal cannula or breathing tube. The analyzer itself measures 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 for every 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.
FIG. 3D shows the situation at time t.sub.3 when the test has been
completed and analysis terminated, either because the desired
percentage level of the isotopically labeled gas has been reached,
or because a time limit has been reached without a definitive
delta-over-baseline percentage of gas having been reached. The PC
is ready to show the results of the analysis prior to printout.
Since the test is complete, the patient has removed the sampling
device.
FIGS. 4A to 4C show the various stages of a complete breath test
cycle according to another preferred embodiment 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.
In FIG. 4A, the patient is shown at time t.sub.0 ingesting the
isotopically labeled substance, in this example in a glass of
liquid.
In FIG. 4B, the patient is shown at time t.sub.1 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.
FIG. 4C shows the situation at time t.sub.2 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 shows the results of the analysis prior to the
printout. Since the test is complete, the patient has removed the
sampling device.
FIG. 5 is a schematic flow chart of the test procedures described
in FIGS. 3A to 3D, and in FIGS. 4A to 4C.
FIG. 6 shows a typical graph 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.
DETAILED DESCRIPTIONS OF PREFERRED EMBODIMENTS
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 CO.sub.2 and the natural CO.sub.2 in the
breath sample being analyzed.
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.
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 .sup.12 CO.sub.2 or
.sup.13 CO.sub.2 respectively. By excitation of an RF field, the
gas discharge generates an emission which is typical of the
CO.sub.2 enclosed within the lamp. The average width of the
emission lines from these lamps is only 0.006 cm.sup.-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.
In order to obtain the ratio of .sup.13 CO.sub.2 /.sup.12 CO.sub.2
of a breath sample, the absorption of the sample is measured with a
.sup.12 CO.sub.2 lamp and a .sup.13 CO.sub.2 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.
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.
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.
In FIG. 3A, the patient 31 is shown at time t.sub.0 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.
FIG. 3B shows the patient at time t.sub.1 drinking the isotopically
labeled substance 32, shown in this instance in a glass of
liquid.
FIG. 3C is a view of the patient at time t.sub.2 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.
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.
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 t.sub.0 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.
FIG. 3D shows the situation at time t.sub.3 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.
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.
In FIG. 4A, the patient 41 is shown at time t.sub.0 ingesting the
isotopically labeled substance, in this example in a glass of
liquid.
In FIG. 4B, the patient is shown at time t.sub.1 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.
FIG. 4C shows the situation at time t.sub.2 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.
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.
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 .sup.13 CO.sub.2 in the breath of patients after ingestion
of .sup.13 C-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.
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.
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.
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.
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.
* * * * *