U.S. patent application number 10/742721 was filed with the patent office on 2004-07-15 for disposable hand-held device for collection of exhaled breath condensate.
Invention is credited to Kline, Jeffrey A..
Application Number | 20040138577 10/742721 |
Document ID | / |
Family ID | 32685345 |
Filed Date | 2004-07-15 |
United States Patent
Application |
20040138577 |
Kind Code |
A1 |
Kline, Jeffrey A. |
July 15, 2004 |
Disposable hand-held device for collection of exhaled breath
condensate
Abstract
A breath condensate collection apparatus comprising a central
chamber, a breath input assembly, a plunger assembly and a breath
condensate collection port. The central chamber has inner and outer
side walls with a coolant material sealed in between. The breath
input assembly is disposed on the side of the central chamber in
fluid communication with the chamber interior. The plunger assembly
has a piston, slidably disposed in the chamber, and a handle
extending from a first end of the chamber. The collection port is
disposed at the second end of the central chamber in fluid
communication with the interior of the chamber. Obstructive
structures may be arranged in the chamber interior for increasing
the surface area on which condensate may form. The apparatus may
also include an outlet assembly that may be removed and replaced
with a sampling well into which the condensate may be washed with a
buffer solution.
Inventors: |
Kline, Jeffrey A.;
(Charlotte, NC) |
Correspondence
Address: |
KENNEDY COVINGTON LOBDELL & HICKMAN, LLP
214 N. TRYON STREET
HEARST TOWER, 47TH FLOOR
CHARLOTTE
NC
28202
US
|
Family ID: |
32685345 |
Appl. No.: |
10/742721 |
Filed: |
December 19, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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60434916 |
Dec 20, 2002 |
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60447581 |
Feb 14, 2003 |
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Current U.S.
Class: |
600/543 |
Current CPC
Class: |
A61B 5/097 20130101;
A61B 2010/0087 20130101 |
Class at
Publication: |
600/543 |
International
Class: |
A61B 005/08 |
Claims
What is claimed is:
1. A breath condensate collection apparatus comprising: a central
chamber having double side walls and first and second opposing
ends, wherein the double side walls include an inner side wall and
an outer side wall in spaced relationship to one another; a coolant
material sealed between the inner and outer side walls for cooling
at least the inner walls of the central chamber; a breath input
assembly disposed on the outside of the outer side wall of the
central chamber and penetrating both the inner and outer side walls
such that the interior of the breath input assembly is in fluid
communication with the interior of the central chamber; a plunger
assembly having a piston and a handle, wherein the piston is
slidably disposed in the interior of the central chamber in snug
contact with the inner side wall and wherein the handle extends
from the first end of the central chamber so as to permit the
piston to be moved within the central chamber; and a breath
condensate collection port, disposed at the second end of the
central chamber, in fluid communication with the interior of the
central chamber.
2. The breath condensate collection apparatus of claim 1, wherein
the plunger assembly is adjustable between a fully retracted
position and a fully depressed position, and wherein when the
plunger is in its fully retracted position, the fluid connection
between the breath input assembly and the central chamber lies in
between the piston and the second end of the central chamber.
3. The breath condensate collection apparatus of claim 2, wherein
the location of the breath input assembly on the outside of the
outer side wall of the central chamber is adjacent the first end of
the central chamber.
4. The breath condensate collection apparatus of claim 3, wherein
the location of the breath input assembly is underneath the central
chamber.
5. The breath condensate collection apparatus of claim 3, wherein
the central chamber includes an end wall at the second end thereof,
and wherein the breath condensate collection port is disposed in
the end wall of the central chamber.
6. The breath condensate collection apparatus of claim 5, wherein
the piston includes a surface facing toward the second end of the
central chamber, wherein a protrusion is disposed on the surface of
the piston, and wherein the protrusion is adapted to fit into the
breath condensate collection port when the plunger assembly is
fully depressed into the central chamber.
7. The breath condensate collection apparatus of claim 6, wherein
the breath condensate collection port and the protrusion are each
semi-conical in shape.
8. The breath condensate collection apparatus of claim 6, wherein
one or more grooves are disposed in the sides of the protrusion to
facilitate guiding breath condensate toward the breath condensate
collection port.
9. The breath condensate collection apparatus of claim 6, wherein
one or more internal passages are disposed in the interior of the
protrusion to facilitate guiding breath condensate toward the
breath condensate collection port.
10. The breath condensate collection apparatus of claim 9, further
comprising a rigid, hollow tube structure extending from one of the
internal passages through which fluid from the interior of the
protrusion may be directed.
11. The breath condensate collection apparatus of claim 2, wherein
the breath condensate collection port is disposed on the outside of
the outer side wall of the central chamber adjacent the second end
thereof.
12. The breath condensate collection apparatus of claim 11, wherein
the breath condensate collection port is disposed on the bottom of
the central chamber, the breath condensate collection apparatus
further comprising an outlet and an outlet valve disposed on the
top of the outer side wall of the central chamber adjacent the
second end thereof.
13. The breath condensate collection apparatus of claim 12, further
comprising a cap for temporarily sealing the breath condensate
collection port.
14. The breath condensate collection apparatus of claim 2, wherein
the breath condensate collection apparatus defines a main axis,
wherein the breath input assembly includes a mouthpiece and a tube
structure connecting the mouthpiece to the side of the central
chamber, and wherein the mouthpiece is generally oriented in
parallel to the main axis of the breath condensate collection
apparatus.
15. The breath condensate collection apparatus of claim 2, further
comprising at least one clip, mounted at the first end of the
central chamber, for locking the handle of the plunger assembly in
a fully depressed position to facilitate transport or handling of
the breath condensate collection apparatus until breath condensate
collected therein may be removed.
16. A method of collecting breath condensate, the method
comprising: providing a central chamber having double side walls,
first and second opposing ends, a coolant material sealed between
the inner and outer side walls for cooling at least the inner walls
of the central chamber, and a breath condensate collection port
disposed at the second end of the central chamber; lowering the
temperature of the coolant material to chill at least the inner
walls of the central chamber; receiving, in the interior of the
central chamber, exhaled breath from a patient, delivered through
the inner and outer side walls via a breath input assembly disposed
on the outside of the outer side wall of the central chamber;
condensing portions of the exhaled breath on the inner surfaces of
the inner walls of the central chamber; expressing condensate,
produced during the condensing step, from the central chamber by
depressing a plunger assembly through the central chamber, thereby
forcing the condensate into the breath condensate collection port;
and aspirating the expressed condensate from the breath condensate
collection port for analysis thereof.
17. The method of claim 16, wherein the aspirating step includes
aspirating the expressed condensate into a pipette, the method
further comprising: transferring the condensate from the pipette to
a separate assay well for analysis thereof.
18. The method of claim 17, wherein providing a central chamber
includes providing a central chamber having an outlet and outlet
valve disposed on the top of the outer side wall of the central
chamber adjacent the second end thereof and the breath condensate
collection port disposed on the bottom of the central chamber, the
method further comprising: temporarily sealing the breath
condensate collection port during the receiving and condensing
steps.
19. The method of claim 17, wherein providing a central chamber
includes providing a central chamber having at least one clip
mounted at the first end of the central chamber, the method further
comprising: after expressing the condensate by depressing the
plunger assembly, locking, via the at least one clip, the handle of
the plunger assembly in a fully depressed position to facilitate
transport or handling of the breath condensate collection apparatus
until aspirating the expressed condensate.
20. The method of claim 17, wherein receiving exhaled breath
includes receiving the exhaled breath delivered through the inner
and outer side walls via a breath input assembly disposed
underneath the central chamber.
21. A breath condensate collection apparatus comprising: a central
chamber having double side walls including an inner side wall and
an outer side wall in spaced relationship to one another; a coolant
material sealed between the inner and outer side walls for cooling
at least the inner walls of the central chamber; a breath input
assembly, the interior of which is in fluid communication with the
interior of the central chamber; one or more obstructive structures
arranged in the interior of the central chamber for increasing the
surface area on which condensate may form; and a breath condensate
collection port in fluid communication with the interior of the
central chamber.
22. The breath condensate collection apparatus of claim 21, wherein
the obstructive structures include grid-like structures.
23. The breath condensate collection apparatus of claim 21, wherein
the obstructive structures include discrete geometric
structures.
24. The breath condensate collection apparatus of claim 23, wherein
the discrete geometric structures include spherical objects.
25. The breath condensate collection apparatus of claim 23, wherein
the discrete geometric structures are formed from metal.
26. The breath condensate collection apparatus of claim 23, wherein
the discrete geometric structures are formed from glass.
27. The breath condensate collection apparatus of claim 21, wherein
the obstructive structures are fixed in place within the interior
of the central chamber.
28. The breath condensate collection apparatus of claim 21, wherein
the obstructive structures are free-floating within the interior of
the central chamber.
29. The breath condensate collection apparatus of claim 28, wherein
movement of the obstructive structures is restricted to a
particular portion of the central chamber.
30. The breath condensate collection apparatus of claim 21, wherein
the location of the breath input assembly is underneath the central
chamber.
31. A method of collecting breath condensate, the method
comprising: providing a double-walled central chamber having one or
more obstructive structures arranged in the interior thereof and a
coolant material sealed between the inner and outer side walls for
cooling at least the inner walls of the central chamber; lowering
the temperature of the coolant material to chill at least the inner
walls of the central chamber and the obstructive structures;
receiving, in the interior of the central chamber, exhaled breath
from a patient; condensing portions of the exhaled breath on the
inner surfaces of the inner walls of the central chamber and on the
obstructive structures; and removing condensate, produced during
the condensing step, from the central chamber.
32. The method of claim 31, wherein the removing step includes
washing the condensate from the obstructive structures.
33. The method of claim 32, wherein the washing step includes
adding an amount of liquid to the central chamber, wherein the
amount is selected to correspond to the amount of condensate
present in the central chamber.
34. The method of claim 32, wherein the washing step includes
adding an amount of liquid to the central chamber, wherein the
amount is selected to correspond to the amount of condensate likely
to be present in the central chamber after the patient exhales into
the central chamber for a predetermined period of time.
35. The method of claim 32, wherein the washing step includes
adding an amount of liquid to the central chamber, wherein the
amount is selected to correspond to the amount of condensate likely
to be present in the central chamber after the patient completes a
predetermined number of exhalations into the central chamber.
36. The method of claim 32, further comprising the step of removing
the obstructive structures from the central chamber before carrying
out the washing step.
37. A method of collecting breath condensate, the method
comprising: providing a double-walled central chamber having a
removable outlet assembly and a coolant material sealed between the
inner and outer side walls for cooling at least the inner walls of
the central chamber; lowering the temperature of the coolant
material to chill at least the inner walls of the central chamber;
receiving, in the interior of the central chamber, exhaled breath
from a patient; condensing portions of the exhaled breath on the
inner surfaces of the inner walls of the central chamber; removing
the outlet assembly and replacing it with a sampling well; and
moving condensate, produced during the condensing step, from the
central chamber to the sampling well.
38. The method of claim 37, wherein the step of moving condensate
includes washing condensate from the central chamber into the
sampling well with a known liquid.
39. The method of claim 38, wherein the step of washing condensate
includes: introducing a predetermined quantity of the known liquid
into the central chamber; mixing the predetermined quantity of the
known liquid with the condensate; and draining the known liquid and
the condensate from the central chamber into the sampling well.
40. The method of claim 39, wherein the step of removing the outlet
assembly includes creating an opening into the central chamber, and
wherein the step of introducing includes introducing the known
liquid through the opening.
41. The method of claim 39, further comprising: before replacing
the outlet assembly with the sampling well, storing the known
liquid in the sampling well.
42. The method of claim 38, wherein the known liquid is a buffer
solution.
43. The method of claim 42, wherein the buffer solution is
distilled water.
44. The method of claim 42, wherein the buffer solution includes an
organic dye to indicate the pH of the solution.
45. The method of claim 38, further comprising: before replacing
the outlet assembly with the sampling well, storing the known
liquid in the sampling well.
46. The method of claim 38, further comprising: before replacing
the outlet assembly with the sampling well, storing the known
liquid in the sampling well.
47. A method of collecting breath condensate, the method
comprising: providing a double-walled central chamber having one or
more obstructive structures arranged in the interior thereof and a
coolant material sealed between the inner and outer side walls for
cooling at least the inner walls of the central chamber;
calibrating the walls and coolant material of the double-walled
central chamber such that, when beginning at a predetermined
temperature, a chosen number of breaths, received from a typical
patient, creates a sufficient amount of breath condensate to be
collected on the inner surfaces of the inner walls of the central
chamber; lowering the temperature of the coolant material to the
predetermined temperature to chill at least the inner walls of the
central chamber; receiving, in the interior of the central chamber,
a plurality of exhalations from a particular patient, wherein the
number of exhalations is within a predetermined range established
on the basis of the chosen number of breaths; condensing portions
of the exhalations, received from the patient, on the inner
surfaces of the inner walls of the central chamber; and removing
condensate, produced during the condensing step, from the central
chamber.
48. The method of claim 47, wherein the predetermined range is 10
to 25 breaths, inclusive.
49. The method of claim 47, wherein the predetermined temperature
is the temperature of a standard freezer.
50. The method of claim 49, wherein the predetermined temperature
is 0.degree. F.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is entitled to the benefit of, and claims
priority to, provisional U.S. Patent Application Serial No.
60/434,916 filed Dec. 20, 2002 and entitled "DISPOSABLE HAND-HELD
DEVICE FOR COLLECTION OF EXHALED BREATH CONDENSATE FOR ASSAY OF
BIOMARKERS FOR THE DETECTION AND PROGNOSIS OF LUNG ISCHEMIA," and
provisional U.S. Patent Application Serial No. 60/447,581 filed
Feb. 14, 2003 and entitled "DEVICE AND METHOD FOR COLLECTION OF
EXHALED ALVEOLAR BREATH CONDENSATE," the entirety of each of which
is incorporated herein by reference.
BACKGROUND OF THE PRESENT INVENTION
[0002] 1. Field of the Present Invention
[0003] The present invention relates to the collection of breath
condensate medical testing and diagnosis, and, in particular, to a
double-walled chamber having a coolant material embedded between
the inner and outer walls, a side-mounted breath input assembly, an
outlet from which condensate may be collected, and a plunger for
expressing the condensate through the outlet. The collected sample
may then be tested for biomarkers indicating the presence and
severity of lung ischemia and associated pulmonary
vasoconstriction.
[0004] 2. Background
[0005] Approximately 6% of exhaled breath is water vapor and water
droplets. One source of water in breath is from the fluids that
line the alveoli of the lung. In other words, the water vapor
exhaled from the breath equilibrates with fluid in the bronchi and
alveoli, and therefore breath condensate collection provides a
noninvasive means of sampling these fluids.
[0006] Exhaled breath condensate contains water soluble and water
insoluble molecules, including dissolved gases, organic solutes,
ions and proteins. Breath condensate samples from patients with
certain diseases have been shown to contain elevated content of
inflammatory molecules. For example, previous work has demonstrated
that smoking, asthma and cystic fibrosis increase the presence of
prostaglandin derivatives, thromboxane, leukotrienes and cytokines.
(S A Kharitonov and P J Barnes, Exhaled markers of pulmonary
disease, Am J Respir Crit Care Med 163:1693-1722, 2001.) Until
recently, though, little work has been done to identify biomarkers
in exhaled breath water vapor that may be able to assist in
determining the presence and severity of lung ischemia.
[0007] However, recent research indicates that it may be possible
to detect lung ischemia by performing a battery of tests on
relatively small breath condensate samples. A proposed battery of
tests for lung ischemia may include fibrinopeptides, thromboxane
B2, platelet activating factor, leukotrienes C, D and E, carbon
monoxide-to-nitric oxide ratio and chemokine and other proteins.
Measurement of fibrinopeptides in breath condensate is believed to
have the potential to allow more localized measurement of the
presence of clot in the lung vasulature. It is publicly known that
thrombin cleaves fibrinogen A peptide from fibrinogen as a
prerequisite to fibrin gelation. Owing to its small size, it is
hypothesized that fibrinopeptides will traverse the alveolar
membrane, and equilibrate in alveolar fluid, and thus will be found
in exhaled condensate.
[0008] It is also believed that pulmonary vascular constriction may
be detected by measuring PGF.sub.2.alpha., thromboxane B.sub.2,
PAF, leukotrienes C, D, and E, and the ratio of CO to NO in
condensate, thus providing a basis for initiating pulmonary
vasodilator therapy or COX1,2 inhibition. Our laboratory has used
an experimental pulmonary vascular occlusion (PVO), induced by
venous infusion of polystyrene microspheres in a rat, to determine
three major findings related to breath condensate analysis. We and
others have found increased content of PGF.sub.2.alpha.,
thromboxane B.sub.2, platelet activating factor (PAF) and
vasoconstrictive leukotrienes C, D, and E in the lung washings in
our rat model. (Nakos, Am J Resp Crit Care Med 1998, 158:1504) The
magnitude of the concentration of these vasoconstrictive agents
correlated with the severity of hypoxemia and pulmonary
hypertension. We also have found extremely elevated expression of
the gene encoding heme oxygenase-1 but the nearly complete absence
of expression of the gene encoding for the inducible enzyme, nitric
oxide synthase. Heme oxygenase produces carbon monoxide (CO) from
heme substrate whereas nitric oxide synthase produces nitric oxide
(NO). Both are vasodilator substances. In rats subjected to PVO, we
have also found early increases in lung gene expression of cytokine
induced neutrophil attractant 1 and 2 (CINC 1 & 2), and
monocyte/macrophage chemoattractant protein (MCP) 1 and 2, and
monocyte/macrophage inflammatory proteins (MIP) 1.alpha. and
1.beta. with concomitant increases in each protein in the washings
from the lung airways and alveoli obtained as soon as 2 hours after
induction of PE, and lasting up to 18 hours after PE induction. The
chemoattractant molecules can cause the migration of leukocytes
into the affected area, and through this mechanism, can potentiate
injury during therapeutic reperfusion.
[0009] Further, the presence of certain chemokines in exhaled
condensate is believed to predispose reperfusion injury. The
chemokines discovered in rats included CINC 1, CINC 2, MIP
1.alpha., MIP 1.beta., and MCP 1 and 2. The human homologues that
will be tested in our device will include CXCL1, CXCL 2 and CXCL 3;
CCL 2, CCL 3, CCL 4 and CCL 8, using nomenclature outlined by
Zlotnick and Yoshie, Immunity, 2000, 12:121-127. Chemokines have
been found with an inflammatory model of pulmonary hypertension.
(Kimura, Lab Invest 1998 78:571-81; Ikeda, Am J Physiol Heart Circ
Physiol, 2002, 283(5):H2021-8). Unlike the in-vivo PVO model, which
causes primarily obstructed blood flow, the model in the latter
study incites inflammation and remodeling, which over weeks leads
to vascular occlusion. Likewise, investigators have also found
increased chemokine expression in lungs subjected to hilar ligation
or clamping, which interrupts both perfusion and ventilation. The
latter model differs significantly from in-vivo PVO because
alveolar ventilation continues with in-vivo PVO. Thus the ischemic
insult differs with in-vivo PVO versus hilar ligation.
[0010] Attempts have been made to analyze exhaled breath, including
breath condensate, or otherwise measure certain components of
exhaled breath. For example, U.S. Pat. Nos. 6,419,634 and 6,033,368
to Gaston IV et al. disclose a disposable device with a coolant
coaxially surrounding a tube in order to cool exhaled breath
sufficiently to cause condensation on the walls of the inner tube.
Unfortunately, the device is designed for the measurement of
nitrogen oxides and is not intended to facilitate protein or
eicosinoid determinations on breath condensate. As a result, it
suffers from a number of drawbacks. First, the Gaston device is
mounted directly on the analyzer, and thus is too large and too
cumbersome to use at the bedside for collection of small volumes of
condensate in emergency department or other ambulatory patients.
The Gaston device also suffers from inefficient sample collection
inasmuch as the sample must be aggregated in one chamber and then
transferred by the combined actions of droplet accretion and
gravity to a separate second chamber for analysis. Perhaps worse,
the Gaston device is incapable of use separate from the analyzer,
in that the apparatus collects condensate in a chamber specifically
designed for spectrophotometric analysis for nitrogen oxides, and
thus has no port or other accessible reservoir from which
condensate may be aspirated, aliquotted or otherwise withdrawn and
subsequently transferred to a separate assay well to measure the
components of the panel described above.
[0011] Further, although Gaston mentions the use of a device
similar to a syringe plunger in expressing condensed fluid down its
inner tube, Gaston fails to solve the problem of how to integrate
such a plunger with the inlet tube. Also, even the inclusion of a
plunger to express fluid down the inner tube of the Gaston device
would still fail to solve the additional problem described
previously; that is, Gaston still discloses no simple way to remove
the fluid for removing and transferring the collected fluid for
testing outside of the analyzing chamber. Finally, the Gaston
coolant is not calibrated to permit condensation of a calibrated
amount of condensate from a limited number of breaths. Instead, the
Gaston device requires a lengthy period of sustained breathing in
order to collect a sufficient quantity of condensate, a problem
that is exacerbated by the absence of a plunger to more efficiently
remove condensate from the device. This is due in large part to the
considerable quantities of condensate that are necessary in Gaston
for the intended type of testing to be performed thereon. As
discussed previously, a major purpose of the present application is
to collect relatively the small quantities of condensate necessary
to perform the types of tests described above. Because such testing
was not anticipated by Gaston, the Gaston device was not developed
to permit such testing. Thus, a need exists for a fast and
convenient apparatus and method for collecting small amounts of
breath condensate in a manner that permits aliquotting as desired
for the performance of tests such as the ones described above.
SUMMARY OF THE PRESENT INVENTION
[0012] It is hypothesized that the ability to measure particular
biomarkers in exhaled breath water vapor, such as the ones
described above, can assist in determining the presence and
severity of lung ischemia. Lung ischemia can be caused by multiple
processes, including thromboembolism, sickle cell disease, fat and
air embolism. The ability to collect breath condensate rapidly and
easily with a point-of-care device would improve the clinical
utility of breath-based diagnosis for this purpose, particularly in
the emergency department or clinic setting. The devices described
herein are designed to allow a patient to breath into a handheld
disposable chamber to facilitate the collection of approximately
100-1000 microliters of aerosolized and vaporized water and
solutes, which can then be analyzed for the presence of specific
proteins and other organic compounds, using enzyme-linked
immunoassay, and the measurement of the proportion of carbon
monoxide relative to nitric oxide using laser
spectrophotometry.
[0013] It is an object of the present invention to provide a method
of allowing cold-trapping of exhaled water vapor in a portable
device.
[0014] It is another object of the present invention to provide a
mechanism to permit use of frozen water of a known volume such that
the ice melts after a known number of exhalations to permit
collection of condensed exhaled water aerosol and vapor.
[0015] It is yet another object of the present invention to provide
a breath condensate collection device having a series of valves to
prevent contamination by water vapor and ambient air.
[0016] It is still another object of the present invention to
provide a breath condensate collection device using a plunger-type
mechanism to express collected condensate into a small reservoir to
facilitate fluid collection.
[0017] It is yet another object of the present invention to
construct a breath condensate collection device using materials to
allow minimal cost of the device such that it is a disposable unit
to minimize cost of the device.
[0018] It is still another object of the present invention to
provide a method for the collection and aliquotting of a breath
condensate sample in an expeditious fashion to facilitate testing
for vasoconstrictor molecules, the measurement of the CO-to-NO
ratio and the measurement of chemokine proteins.
[0019] The present invention comprises apparatuses and methods for
non-invasively collecting breath condensate from a patient for
testing purposes. Broadly defined, the present invention according
to one aspect is a breath condensate collection apparatus,
including: a central chamber having double side walls and first and
second opposing ends, where the double side walls include an inner
side wall and an outer side wall in spaced relationship to one
another; a coolant material sealed between the inner and outer side
walls for cooling at least the inner walls of the central chamber;
a breath input assembly disposed on the outside of the outer side
wall of the central chamber and penetrating both the inner and
outer side walls such that the interior of the breath input
assembly is in fluid communication with the interior of the central
chamber; a plunger assembly having a piston and a handle, the
piston being slidably disposed in the interior of the central
chamber in snug contact with the inner side wall and the handle
extending from the first end of the central chamber so as to permit
the piston to be moved within the central chamber; and a breath
condensate collection port, disposed at the second end of the
central chamber, in fluid communication with the interior of the
central chamber.
[0020] In features of this aspect, the plunger assembly is
adjustable between a fully retracted position and a fully depressed
position, and when the plunger is in its fully retracted position,
the fluid connection between the breath input assembly and the
central chamber lies in between the piston and the second end of
the central chamber; the location of the breath input assembly on
the outside of the outer side wall of the central chamber is
adjacent the first end of the central chamber; the central chamber
includes an end wall at the second end thereof, and the breath
condensate collection port is disposed in the end wall of the
central chamber; the piston includes a surface facing toward the
second end of the central chamber, a protrusion is disposed on the
surface of the piston, and the protrusion is adapted to fit into
the breath condensate collection port when the plunger assembly is
fully depressed into the central chamber; the breath condensate
collection port and the protrusion are each semi-conical in shape;
one or more grooves are disposed in the sides of the protrusion to
facilitate guiding breath condensate toward the breath condensate
collection port; one or more internal passages are disposed in the
interior of the protrusion to facilitate guiding breath condensate
toward the breath condensate collection port; the breath condensate
collection port is disposed on the outside of the outer side wall
of the central chamber adjacent the second end thereof, the breath
condensate collection port is disposed on the bottom of the central
chamber, and the breath condensate collection apparatus also
includes an outlet and an outlet valve disposed on the top of the
outer side wall of the central chamber adjacent the second end
thereof; the breath condensate collection apparatus also includes a
cap for temporarily sealing the breath condensate collection port;
the breath condensate collection apparatus defines a main axis, the
breath input assembly has a mouthpiece and a tube structure
connecting the mouthpiece to the side of the central chamber, and
the mouthpiece is generally oriented in parallel to the main axis
of the breath condensate collection apparatus; and the breath
condensate collection apparatus also includes at least one clip,
mounted at the first end of the central chamber, for locking the
handle of the plunger assembly in a fully depressed position to
facilitate transport or handling of the breath condensate
collection apparatus until breath condensate collected therein may
be removed.
[0021] The present invention, according to another aspect of the
present invention, is a method of collecting breath condensate,
including: providing a central chamber having double side walls,
first and second opposing ends, a coolant material sealed between
the inner and outer side walls for cooling at least the inner walls
of the central chamber, and a breath condensate collection port
disposed at the second end of the central chamber; lowering the
temperature of the coolant material to chill at least the inner
walls of the central chamber; receiving, in the interior of the
central chamber, exhaled breath from a patient, delivered through
the inner and outer side walls via a breath input assembly disposed
on the outside of the outer side wall of the central chamber;
condensing portions of the exhaled breath on the inner surfaces of
the inner walls of the central chamber; expressing condensate,
produced during the condensing step, from the central chamber by
depressing a plunger assembly through the central chamber, thereby
forcing the condensate into the breath condensate collection port;
and aspirating the expressed condensate from the breath condensate
collection port for analysis thereof.
[0022] In features of this aspect, the aspirating step includes
aspirating the expressed condensate into a pipette, and the method
also includes transferring the condensate from the pipette to a
separate assay well for analysis thereof; the providing step
includes providing a central chamber having an outlet and outlet
valve disposed on the top of the outer side wall of the central
chamber adjacent the second end thereof and having the breath
condensate collection port disposed on the bottom of the central
chamber, and the method also includes temporarily sealing the
breath condensate collection port during the receiving and
condensing steps; and the step of providing includes providing a
central chamber having at least one clip mounted at the first end
of the central chamber, and the method also includes, after
expressing the condensate by depressing the plunger assembly, a
step of locking, via the at least one clip, the handle of the
plunger assembly in a fully depressed position to facilitate
transport or handling of the breath condensate collection apparatus
until aspirating the expressed condensate.
[0023] The present invention, according to another aspect of the
present invention, is a breath condensate collection apparatus,
including: a central chamber having double side walls including an
inner side wall and an outer side wall in spaced relationship to
one another; a coolant material sealed between the inner and outer
side walls for cooling at least the inner walls of the central
chamber; a breath input assembly, the interior of which is in fluid
communication with the interior of the central chamber; one or more
obstructive structures arranged in the interior of the central
chamber for increasing the surface area on which condensate may
form; and a breath condensate collection port in fluid
communication with the interior of the central chamber.
[0024] In features of this aspect, the obstructive structures
include grid-like structures; the obstructive structures include
discrete geometric structures; the discrete geometric structures
include spherical objects; the discrete geometric structures are
formed from metal; the discrete geometric structures are formed
from glass; the obstructive structures are fixed in place within
the interior of the central chamber; the obstructive structures are
free-floating within the interior of the central chamber; and
movement of the obstructive structures is restricted to a
particular portion of the central chamber.
[0025] The present invention, according to another aspect of the
present invention, is a method of collecting breath condensate,
including: providing a double-walled central chamber having one or
more obstructive structures arranged in the interior thereof and a
coolant material sealed between the inner and outer side walls for
cooling at least the inner walls of the central chamber; lowering
the temperature of the coolant material to chill at least the inner
walls of the central chamber and the obstructive structures;
receiving, in the interior of the central chamber, exhaled breath
from a patient; condensing portions of the exhaled breath on the
inner surfaces of the inner walls of the central chamber and on the
obstructive structures; and removing condensate, produced during
the condensing step, from the central chamber.
[0026] In features of this aspect, the removing step includes
washing the condensate from the obstructive structures; the washing
step includes adding an amount of liquid to the central chamber,
and the amount is selected to correspond to the amount of
condensate present in the central chamber; the washing step
includes adding an amount of liquid to the central chamber, and the
amount is selected to correspond to the amount of condensate likely
to be present in the central chamber after the patient exhales into
the central chamber for a predetermined period of time; the washing
step includes adding an amount of liquid to the central chamber,
and the amount is selected to correspond to the amount of
condensate likely to be present in the central chamber after the
patient completes a predetermined number of exhalations into the
central chamber; and the method further includes removing the
obstructive structures from the central chamber before carrying out
the washing step.
[0027] The present invention, according to another aspect of the
present invention, is a method of collecting breath condensate,
including: providing a double-walled central chamber having a
removable outlet assembly and a coolant material sealed between the
inner and outer side walls for cooling at least the inner walls of
the central chamber; lowering the temperature of the coolant
material to chill at least the inner walls of the central chamber;
receiving, in the interior of the central chamber, exhaled breath
from a patient; condensing portions of the exhaled breath on the
inner surfaces of the inner walls of the central chamber; removing
the outlet assembly and replacing it with a sampling well; and
moving condensate, produced during the condensing step, from the
central chamber to the sampling well.
[0028] In features of this aspect, the step of moving condensate
includes washing condensate from the central chamber into the
sampling well with a known liquid; the step of washing condensate
includes introducing a predetermined quantity of the known liquid
into the central chamber, mixing the predetermined quantity of the
known liquid with the condensate, and draining the known liquid and
the condensate from the central chamber into the sampling well; the
step of removing the outlet assembly includes creating an opening
into the central chamber, and the step of introducing includes
introducing the known liquid through the opening; the method
further includes storing the known liquid in the sampling well
before replacing the outlet assembly with the sampling well; and
the known liquid is a buffer solution.
[0029] The present invention, according to another aspect of the
present invention, is a method of collecting breath condensate,
including: providing a double-walled central chamber having one or
more obstructive structures arranged in the interior thereof and a
coolant material sealed between the inner and outer side walls for
cooling at least the inner walls of the central chamber;
calibrating the walls and coolant material of the double-walled
central chamber such that, when beginning at a predetermined
temperature, a chosen number of breaths, received from a typical
patient, creates a sufficient amount of breath condensate to be
collected on the inner surfaces of the inner walls of the central
chamber; lowering the temperature of the coolant material to the
predetermined temperature to chill at least the inner walls of the
central chamber; receiving, in the interior of the central chamber,
a plurality of exhalations from a particular patient, where the
number of exhalations is within a predetermined range established
on the basis of the chosen number of breaths; condensing portions
of the exhalations, received from the patient, on the inner
surfaces of the inner walls of the central chamber; and removing
condensate, produced during the condensing step, from the central
chamber.
[0030] In features of this aspect, the predetermined range is 10 to
25 breaths, inclusive; the predetermined temperature is the
temperature of a standard freezer; and the predetermined
temperature is 0.degree. F.
BRIEF DESCRIPTION OF THE DRAWINGS
[0031] Further features, embodiments, and advantages of the present
invention will become apparent from the following detailed
description with reference to the drawings, wherein:
[0032] FIG. 1 is a side cross-sectional schematic view of a breath
condensate collection apparatus in accordance with a first
preferred embodiment of the present invention;
[0033] FIG. 2 is a right end cross-sectional view of the apparatus
of FIG. 1, taken along line 2-2, showing the double-wall
construction;
[0034] FIG. 3 is a right end view of the apparatus of FIG. 1;
[0035] FIG. 4 is a side cross-sectional schematic view of the
breath condensate collection apparatus of FIG. 1 with the plunger
assembly in a fully depressed position;
[0036] FIG. 5 is a side cross-sectional schematic view of a breath
condensate collection apparatus in accordance with a second
preferred embodiment of the present invention;
[0037] FIG. 6A is a partial side view of the plunger assembly of
FIG. 5, illustrating one type of protrusion;
[0038] FIG. 6B is a right end view of the plunger assembly of FIG.
6A;
[0039] FIG. 7A is a partial side view of the plunger assembly of
FIG. 5, illustrating another type of protrusion;
[0040] FIG. 7B is a right end view of the plunger assembly of FIG.
7A;
[0041] FIG. 7C is a partial side cross-sectional view of the
plunger assembly of FIG. 7A;
[0042] FIG. 8 is a side cross-sectional schematic view of a breath
condensate collection apparatus in accordance with a third
preferred embodiment of the present invention;
[0043] FIG. 9 is a side cross-sectional schematic view of the
breath condensate collection apparatus of FIG. 1, shown in an
inverted orientation;
[0044] FIG. 10 is a side cross-sectional schematic view of a breath
condensate collection apparatus in accordance with a fourth
preferred embodiment of the present invention;
[0045] FIG. 11 is a cross-sectional schematic view of a removable
outlet cap for use with the apparatus of FIG. 10;
[0046] FIG. 12 is a cross-sectional schematic view of a removable
sampling well for use with the apparatus of FIG. 10; and
[0047] FIG. 13 is a side cross-sectional schematic view of the
breath condensate collection apparatus of FIG. 10 with the sampling
well installed thereon.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0048] Referring now to the drawings, in which like numerals
represent like components throughout the several views, a variety
of breath condensate collection apparatuses 10, 110, 210, 310, in
accordance with the preferred embodiments of the present invention,
is next shown and described.
[0049] FIG. 1 is a side cross-sectional schematic view of a breath
condensate collection apparatus 10 in accordance with a preferred
embodiment of the present invention. The breath condensate
collection apparatus 10 includes a double-walled syringe 20 and a
breath input assembly 50. The inner wall 22 of the syringe 20
defines a central cylinder 24 in which is fitted a plunger assembly
25 that includes a piston 26, a rubber gasket 28 and a handle 30
extending from one end of the syringe 20. The outer wall 32 is
arranged around the inner wall 22 in such a way as to create a
narrow space between the inner and outer walls 22, 32. FIG. 2 is a
right end cross-sectional view of the apparatus 10 of FIG. 1, taken
along line 2-2, showing the double-wall construction, and FIG. 3 is
a right end view of the apparatus 10 of FIG. 1. During manufacture,
the space between the inner and outer walls 22, 32 may be filled
with a jacket of coolant material 34, and the outer wall 32 may
then be sealed to the inner wall 22 to prevent leakage. In a
preferred embodiment, water may be used as the coolant material 34,
but it should be clear that other materials may likewise be used,
such as polyethylene glycol ("PEG") and the like.
[0050] The syringe 20 further includes an inlet 36, an outlet 38, a
collection port 39 and a pair of one-way valves 40, 42. The first
valve 40 is an intake valve that may be disposed in or adjacent to
the inlet 36, while the second valve 42 is an exit valve that may
be disposed in or adjacent to the outlet 38 in order to facilitate
the passage of exhaled air through the central cylinder 24 in only
a single direction. The outlet valve 42 is preferably disposed
between the central cylinder 24 and the collection port 39 for
purposes that will be made evident hereinbelow. The outlet 38 is
preferably disposed at the end opposite the plunger handle 30 in
order to permit materials collected within the central cylinder 24
to be expressed through the outlet 38 by the piston 26. The valves
40, 42 are illustrated only schematically in the various drawings,
but they may, for example, include two or three self-sealing leaves
formed from plastic or another deformable polymer. The design of
such valves would be apparent to those of ordinary skill in the
art.
[0051] Further, because the piston 26 fills one end of the syringe
20 and the outlet 38 is disposed in the opposite end, the inlet 36
is preferably arranged to penetrate both the inner and outer walls
22, 32 on the side of the syringe 20. In order to cause the most
interaction between exhaled air passing through the central
cylinder 24 and the inner surfaces 44 of the inner wall 22, the
inlet 36 is preferably disposed as close to the piston 26 as
possible; however, it will be clear that other arrangements of
these components are likewise possible without departing from the
scope of the present invention.
[0052] The breath input assembly 50 includes a mouthpiece 52, a
filter 54 and any tubing 56 necessary to guide exhaled breath from
the mouthpiece 52 to the inlet 36 of the syringe 20. The mouthpiece
52 is of suitable size and shape so as to permit comfortable
contact with the mouth area of a patient. The filter 54, which may
comprise a polymer material having perforations or successive
intrusions therein, may be arranged within the tubing 56 between
the mouthpiece 52 and the syringe inlet 36 to prevent saliva and
other liquid or solid matter of a minimum size from passing
therethrough and into the syringe 20. Saliva may be further
prevented from reaching the central cylinder 24 by arranging the
breath input assembly 50 beneath the syringe 20, so that air
passing through the breath input assembly 50 moves upward. In this
arrangement, the effect of gravity on the saliva and other liquid
or solid matter helps to prevent such matter from passing up into
the central chamber 24, as it instead tends to collect in the
tubing 56.
[0053] The tubing 56 is preferably configured so as to avoid
interference between the mouthpiece 52, or any other part of the
tubing 56, and the operation of the plunger assembly 25, as such
operation is described herein. More preferably, the mouthpiece 52
is oriented to be generally parallel with the syringe 20 and the
plunger assembly 25 therein, or in other words, the mouthpiece 52
is oriented in parallel to the main axis defined by the syringe 20.
In this orientation, exhaled breath may be received from a patient
without causing interference to the operation of the plunger
assembly 25, and condensate formed on the inside of the syringe 20
as the patient uses the apparatus 10 will tend to drain downward
toward the outlet 38.
[0054] The dimensions of the apparatus 10 are chosen so that a
sufficient volume of condensate may be collected in a relatively
short period of time using an apparatus 10 that is small and light
enough to be easily held by a patient or attendant and that does
not require the patient to change his breathing patterns. The walls
22, 32 and other structures of the apparatus 10 are preferably
constructed of a material that tends not to bind to proteins, such
as platinum-cured silicon, but other suitable materials may
include, but are not limited to, glass, plastic, polyethylene,
polycarbonate, or polyvinyl or other synthetic polymer. The plunger
assembly 25 may is likewise preferably constructed from a
non-protein-binding material, but may be constructed from any
suitable inert material including, but not limited to, plastic,
vinyl, polyethylene, rubber, platinum-cured silicon or TEFLON.RTM..
In a preferred embodiment, the syringe 20 is between 10 and 20 cm
long with a diameter of between 2 and 5 cm, and the collection port
39 is between 5 and 20 mm long with an internal diameter of between
3 and 10 mm. The thickness of the coolant jacket 34 may be between
1 and 10 mm, and the sample volume, expressed from a single use, is
preferably between 100 .mu.L and 1000 .mu.L, although it may be
possible to obtain useful results from samples as small as 25
.mu.L.
[0055] In operation, one or more syringes 20 are first stored in a
refrigeration device, such as a conventional household or
commercial freezer, that is capable of lowering the temperature to
approximately 0.degree. F., thus freezing the jacket of coolant
material 34 contained between the inner and outer walls 22, 32 of
the syringe 20. When a patient is to be examined, a single syringe
20 is first withdrawn from the freezer. If the breath input
assembly 50 or mouthpiece 52 is stored separately from the rest of
the apparatus 10, then the apparatus 10 is assembled for use by
coupling the various components together. Next, the patient
positions the mouthpiece 52 in a sealed relationship to his mouth
area and exhales into the mouthpiece 52. The exhaled breath is
guided through the tubing 56 and into the central cylinder 24 via
the inlet 36. The intake valve 40 is forced open by positive
pressure, but in the absence of such pressure it prevents air
within the central cylinder 24 from escaping through the inlet 36.
The exhaled breath then exits through the outlet 38 on the end of
the cylinder 24 opposite the intake end. The exit valve 42 permits
air to pass out of the central cylinder 24 only when positive
pressure exists on the cylinder side of the valve 42, while in the
absence of such pressure the valve 42 prevents ambient air from
entering the central cylinder 24 via the outlet 38.
[0056] As the patient exhales through the apparatus 10, the
moisture in the exhaled breath begins to condense on the inner
surfaces 44 of the central cylinder 24. Because of the depressed
temperature of the coolant 34 and the syringe 20, the condensate
may freeze immediately on the inner surface 44. The collection port
39 is preferably nipple-shaped and approximately 1 cm long with a
diameter small enough to cause some minimal resistance to the
exhalation of the patient. The diameter is preferably chosen so as
to slow the rate of expiration such that each exhalation requires
approximately 5 seconds to complete. This increases the amount of
time for exhaled breath to equilibrate with the inside surfaces 44
of the central cylinder 24.
[0057] As the patient continues to exhale through the apparatus 10,
the frozen coolant 34 begins to melt. The composition, volume and
thickness of the coolant jacket 34 surrounding the internal
cylinder 24 is preferably calibrated such that the coolant 34
begins to melt after approximately 10-15 exhalations by the
patient. Once the material 34 melts or thaws after the desired
number of exhalations, the condensate likewise can begin to melt.
Once the condensate is melted, the plunger assembly 25 may be
depressed to express the collected condensate sample through the
outlet 38 and into the collection port 39. FIG. 4 is a side
cross-sectional schematic view of the breath condensate collection
apparatus 10 of FIG. 1 with the plunger assembly 25 in a fully
depressed position. The location of the exit valve 42 in the outlet
38 between the central cylinder 24 and the collection port 39 then
permits the collected condensate to be aspirated from the
collection port 39 using a conventional pipette (not shown). The
condensate may then be transferred from the pipette to a separate
assay well for analysis thereof as desired. Finally, once the
condensate has been collected and withdrawn from the collection
port 39, the entire apparatus 10 may be disposed of according to
conventional waste disposition procedures.
[0058] Although not required, the plunger assembly 25 of the breath
condensate collection apparatus 10 may further include one or more
clips 31 disposed around the end of the syringe 20 opposite the
collection port 39. These clips 31 are preferably formed from a
resilient material and are designed to be deformed away from the
syringe 20 as the plunger handle 30 is forced therebetween. The
clips 31 are then biased back into place by their natural
resiliency once the handle 30 is completely depressed into the
syringe 20 as shown in FIG. 4. Once in this position, the plunger
assembly 25 is effectively and conveniently locked in place by the
clips 31, thereby permitting the syringe 20 to be transported and
handled much more safely and reliably. It should be apparent,
however, that such clips 31 are not necessary in order to be able
to practice the various embodiments of the present invention.
[0059] FIG. 5 is a side cross-sectional schematic view of a breath
condensate collection apparatus 110 in accordance with a second
preferred embodiment of the present invention. This apparatus 110
may be identical to the apparatus 10 of the first preferred
embodiment, except that a semi-conical protrusion 127 (shown
schematically in FIG. 5) is disposed on the surface of the piston
26 facing the outlet 38, the collection port 139 is sized and
shaped to matingly receive the protrusion 127 therein, and the exit
valve 42 is located at the distal end of the collection port 139.
The collection port 139 may then be connected to a colorimetric
device designed to detect condensate analytes.
[0060] Notably, although the exit valve 42 and protrusion 127 are
shown only schematically in the drawings, the exit valve 42 is
preferably positioned as close to the end of the collection port
139 as possible, and the protrusion 127 is preferably sized and
shaped so as to abut the valve 42 when the plunger assembly 25 is
fully depressed into the central cylinder 24. This design minimizes
the amount of fluid that will remain in the syringe 20 when the
plunger assembly 25 is fully depressed, and thus minimizes the
amount of condensate that is available for subsequent testing.
[0061] FIGS. 6A and 6B are a partial side view and a right end
view, respectively, of the plunger assembly 25 of FIG. 5,
illustrating one type of protrusion 127. This type of protrusion
127 includes a series of grooves 129 arranged in the surface
thereof and extending from the base of the protrusion 127 to the
tip. As the piston 26 is pushed into the very end of the central
cylinder 24, the grooves 129 serve as conduits for the condensate
remaining in the syringe 20, thus permitting a small amount of
additional condensate to be collected via the collection port 139
rather than be trapped in the end of the central cylinder 24. This
effect could be further enhanced by the inclusion of additional
groove structures (not shown) in the flat surface of the piston 26
that could be used to guide condensate to the grooves 129 in the
protrusion 127.
[0062] FIGS. 7A, 7B and 7C are a partial side view, a right end
view and a partial side cross-sectional view, respectively, of the
plunger assembly 25 of FIG. 5, illustrating another type of
protrusion 127. This type of protrusion 127 includes a plurality of
openings 231 arranged around the base of the protrusion 127 and
connecting to a hollow shaft 233 that exits through the tip of the
protrusion 127. The openings 231 and central shaft 233 may be
between 1 and 2 mm in diameter. Once again, as the piston 26 is
pushed into the very end of the central cylinder 24, the openings
231 and hollow shaft 233 serve as conduits for the condensate
remaining in the syringe 20, thus permitting a small amount of
additional condensate to be collected via the collection port 139
rather than be trapped in the end of the central cylinder 24. This
effect could also be further enhanced by the inclusion of
additional groove structures (not shown) in the flat surface of the
piston 26 that could be used to guide condensate to the openings
231 in the protrusion 127. The central shaft 233 could also be
fitted with a rigid but hollow tube structure (not shown) of
between 1 and 2 mm (external diameter) to provide a needle-like
extension through which the fluid sample could be directed and
extruded when the plunger assembly 25 is fully depressed.
[0063] FIG. 8 is a side cross-sectional schematic view of a breath
condensate collection apparatus 210 in accordance with a third
preferred embodiment of the present invention. Like the apparatuses
of the first and second embodiments 10, 110, this breath condensate
collection apparatus 210 includes a syringe 220, having inner and
outer walls 222, 232, and a breath input assembly 50. The syringe
220 and the breath input assembly 50 are generally similar to those
of the first embodiment. However, unlike the first embodiment, the
outlet 238 and the outlet valve 42 are disposed on the top of the
syringe 220, near the end opposite the plunger handle 30, and the
syringe 220 further includes a collection port 239, disposed on the
bottom of the syringe 220 at the very end of the central cylinder
224, and a cap 37 for covering the collection port 239. The cap may
be threaded or otherwise adapted for secure connection of the cap
37 to the collection port 239 in order to temporarily close the
collection port 239. This apparatus 210 functions the same way as
the first apparatus embodiment 10 except that exhaled breath exits
through the outlet 238 on the top of the syringe 220, but
condensate may be collected and expressed from the central cylinder
224 via the collection port 239 on the bottom of the syringe 220.
The cap 37 prevents exhaled air from passing through the collection
port 239, but may be unscrewed or otherwise removed when it is
desired to collection the condensate from the central cylinder 224.
This may be particularly useful, for example, in expressing
condensate directly into an analyzer temporarily or permanently
mounted on or adjacent the syringe 220, as described in co-pending
and commonly-assigned U.S. Provisional Patent Application No.
60/447,581, filed Feb. 14, 2003.
[0064] As described previously, it is advantageous for the breath
input assembly 50 in each of the three embodiments 10, 110, 210
discussed thus far to be arranged beneath the respective syringe
20, 220 in order to aid in preventing saliva and other matter from
reaching the central cylinder or chamber 24, 224. However, it will
be apparent that the breath input assembly 50 may instead be
oriented such that the breath input assembly 50 is located at the
top of the syringe 20, 220. FIG. 9 is a side cross-sectional
schematic view of the breath condensate collection apparatus 10 of
FIG. 1, shown in an inverted orientation, whereby the breath input
assembly 50 is disposed at the top of the syringe 20. Although
saliva may be more likely to enter the syringe 20, it should be
apparent that other features of the present invention may not be
affected by this arrangement. Although not shown, the apparatuses
110, 210 of the second and third embodiments may likewise be
rearranged, although it should be noted that the breath input
assembly 50 in the third apparatus 210 would have to be placed on
the opposite side of the collection port 239 in order to facilitate
proper operation thereof.
[0065] FIG. 10 is a side cross-sectional schematic view of a breath
condensate collection apparatus 310 in accordance with a fourth
preferred embodiment of the present invention. Like the apparatus
10 of the first embodiment, this breath condensate collection
apparatus 310 includes a double-walled syringe 320 and a breath
input assembly 350. The inner wall 322 of the syringe 320 defines a
central chamber 324, but unlike the central cylinder 24 of the
first embodiment, the central chamber 324 of the alternative
embodiment need not be cylindrical. The outer wall 332 is arranged
around the inner wall 322 in such a way as to create a narrow space
between the inner and outer walls 322, 332. Like the apparatus 10
of the first embodiment, however, the space between the inner and
outer walls 322, 332 may be filled during manufacture with a jacket
of coolant material 34, and the outer wall 332 is then sealed to
the inner wall 322 to prevent leakage.
[0066] The syringe 320 further includes an inlet 36, an outlet cap
60 and a first one-way valve 40. The first valve 40 is an intake
valve that may be disposed in or adjacent to the inlet 36. FIG. 11
is a cross-sectional schematic view of a removable outlet cap 60
for use with the apparatus of FIG. 10. The outlet cap 60 includes
an outlet 338 and a second valve 342, which is an exit valve
disposed in or adjacent to the outlet 338 in order to facilitate
the passage of exhaled air through the central chamber 324 in only
a single direction. The outlet cap 60 is preferably disposed at the
end of the central chamber 324 opposite the inlet 36.
[0067] The breath input assembly 350 includes a mouthpiece 52, a
filter 54 and any tubing 356 necessary to guide exhaled breath from
the mouthpiece 52 to the inlet 36 of the syringe 320. As with the
first embodiment of the apparatus 10, the mouthpiece 52 is of
suitable size and shape so as to permit comfortable contact with
the mouth area of a patient, and the filter 54 may be arranged
within the tubing 356 between the mouthpiece 52 and the syringe
inlet 36 to prevent saliva and other liquid or solid matter of a
minimum size from passing therethrough and into the syringe
320.
[0068] Unlike the embodiments described previously, the apparatus
310 of the fourth embodiment does not include a plunger assembly.
Instead, as illustrated in FIG. 10, one or more obstructive
internal structures 62 may be arranged inside the central chamber
324 in order to increase the surface area with which exhaled breath
that passes through the central chamber 324 may come in contact.
Suitable obstructive structures 62 may include grid-like structures
and other baffles, spheres such as those shown in FIG. 10, or other
geometric shapes formed from metal, glass, or other suitable
materials. These structures 62 may be held in place within the
syringe 320 using appropriate screens, bosses or the like (not
shown). If cooled in like manner to the syringe 20 of the first
embodiment, breath condensate may subsequently be produced inside
the central chamber 324 more efficiently.
[0069] However, because the obstructive structures 62 occupy the
interior of the central chamber 324, removal of the condensate
collected thereon may require flushing the interior of the central
chamber 324 with a suitable buffer solution 72 of known volume and
composition. For example, the solution may consist of distilled
water, or water containing an organic dye to indicate the pH of the
solution using visual or spectrophotometric colorimetry. In a
preferred method of operation of the alternative embodiment shown
in FIG. 10, the apparatus 310 is oriented horizontally (not shown),
and breath condensate is collected on the inner surfaces 44 of the
central chamber 324 and on the obstructive structures 62 in the
same manner as described with respect to the first embodiment. The
apparatus 310 may then be rotated to the vertical orientation shown
in FIG. 10. With the apparatus 310 in the illustrated orientation,
the outlet cap 60 may be removed without danger of the condensate
inside the syringe 320 escaping. Suitable connection means, such as
corresponding screw threads or the like, are preferably provided on
the syringe 320 and the outlet cap 60 to facilitate such
removal.
[0070] Once the outlet cap 60 has been removed, the buffer solution
72 may be added to the central chamber 324 in order to wash the
collected condensate therefrom. Suitable buffer solutions and
volumes will be apparent to those of ordinary skill of the art.
FIG. 12 is a cross-sectional schematic view of a removable sampling
well 70 for use with the apparatus of FIG. 10. With the outlet cap
60 removed and the apparatus oriented as shown in FIG. 10, a
sampling well 70 such as that shown in FIG. 12 may be fastened onto
the open end of the syringe 320 to close that end. FIG. 13 is a
side cross-sectional schematic view of the breath condensate
collection apparatus 310 of FIG. 10 with the sampling well 70
installed thereon. Once the sampling well 70 is in place, the
entire apparatus 310 may be inverted to the orientation shown in
FIG. 13, thus causing the buffer solution 72 to wash the collected
breath condensate out the bottom of the syringe 320 and into the
sampling well 70. Once collected in the sampling well 70, the
sampling well 70 may once again be removed and the buffered
condensate 74 may be aliquotted for testing as desired.
[0071] In a variation of the various embodiments described herein,
any of the syringes 10, 110, 210, 310 may alternatively be cooled
via an endothermic reaction, such as that created when
NH.sub.4NO.sub.3 is hydrated with water in a 1:4 molar ratio, to
produce a temperature below 0.degree. C. for approximately 10
minutes. This may be facilitated by storing water in the space
between the walls of the syringe 10, 110, 210, 310 in breakable
ampules, surrounded by dry NH.sub.4NO.sub.3, or by sealing only the
NH.sub.4NO.sub.3 in the same space, to be hydrated or otherwise
injected with water via a needle port. NH.sub.4NO.sub.3 may be
prepared because the reaction may be triggered by injecting the
NH.sub.4NO.sub.3 material with a preset volume of tap water or
saline via the needle port, similar to the way a nurse would
"flush" an IV line, but it should be apparent that other materials
may likewise be used to create a suitable endothermic reaction. For
example, a commercial gel refrigerant that may be activated by
slight compression of the outer wall of the syringe may likewise be
used. One such material is Cold Ice, produced by Cold Ice, Inc. of
Oakland, Calif.
[0072] Once the sample is obtained using any of the various
apparatuses 10, 110, 210, 310 described herein, or by some
alternative means, a battery of tests may be performed on the
sample in order to detect lung ischemia. The battery of tests may
include measuring or testing for fibrinopeptides, thromboxane B2,
platelet activating factor, leukotrienes C, D and E, carbon
monoxide-to-nitric oxide ratio and chemokine and other proteins.
Each of these has specific purposes, as described below. The
various tests may all be performed in a manner well known to those
of ordinary skill in the art.
[0073] Measurement of fibrinopeptides in breath condensate is
believed to have the potential to allow more localized measurement
of the presence of clot in the lung vasulature. As described
previously, thrombin cleaves fibrinogen A peptide from fibrinogen
as a prerequisite to fibrin gelation. Owing to its small size, it
is hypothesized that fibrinopeptides will traverse the alveolar
membrane, and equilibrate in alveolar fluid, and thus will be found
in exhaled condensate. Thus, the presence of fibrinopeptides in the
breath condensate sample would indicate the presence of clot.
[0074] Also, pulmonary vascular constriction may be detected by
measuring PGF.sub.2., thromboxane B.sub.2, PAF, leukotrienes C, D,
and E, and the ratio of CO:NO in condensate, thus providing a basis
for initiating pulmonary vasodilator therapy or COX1,2 inhibition.
Our laboratory has used an experimental pulmonary vascular
occlusion (PVO), induced by venous infusion of polystyrene
microspheres in a rat, to determine three major findings related to
breath condensate analysis. We and others have found increased
content of PGF.sub.2.alpha., thromboxane B.sub.2, platelet
activating factor (PAF) and vasoconstrictive leukotrienes C, D, and
E in the lung washings in our rat model. (Nakos, Am J Resp Crit
Care Med 1998, 158:1504) The magnitude of the concentration of
these vasoconstrictive agents correlated with the severity of
hypoxemia and pulmonary hypertension. We also have found extremely
elevated expression of the gene encoding heme oxygenase-1 but the
nearly complete absence of expression of the gene encoding for the
inducible enzyme, nitric oxide synthase. Heme oxygenase produces
carbon monoxide (CO) from heme substrate whereas nitric oxide
synthase produces nitric oxide (NO). Both are vasodilator
substances. In rats subjected to PVO, we have also found early
increases in lung gene expression of cytokine induced neutrophil
attractant 1 and 2 (CINC 1 & 2), and monocyte/macrophage
chemoattractant protein (MCP) 1 and 2, and monocyte/macrophage
inflammatory proteins (MIP) 1.alpha. and 1.beta. with concomitant
increases in each protein in the washings from the lung airways and
alveoli obtained as soon as 2 hours after induction of PE, and
lasting up to 18 hours after PE induction. The chemoattractant
molecules can cause the migration of leukocytes into the affected
area, and through this mechanism, can potentiate injury during
therapeutic reperfision.
[0075] Further, the presence of certain chemokines in exhaled
condensate is believed to predispose reperfusion injury. The
chemokines discovered in rats included CINC 1, CINC 2, MIP
1.alpha., MIP 1.beta., and MCP 1 and 2. The human homologues that
will be tested in our device will include CXCL1, CXCL 2 and CXCL 3;
CCL 2, CCL 3, CCL 4 and CCL 8, using nomenclature outlined by
Zlotnick and Yoshie, Immunity, 2000; 12:121-127. Investigators have
found chemokines with an inflammatory model of pulmonary
hypertension. (Kimura, Lab Invest 1998-78:571-81; Ikeda, Am J
Physiol Heart Circ Physiol, 2002, 283(5):H2021-8). Unlike the
in-vivo PVO model, which causes primarily obstructed blood flow,
the model in the latter study incites inflammation and remodeling,
which over weeks leads to vascular occlusion. Likewise,
investigators have also found increased chemokine expression in
lungs subjected to hilar ligation or clamping, which interrupts
both perfusion and ventilation. The latter model differs
significantly from in-vivo PVO because alveolar ventilation
continues with in-vivo PVO. Thus the ischemic insult differs with
in-vivo PVO versus hilar ligation.
[0076] Based on the foregoing information, it is readily understood
by those persons skilled in the art that the present invention is
susceptible of broad utility and application. Many embodiments and
adaptations of the present invention other than those specifically
described herein, as well as many variations, modifications, and
equivalent arrangements, will be apparent from or reasonably
suggested by the present invention and the foregoing descriptions
thereof, without departing from the substance or scope of the
present invention. Accordingly, while the present invention has
been described herein in detail in relation to its preferred
embodiment, it is to be understood that this disclosure is only
illustrative and exemplary of the present invention and is made
merely for the purpose of providing a full and enabling disclosure
of the invention. The foregoing disclosure is not intended to be
construed to limit the present invention or otherwise exclude any
such other embodiments, adaptations, variations, modifications or
equivalent arrangements; the present invention being limited only
by the claims appended hereto and the equivalents thereof. Although
specific terms are employed herein, they are used in a generic and
descriptive sense only and not for the purpose of limitation.
* * * * *