U.S. patent application number 11/869249 was filed with the patent office on 2008-04-17 for methods and devices for retrieval of a medical agent from a physiological efferent fluid collection site.
This patent application is currently assigned to CATHAROS MEDICAL SYSTEMS, INC.. Invention is credited to BRIAN K. COURTNEY, PETER J. FITZGERALD, ALI HASSAN.
Application Number | 20080091166 11/869249 |
Document ID | / |
Family ID | 36148987 |
Filed Date | 2008-04-17 |
United States Patent
Application |
20080091166 |
Kind Code |
A1 |
FITZGERALD; PETER J. ; et
al. |
April 17, 2008 |
METHODS AND DEVICES FOR RETRIEVAL OF A MEDICAL AGENT FROM A
PHYSIOLOGICAL EFFERENT FLUID COLLECTION SITE
Abstract
Methods and devices for selectively removing an agent from a
physiological efferent fluid collection site are provided. A
feature of the invention is that a non-occlusive aspiration device
is employed to selectively remove the target agent from the site
only when the target agent is present in the site. Also provided
are systems and kits for performing the subject methods. The
subject invention finds use in a variety of different applications,
including the selective removal of both therapeutic and diagnostic
agents from a variety of different physiological sites.
Inventors: |
FITZGERALD; PETER J.;
(Portola Valley, CA) ; HASSAN; ALI; (Mountain
View, CA) ; COURTNEY; BRIAN K.; (Toronto,
CA) |
Correspondence
Address: |
BOZICEVIC, FIELD & FRANCIS LLP
1900 UNIVERSITY AVENUE
SUITE 200
EAST PALO ALTO
CA
94303
US
|
Assignee: |
CATHAROS MEDICAL SYSTEMS,
INC.
548 Division Street
Campbell
CA
95008
|
Family ID: |
36148987 |
Appl. No.: |
11/869249 |
Filed: |
October 9, 2007 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10962205 |
Oct 7, 2004 |
7300429 |
|
|
11869249 |
Oct 9, 2007 |
|
|
|
10803468 |
Mar 17, 2004 |
7211073 |
|
|
10962205 |
Oct 7, 2004 |
|
|
|
60456107 |
Mar 18, 2003 |
|
|
|
Current U.S.
Class: |
604/500 |
Current CPC
Class: |
A61M 2025/0073 20130101;
A61M 25/0074 20130101; A61B 5/0084 20130101; A61B 5/01 20130101;
A61B 8/12 20130101; A61M 25/0068 20130101; A61B 5/418 20130101;
A61B 5/0261 20130101; A61B 5/415 20130101; A61M 25/0082 20130101;
A61M 2025/0076 20130101; A61B 5/6853 20130101; A61M 1/008 20130101;
A61M 25/007 20130101; A61M 25/1002 20130101; A61B 5/0086 20130101;
A61B 2017/22082 20130101; A61B 17/22 20130101 |
Class at
Publication: |
604/500 |
International
Class: |
A61M 31/00 20060101
A61M031/00 |
Claims
1. A method for removing an agent from a physiological efferent
fluid collection site, said method comprising: introducing a
non-occlusive aspiration element to a target aspiration site
adjacent said physiological efferent fluid collection site;
introducing an occlusion element to a target occlusion site
proximal of the target aspiration site; and activating said
aspiration element when said agent is at least predicted to be
present in said target site to selectively remove said agent from
said physiological efferent fluid collection site.
2. The method according to claim 1, wherein said physiological
efferent fluid collection site is a vascular fluid collection
site.
3. The method according to claim 2, wherein said vascular fluid
collection site is a cardiovascular fluid collection site.
4. The method according to claim 3, wherein said cardiovascular
fluid collection site is a coronary cardiovascular fluid collection
site.
5. The method according to claim 4, wherein said coronary
cardiovascular fluid collection site is a coronary sinus.
6. The method according to claim 1, wherein said physiological
efferent fluid collection site is present in a mammal.
7. The method according to claim 6, wherein said mammal is a
human.
8. The method according to claim 1, wherein said agent is a
therapeutic agent.
9. The method according to claim 1, wherein said agent is a
diagnostic agent.
10. The method according to claim 9, wherein said diagnostic agent
is a contrast agent.
11. The method according to claim 1, further comprising activating
said occlusion element to prevent flow of fluid proximally of the
target occlusion site.
12. The method according to claim 11, wherein said occlusion
element is configured to abut a tissue structure positioned in
between said target aspiration site and said target occlusion
site.
13. The method according to claim 12, wherein said physiological
efferent fluid collection site is a coronary sinus, said tissue
structure is the coronary sinus os and said target occlusion site
is downstream of said coronary sinus os.
14. The method according to claim 11, wherein said occlusion
element is configured to abut a tissue structure adjacent said
physiological efferent fluid collection site.
15. The method according to claim 14, wherein said physiological
efferent fluid collection site is a coronary sinus, said tissue
structure is a wall of said coronary sinus and said target
occlusion site is upstream of the coronary sinus os.
16. The method of claim 11, wherein said occlusion element is
inflatable and said activating said occlusion element comprises
inflating said occlusion element.
17. The method of claim 11, wherein said occlusion element is
expandable and said activating said occlusion element comprises
expanding said occlusion element.
18. The method of claim 11, wherein said activating said occlusion
element is accomplished passively.
19. A system for selectively removing an agent from a physiological
efferent fluid collection site, said system comprising: (a) a
non-occlusive aspiration lumen; (b) an aspiration mechanism
operatively connected to said non-occlusive aspiration lumen; (c)
an actuation controller element for controlling actuation of said
aspiration mechanism; and (d) an occlusion mechanism operatively
connected to said non-occlusive aspiration lumen and positioned
proximally of said aspiration mechanism.
20. The system according to claim 19, wherein said occlusion
mechanism is activated passively upon actuation of said aspiration
mechanism.
21. The system according to claim 20, wherein said occlusion
mechanism comprises a parachute configuration.
22. The system according to claim 19, wherein said occlusion
mechanism comprises an inflatable member.
23. The system according to claim 22, wherein said aspiration lumen
comprises an inflation port by which said inflatable member is
inflated.
24. The system according to claim 19, further comprising a sheath
extendable over said aspiration lumen and said occlusion mechanism,
and wherein said occlusion mechanism comprises an expandable
member, wherein removal of said sheath expands said expandable
member.
25. The system according to claim 19, further comprising a
mechanism for advancing said occlusion member over said aspiration
lumen.
26. The system according to claim 19, wherein said occlusion member
is fixed to said aspiration lumen.
27. A kit for selectively removing an agent from a physiological
efferent fluid collection site, said kit comprising: (a) an
aspiration element comprising: (i) a non-occlusive aspiration
lumen; (ii) an aspiration mechanism operatively connected to said
non-occlusive aspiration lumen; (iii) an actuation controller
element for controlling actuation of said aspiration element; and
(iv) an occlusion mechanism operatively connected to said
non-occlusive aspiration lumen and positioned proximally of said
aspiration mechanism; and (b) instructions for practicing the
method of claim 1.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/962,205 filed Oct. 7, 2004 which is a
continuation-in-part of U.S. patent application Ser. No. 10/803,468
filed Mar. 17, 2004 which claims priority to the filing date of
U.S. Provisional Patent Application Ser. No. 60/456,107 filed Mar.
18, 2003 pursuant to 35 U.S.C. .sctn. 119 (e); the disclosures of
which are herein incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Administration of therapeutic or diagnostic agents to a
subject is typically accomplished by either localized or systemic
routes. With many types of agents, localized delivery methods are
desirable. For example, medical compounds of interest may have
desired diagnostic or therapeutic effects within the region into
which they are introduced, but also exhibit toxic or other
undesirable effects when they are allowed to circulate elsewhere.
In certain cases, it is desirable to introduce a higher volume of a
compound to the local region than can be tolerated by other body
tissues if that volume were to ultimately cause the systemic
concentration to exceed a safe threshold.
[0003] A common example of such a compound is radio-opaque dye.
Iodinated forms of such a dye are used routinely during
catheter-based interventional procedures such as coronary, renal,
neurological and peripheral arteriography. The iodine component has
a high absorption of x-rays and therefore provides a contrast
medium for the radiological identification of vessels when
introduced within an upstream artery. However, the use of such dyes
is known to have potential toxic effects depending on the specific
formulation, including direct injury to renal tubule cells,
endothelial injury, bronchospasm, inflammatory reactions,
pro-coagulation, anti-coagulation, vasodilation and
thyrotoxicosis.
[0004] Other materials that may be introduced locally for desired
effects but whose direct or other effects would be undesired
elsewhere include vasoactive agents, cytotoxic agents, genetic
vectors, apoptotic agents, anoxic agents (including saline),
photodynamic agents, emboli-promoting particles or coils,
antibodies, cytokines, immunologically targeted agents and
hormones.
[0005] An important anatomic concept with respect to the
vasculature and other conduits supplying and draining an organ is
the principle that a tissue or organ and regions of the organ have
a limited number of primary supply conduits and a limited number of
draining conduits. Material introduced into the upstream side of
the target tissue will typically be dispersed among the diverging
arterioles and capillaries, which then reconverge into a collection
of common venules and vein(s) downstream, e.g., in a physiological
efferent fluid collection site. For example, the myocardium of the
heart is fed by the right coronary, left anterior descending and
left circumflex arteries. Each of these arteries enters a capillary
network that eventually converges into the small and middle cardiac
vein, anterior interventricular vein and posterior vein of the left
ventricle. These veins are all tributaries of the coronary sinus,
which may be viewed as a cardiovascular efferent fluid collection
site. Material introduced into any of the aforementioned coronary
arteries that travels through the capillary network will enter the
coronary sinus providing an opportunity to collect it before it
returns to the systemic circulation. In another example, the brain
is fed by the carotid and vertebral arteries which enter a highly
anastomotic network. Blood flow through the brain substantially
drains to the systemic circulation via a network of sinuses that
converge onto the internal jugular veins. In yet another example,
each kidney is substantially supplied by a renal artery and drained
by a renal vein. In yet another example, a tumor or metastatic
lymph node may have a set of primary afferent (supply) conduits and
a set of primary efferent (drainage) conduits. In yet another
example, the lungs are supplied by a pulmonary artery and its
branches, and are drained by the pulmonary veins and their
tributaries into the left atrium.
[0006] As indicated above, there are many instances where localized
delivery of an agent is desired. Of particular interest in certain
situations is the localized delivery and then subsequent removal of
an active agent in an administration approach which would limit the
systemic exposure of a subject to an agent even more effectively
than localized delivery alone. The present invention satisfies this
need.
RELEVANT LITERATURE
[0007] PCT Publication Nos. WO 02/058777 and WO 02/060511.
SUMMARY OF THE INVENTION
[0008] Methods and devices for selectively removing an agent from a
physiological efferent fluid collection site are provided. A
feature of the invention is that a non-occlusive aspiration device
is employed to selectively remove the target agent from the site,
e.g., by removing fluid from the target site primarily when the
target agent is at least predicted to be, e.g., anticipated and/or
known to be, present in the site. Also provided are systems and
kits for performing the subject methods. The subject invention
finds use in a variety of different applications, including the
selective removal of both therapeutic and diagnostic agents from a
variety of different physiological sites.
BRIEF DESCRIPTION OF THE FIGURES
[0009] FIG. 1 provides a block diagram of a representative system
according to the subject invention.
[0010] FIG. 2 depicts a non-occlusive catheter whose distal tip
obtains a profile that aids in delivering the distal tip into the
coronary sinus from the right atrium.
[0011] FIG. 3 provides a three-dimension view of the distal end of
a device according to the present invention.
[0012] FIGS. 4A and 4B depict representative catheter aspiration
elements of devices according to the subject invention, where the
distal ends include a plurality of fluid entry ports.
[0013] FIG. 5 provides depicts yet another representative
embodiment.
[0014] FIGS. 6A and 6B depict another representative catheter
aspiration element of a device according to the subject invention,
where the aspiration lumen has an expandable distal end, where the
distal end may be fenestrated with sealable fenestrae as shown in
FIGS. 6A and 6B.
[0015] FIGS. 7A and 7B provide a representative embodiment of a
device according to the present invention.
[0016] FIGS. 8A to 8C provide depictions of representative
embodiments of closable fluid exit ports or windows that may be
found on devices according to the present invention.
[0017] FIG. 9 provides a depiction of a device according to an
embodiment of the present invention in which fluid from the
coronary sinus is collected into the device in the right
atrium.
[0018] FIG. 10 provides a depiction of a device according to an
embodiment of the present invention in which a spiral balloon
element is present to modulate fluid flow through the coronary
sinus.
[0019] FIGS. 11, 12 and 13 show alternative embodiments of the
subject devices that including positioning elements.
[0020] FIGS. 14A to 14C provide different depictions of a device
that collects fluid from a target site proximal to an efferent
fluid collection site.
[0021] FIGS. 15A to 15B provide different depictions of a device
that includes a passive shunting element.
[0022] FIGS. 16A and 16B provide a depiction of a device that
includes an active shunting element.
[0023] FIG. 17 provides a representation of a device employed in
the Experimental Section, below.
[0024] FIGS. 18 to 20 provide graphical results of data obtained
during experiments reported in the Experimental Section, below.
[0025] FIGS. 21A and 21B illustrate a device that includes a
passive flow occlusion element.
[0026] FIGS. 22A and 22B illustrate devices that occlude fluid flow
at a target site proximal to an efferent fluid collection site.
DESCRIPTION OF THE SPECIFIC EMBODIMENTS
[0027] Methods and devices for selectively removing an agent from a
physiological efferent fluid collection site are provided. A
feature of the invention is that a non-occlusive aspiration device
is employed to selectively remove the target agent from the site,
e.g., by removing fluid from the target site primarily when the
target agent is at least predicted to be, e.g., anticipated and/or
known to be, present in the site. Also provided are systems and
kits for performing the subject methods. The subject invention
finds use in a variety of different applications, including the
selective removal of both therapeutic and diagnostic agents from a
variety of different physiological sites.
[0028] Before the subject invention is described further, it is to
be understood that the invention is not limited to the particular
embodiments of the invention described below, as variations of the
particular embodiments may be made and still fall within the scope
of the appended claims. It is also to be understood that the
terminology employed is for the purpose of describing particular
embodiments, and is not intended to be limiting. Instead, the scope
of the present invention will be established by the appended
claims.
[0029] It must be noted that, as used in this specification and the
appended claims, the singular forms "a," "an" and "the" include
plural reference unless the context clearly dictates otherwise.
Unless defined otherwise all technical and scientific terms used
herein have the same meaning as commonly understood to one of
ordinary skill in the art to which this invention belongs.
[0030] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower
limit, unless the context clearly dictates otherwise, between the
upper and lower limit of that range and any other stated or
intervening value in that stated range, is encompassed within the
invention. The upper and lower limits of these smaller ranges may
independently be included in the smaller ranges, and such
embodiments are also encompassed within the invention, subject to
any specifically excluded limit in the stated range. Where the
stated range includes one or both of the limits, ranges excluding
either or both of those included limits are also included in the
invention.
[0031] All publications mentioned herein are incorporated herein by
reference for the purpose of describing and disclosing components
that are described in the publications that might be used in
connection with the presently described invention.
[0032] As summarized above, the present invention provides methods
and devices, as well as systems and kits, for selectively removing
an agent from a physiological efferent fluid collection site. In
further describing the subject invention, the subject methods are
reviewed first in greater detail, followed by a more in-depth
description of representative embodiments of systems and devices
for practicing the subject methods, as well as a review of various
representative applications in which the subject invention finds
use. Finally, a review of representative kits according to the
subject invention is provided.
Methods
[0033] As summarized above, the subject invention provides methods
of selectively removing an agent from a host or patient, and
specifically from a target site which is a region that is or is
proximal to a physiological efferent fluid collection site. By
physiological efferent fluid collection site is meant a site in a
living entity, that may be naturally occurring or artificially
produced (such as by surgical technique), typically an animal,
where fluid from two different sources or inputs combines or flows
into a single location. Generally the animals are "mammals" or
"mammalian," where these terms are used broadly to describe
organisms which are within the class mammalia, including the orders
carnivore (e.g., dogs and cats), rodentia (e.g., mice, guinea pigs,
and rats), lagomorpha (e.g. rabbits) and primates (e.g., humans,
chimpanzees, and monkeys). In many embodiments, the hosts, subjects
or patients will be humans.
[0034] In certain embodiments, the physiological efferent fluid
collection site is a vascular efferent fluid collection site, where
fluid from at least two different vessels joins into a single
vessel. In certain embodiments, the vascular efferent fluid
collection site is a cardiovascular fluid collection site, where
fluid from at least two different veins joins into a single veinous
structure. In a specific embodiment of interest, the cardiovascular
efferent fluid collection site is the coronary sinus. In yet other
embodiments, as indicated above, the efferent fluid collection site
may be an artificially, e.g., surgically produced, fluid collection
site, e.g., a non-naturally occurring fluid collection site
produced by surgically joining two or more vessels together,
etc.
[0035] In practicing the subject methods, an agent (which in many
embodiments has been locally administered to a subject) is
selectively removed from a target site, which target site is the
physiological efferent fluid collection site or a region proximal
thereto, e.g., downstream therefrom, where when the region is
proximal thereto, in certain illustrative embodiments the target
fluid removal site is no more than about 40 mm from the efferent
fluid collection site, e.g., no more than about 15 mm from the
efferent fluid collection site. By selectively removed is meant
that the subject methods remove fluid from the target site in a
manner that selectively or preferentially removes fluid that is at
least predicted to include the agent, where the removed fluid is
not returned to the body, at least not without processing to remove
the target agent present therein. Depending on the particular
protocol and device employed, as described in greater detail below,
the fluid may be continuously collected at the fluid collection
site but not removed from the body unless it is at least predicted
to include agent, e.g., as occurs in those embodiments where fluid
is collected at the fluid collection site but immediately shunted
back to the subject if it is not at least predicted to include
agent. By at least predicted is meant that the bulk or majority of
the fluid removed from the site is fluid that is either anticipated
to include the agent, e.g., fluid in which the presence of the
agent is inferred, or fluid that is known to include the agent,
e.g., fluid in which the presence of the agent is detected.
Depending upon the particular embodiment of the invention being
practiced, in selectively removing fluid from the target fluid
collection site and subject, fluid may be removed from the site and
subject for a period of time which commences prior to when agent is
at least predicted to be in the site, and extend for a period of
time after agent is at least predicted to be in the site. In such
embodiments, the period of time during which fluid is collected
before and/or after agent is at least predicted to be in the site
is a fraction or portion of the total period of time during which
fluid is removed, typically being less than 50%, such as less than
25% including less than 10-15% of the total time period during
which fluid is removed.
[0036] In certain embodiments, the subject methods do not remove
all fluid from a target and efferent fluid collection site, but
just fluid that is at least predicted to include the target agent
of interest. In other words, in practicing the subject methods, not
all fluid from an efferent fluid collection site present over a
given period of time is removed, only fluid that is at least
predicted to include the target agent of interest that is to be
removed. Put another way, over a given period of time where fluid
that does and does not include the target agent flows through the
efferent fluid collection site and/or a target fluid collection
site, only fluid that is at least predicted, e.g., is anticipated
or known to include the agent, is removed from the site and
subject, while fluid that does not likely include the target agent
is preferentially not removed from the site and subject.
[0037] Another feature of certain embodiments of the subject
methods is that not all of the agent that is administered prior to
practice of the subject methods is removed from the subject. In
other words, only a portion of the administered agent is removed
from the host or patient by the subject methods. By portion is
meant at least about 20%, usually at least about 50% and more
usually at least about 70% of the administered agent is removed by
the subject methods, where in certain embodiments, the portion
removed is at least about 75%, at least about 80%, at least about
90% or more. However, as not all of the agent is collected during
practice of the subject methods, in certain embodiments at least 1%
of the originally administered agent remains in the subject or
patient, such as at least about 5% or at least about 10%.
[0038] Agent is selectively removed from the target site, which may
or may not be the efferent fluid collection site, according to the
subject methods by removing, e.g., aspirating, fluid from the
target site and subject/patient/host, substantially only when the
target agent is at least predicted to be present in the target
site, as described above. As such, when agent is at least predicted
to be present in the target site, fluid is removed from the site
and host. Conversely, in many embodiments when agent is not
predicted to be present in the site, fluid is not removed at least
from the host, subject or patient, and in certain embodiments not
from the site. Accordingly, in certain embodiments, upon detection
or anticipation of agent in the fluid collection site fluid is
removed or aspirated from the site and subject, while when the
target agent is not detected or anticipated to be present in the
site, fluid is not removed from the site, with the exception of a
short period of time before and/or after the time when agent is at
least predicted to be in the target site, as described above.
[0039] In certain embodiments, fluid is selectively removed by
actuating a fluid removal element, e.g., aspiration device, such as
the devices described below, a defined period of time following
administration of the agent to the subject, e.g., an absolute
preset period of time, a period of time as defined by a
physiological metric, e.g., heart beat, etc.
[0040] In certain embodiments, the methods include a step of
detecting the presence of target agent in the site and then
removing fluid, and agent present therein, from the site in
response to detection of the presence of target agent in the site.
Typically, when agent is no longer detected in the efferent fluid
collection site, the methods stop removing fluid from the site.
Thus, fluid is only removed from the efferent fluid collection site
and subject over a time period that substantially overlaps the
period in which the target agent is present in the efferent fluid
collection site.
[0041] In practicing these embodiments of the subject methods, the
agent may be detected in the fluid collection site using a number
of different protocols. In certain embodiments, agent is visually
detected by a skilled operator, who then removes fluid in response
to visualizing agent, e.g., according to the protocols described
below, present in the fluid collection site. In yet other
embodiments, agent detection devices that are operatively connected
to a fluid removal device are employed, where a signal from the
detector that agent is present in the fluid collection site
automatically actuates a fluid removal device, e.g., aspiration
unit. Representative embodiments of devices that may be employed in
such embodiments are described in greater detail below.
[0042] To aid in the detection of the agent, in certain embodiments
the agent will be one that is labeled with a detectable label,
e.g., agent that has been labeled with a detectable label prior to
its introduction into the patient. The agent may be directly
labeled with the detectable label, or associated with a detectable
label such that the agent is indirectly detectable in that
detection of the label also indicates the presence of agent which
is presumed or inferred to be within the vicinity of the label. The
nature of the label may vary, and may be a radio label, fluorescent
label, chromogenic label (e.g., that has a pigment detectable in
the optically visible spectrum), etc.
[0043] In certain embodiments, the pressure of the target site
and/or efferent fluid collection site (which may or may not be the
same locations, as described above) and or the tributaries thereof,
including a subset of the tributaries thereof, may be modulated,
e.g., reduced, in order to achieve the desired collection of agent
from the host. The manner in which the pressure may be modulated
may vary depending on the particular device employed and manner in
which it is implemented, where representative devices and protocols
capable of pressure modulation of the target/efferent fluid
collection site are described in greater detail below. By
modulating the pressure in this manner, one can reduce the pressure
within the collection site sufficiently to improve the efficacy of
removing the desired agent without causing collapse of the
tributaries of the efferent fluid collection site, resulting in a
better or more favorable outcome of the method.
[0044] In certain embodiments, devices that include a shunting
element, be it a passive or active shunting element, are employed
in a manner that modulates the pressure of the target site and/or
efferent fluid collection site, as desired. Alternatively and/or in
addition thereto, one can use a pressure sensor within the fluid
collection site. The output from such a sensor may be used to
optimize the maintenance of the pressure in the collection site so
that it is reduced sufficiently in order to increase the likelihood
of higher flow to that region from those tributaries that have
alternative paths, without causing the collapse of such
tributaries.
[0045] In certain embodiments, an extension of an aspiration lumen
of the device employed is extended selectively into one or more
tributaries in order to prevent their collapse during aspiration
and to extend the volume from which fluid is aspirated.
Alternatively, rather than using a lumen to structurally support
the tributaries, a temporary or permanent stent could be introduced
to those tributaries prior to aspiration. As a specific example, in
certain embodiments the small cardiac vein is stented for such
purposes, or a branch of the aspiration lumen from the coronary
sinus is extended through the small cardiac vein for such
purposes.
[0046] In certain embodiments, a specific pattern of aspiration
rates that compensates for the delay time between the detection of
the desired agent and the activation of the aspiration mechanism is
employed. For example, in certain embodiments, there will be a
small but finite delay in time between when the agent enters the
fluid collection site and when the aspiration mechanism begins to
aspirate fluid from the site. During this time delay, some of the
fluid containing the agent may have already passed the region from
which aspiration normally occurs at the distal portion of the
aspiration lumen, thus potentially reducing the efficacy of
retrieving the agent. However, by having a higher rate of
aspiration for the early portion of the period in which aspiration
occurs, as compared to a rate that more closely resembles the
normal physiologic rate of flow within the collection site, e.g.,
where the higher aspiration rate is at least about 2-fold greater,
such as at least about 5-fold or 10-fold greater, one can cause
that fluid which has already passed the region from aspiration to
change direction and return to the aspiration ports. Once this
initial period of a higher rate of aspiration has expired, the
aspiration rate could then occur at a lower rate which more closely
approximates the normal physiologic rate of flow within the
collection site, as desired.
[0047] In some embodiments, more than one kind of detector is
employed to determine the aspiration parameters and time period.
For example, in order to ensure that the leading edge of the agent
is successfully aspirated, the activation of the aspiration
mechanism may be activated by a counter that counts a conservative,
pre-selected number of QRS complexes on an EKG after the beginning
of injection of the agent, while the trigger to deactivate the
aspiration mechanism may be derived from an optical sensor that can
recognize when there is no longer any more agent within the fluid
being aspirated. Alternatively, inputs from more than one detector
can be used in direct combination with each other to determine the
aspiration parameters. For example, due to cardiac motion in the
region of a fiber optic based sensor, and/or variations in the rate
of flow of the fluid in the region of the sensor, the signal
produced may vary in a pattern that is reflective of the cardiac
cycle, regardless of whether or not the agent to be detected is
present, thus producing a noisy signal. In such a case, the
fidelity of the sensor may be augmented by using a filtering
algorithm that uses the input from an EKG signal to filter the
signal produced by the optical detector. By compensating for
changes to the output of the optical detector that are due to the
cardiac cycle, it may be easier to more accurately characterize the
concentration of the agent to be removed in the region of the
detector. Any of the detectors mentioned below may be suitably used
in combination with each other to further optimize the detection
process and/or the efficacy of the aspiration controller.
[0048] Practice of the subject methods results in selective removal
of an agent from a fluid collection site and subject/patient/host,
where the amount of agent removed is, in many embodiments, a
substantial portion of (but not all of in certain embodiments) the
agent that is present in the subject/patient/host, as described
above.
[0049] In certain embodiments, the fluid that is removed from the
subject or patient may be treated extracorporally, e.g., to remove
or neutralize the agent, and then reintroduced into the subject,
e.g., where it is desired to minimize the ultimate or final volume
of fluid, e.g., blood, that is removed from the subject in a given
procedure. For example, where the fluid removed from the subject is
blood, the removed blood may be processed with a blood filtering
device to remove the agent from the blood, and the processed blood,
or at least a component thereof (such as red blood cells) be
returned to the patient. Examples of representative fluid, e.g.,
blood, processing devices include, but are not limited to: the Cell
Saver.RTM. device (available from Haemonetics); autoLog (available
from Medtronic); and the like.
[0050] As such, the subject methods may include a step of
transferring the harvested fluid into a recirculating system to be
reintroduced into the body (as described in U.S. Pat. No.
5,925,016, the disclosure of which is herein incorporated by
reference). The recirculating system may incorporate mechanisms to
separate the substantially undesirable components from the
substantially desirable components. Such a system may incorporate a
filter, a centrifugal separator, flow cytometry or other similar
apparatuses. The aspiration mechanism may incorporate fluid
characterization elements by which aspirated fluid may be
characterized, either quantitatively or qualitatively.
[0051] Accordingly, in certain embodiments the subject may be one
in which it is desired to keep blood loss at a minimum, e.g., the
patient may suffer from coronary artery disease, chronic anemia,
etc. Extracorporeal processing and subsequent reinfusion of the
treated fluid allows for the reintroduction of the desirable
components as an autologous transfusion. Centrifugal mechanisms,
filter-based systems, dialysis membranes and cell-washing
mechanisms are examples of some functional components that can be
employed for this purpose.
[0052] The methods may be carried out using any convenient
system/device, where in certain embodiments, catheter based
systems/devices are of interest. Representative systems/devices for
use in practicing the subject invention are reviewed in greater
detail in the following section.
Devices and Systems
[0053] Also provided by the subject invention are devices and
systems thereof for selectively removing an agent from an efferent
fluid collection site according to the methods described above. The
subject devices are devices specifically designed to selectively
remove fluid from the efferent fluid collection site, where in
certain embodiments of particular interest, as described in greater
detail below, the devices are characterized by being non-occlusive,
in that they lack an occlusive element, specifically at their
distal end. By non-occlusive is meant that, at least while fluid
and agent is not being removed from the collection site and
subject, fluid enters and leaves the device while not passing
outside of the subject, i.e., while remaining intracorporeal. Thus,
in certain embodiments, the device is non-occlusive because at no
time during its operation does it assume a configuration where the
vessel in which it is placed is occluded. In yet other embodiments,
the device may be configured so that it collects all fluid at a
particular fluid collection site, but then provides for exit of the
collected fluid out of the device (when agent is not to be removed
from the subject) at a location such that the fluid always remains
in the body (e.g., at the distal end of the device), and does not
pass out of the body prior to its return to the body, i.e., the
harvested fluid is always intracorporeal. Depending on the
particular device being employed, the fluid may be returned to the
body at essentially the fluid collection site, or at a region
downstream from the fluid collection site. In these latter
embodiments, while the device may be configured to collect all
fluid from the fluid collection site, it is non-occlusive for
purposes of the present invention because the fluid can be
selectively returned to the subject without passing outside of the
body, so as to practice the subject methods in which only fluid
that is at least suspected of containing the target agent is
removed from the subject, as developed more fully above. It should
be noted that in these latter embodiments, when fluid is at least
suspected of containing agent is removed from the body, the device
may assume a configuration such that essentially all fluid is
collected and removed from the fluid collection site.
[0054] The subject systems are collections or combinations of
disparate elements that include the subject devices, such as an
aspiration element and controller thereof, as well as other
components employed in the subject methods, e.g., one or more agent
detectors, data recorders/displayers, delivery systems, and the
like. See FIG. 1 for a diagram of a system according to the subject
invention.
[0055] In using the below described representative devices for
practicing the subject methods, the aspiration element, e.g.,
lumen(s), is placed in the at least one region at which fluid from
the introduction site(s) of the agent to be removed ultimately
converges (i.e., a physiological efferent fluid collection site),
such as the coronary sinus. The aspiration mechanism communicates
to the proximal end of each aspiration lumen and is able to cause
the removal of fluid from the region at the distal end of the
aspiration lumen. The aspiration controller, when present, contains
mechanisms to control the degree to which the aspiration mechanism
is activated over time. Optionally, the invention may incorporate
the use of a detector that provides one or more signals to the
controller that can then be used to determine the timing and degree
to which the aspiration mechanism is activated. Optionally, the
invention may incorporate the use of one or more signals from the
injection/delivery system as inputs to the controller. The
controller may include a timer, or a device able to count EKG
cycles to determine the degree of activation of the aspiration
mechanism over time. Optionally, the invention may incorporate the
use of a recording device and/or interactive display to either log
and/or display the activity of the system during a procedure, or to
change parameters that govern the operation of the system's
components.
[0056] The subject devices and systems are now described in greater
detail separately.
[0057] In certain embodiments of the subject invention, the devices
at least include: an aspiration element; which element is typically
made up of: (a) at least one non-occluding aspiration lumen; (b) an
aspiration mechanism; where in certain embodiments the aspiration
element may further include an aspiration controller. Each of these
elements, both constant and optional, are now reviewed in greater
detail.
[0058] Aspiration Lumens
[0059] In the subject devices, one or more aspiration lumens are
provided, where the aspiration lumen(s) is constructed or
configured in such a manner to be introduced into the target
collection site, e.g., efferent fluid collection site or a site
proximal thereto, e.g., via a body conduit such as the venous
vasculature, so that the distal end can be positioned in the target
site for collection of the introduced medium. In many embodiments
where the target efferent fluid collection site is a cardiovascular
efferent fluid collection site, e.g., as in the case of retrieving
compound-laden fluid from the coronary sinus, there may be a
catheter with a length appropriate for introduction through either
a brachial, jugular or femoral access site to be advanced to the
coronary sinus, likely over a guidewire or similar element, for
percutaneous delivery. In these embodiments, the aspiration lumen
is a catheter device, having dimensions sufficient to be introduced
into the efferent fluid collection site via a vascular, e.g.,
veinous route, where such dimensions are known and readily
determined by those of skill in the art.
[0060] In certain embodiments, the aspiration lumen has more than
one diameter along its length. For example, in order to more easily
enter or approach a collection site, the distal portion of the
aspiration catheter is of a first diameter such that the distal
portion fits within the geometric constraints of the anatomy of the
collection site. In order to reduce the resistance to flow along
the entire length of the aspiration lumen, the aspiration lumen has
a second, larger diameter for one or more proximal segments of the
aspiration lumen. In some cases where a high degree of flow may be
required in order to successfully aspirate all the fluid that
enters the collection site, such a configuration helps to reduce
the total resistance of the lumen, which is proportional to the
fourth power of the radius and is thus very sensitive to lumen
diameter.
[0061] As indicated above, the aspiration lumen is, in certain
embodiments, specifically constructed to be non-occluding. As such,
the aspiration lumen of these embodiments does not include an
occlusive element, e.g., a balloon or other element designed to
occlude a vessel or conduit. As such, the subject devices of these
particular embodiments are occlusive element free devices.
[0062] Aspiration Mechanism
[0063] In the subject devices, each aspiration lumen is operatively
connected to at least one aspiration mechanism. There may be more
than one aspiration lumen connected to each aspiration mechanism.
The aspiration mechanism serves the purpose of withdrawing fluid
from the target region via the aspiration lumens. The aspiration
mechanism may, in certain embodiments, then dispose of the fluid,
transfer the fluid into a recirculating system to be reintroduced
into the body (as described in U.S. Pat. No. 5,925,016, the
disclosure of which is herein incorporated by reference), or simply
store the fluid in a reservoir, as desired. The recirculating
system may incorporate mechanisms to separate the substantially
undesirable components from the substantially desirable components.
Such a system may incorporate a filter, a centrifugal separator,
flow cytometry or other similar apparatuses. The aspiration
mechanism may incorporate fluid characterization elements by which
aspirated fluid may be characterized, either quantitatively or
qualitatively.
[0064] One embodiment of the aspiration mechanism is a
suitably-sized syringe in fluid communication with the aspiration
lumen. Upon activation by the aspiration controller, the plunger of
the syringe is retracted, causing the aspiration of fluid. Any of
several mechanisms can be used to provide the motor force necessary
to retract the syringe. A rotary motor attached to a threaded bar
can be used to cause a pullback motion by coupling the plunger to a
component similar to a mechanical nut or other thread-receiving
implement that attaches to the threaded bar. A variant of such an
embodiment is to attach the thread-receiving implement to the motor
and have the threaded component on the plunger. Alternatively, a
rotary motor can wind a cable attached to the plunger, or a rack
and pinion system may be employed. Alternatively, the motor force
can come from a preloaded spring that has sufficient energy stored
within it to cause the withdrawal of the plunger. Alternatively,
the motor force may come from a compressed gas compartment, or a
vacuum compartment.
[0065] An alternative embodiment is to have a compartment within
which a vacuum exists and the withdrawal of substance occurs by
allowing fluid communication between the vacuum compartment and the
aspiration lumen. This vacuum element would be similar to the
principle used for phlebotomy that is incorporated in the
Vacutainer.RTM. system.
[0066] An alternative embodiment is to use a roller pump, whereby
rollers external to the aspiration lumen near the proximal end of
the aspiration lumen compress a soft portion of the tubing, and
push the contents of the lumen towards the proximal end.
[0067] An alternative embodiment is to have an aspiration lumen
whereby the proximal end of the aspiration lumen is in fluid
communication with the ambient environment or a container whose
internal pressure is equal to that of the ambient environment so
that the pressure differential between the venous circulation and
the ambient environment provides a significant portion of the
necessary mechanical impetus to cause aspiration.
[0068] Yet another alternative embodiment is to have an aspiration
lumen whereby the proximal end of the aspiration lumen is placed at
a lower altitude than the distal end of the aspiration lumen, so
that the difference in potential energy of fluid at each of these
locations causes fluid to flow primarily by gravitational forces
out the proximal end.
[0069] Depending on performance requirements for the particular
application at hand, each of these mechanisms may either have
strict binary activation (on or off), or their degree of activation
may be controllable. Actuators for controlling the extent of
activity may include valves, braking mechanisms, electronic
controllers, amplifiers and other common mechanisms.
[0070] Aspiration Controller
[0071] As indicated above, in certain embodiments the aspiration
element further includes an aspiration controller. In certain
embodiments, however, an aspiration controller is not present,
e.g., in those embodiments where the aspiration mechanism is a
syringe that is operated manually by a health care
professional.
[0072] When present, the aspiration controller is an element that
actuates the aspiration element in response to an input signal,
e.g., where the input signal may be provided by the operator
performing the method or a detector element, as described below.
The aspiration controller may actuate the aspiration element in a
simple on/off manner, or may actuate the aspiration element in a
more complex manner, e.g., to varying degrees over time, such that
the aspiration controller may provide a way for controlling the
degree to which the aspiration mechanism is activated over
time.
[0073] The aspiration controller accepts one or more inputs. Such
inputs can include manual inputs, e.g., from a health care
professional performing the method, or signals from one or more
detectors or instruments. As such, in certain embodiments, the
subject devices are employed with one or more detector components,
where the detector components may or may not be integral to the
devices, i.e., may or may not be part of the devices.
[0074] In certain embodiments of the subject methods, two goals of
the process of selectively retrieving an agent after it has been
introduced are considered in the design and/or operation of the
current invention. The first goal is to retrieve a high percentage
of the introduced material, while the second goal is to remove as
little of the native fluid (e.g., blood) as possible. In certain
embodiments, these goals may be in conflict with each other. For
example, the retrieval of a higher percentage of the introduced
material may most easily be obtained by aspirating a higher volume
of native fluid, while the removal of a lower volume of native
fluid (e.g., blood) may most easily be obtained by aspirating a
lesser volume of the introduced material. Therefore, it may be
desirable to incorporate into the controller a method to vary the
concentration threshold at which the aspiration mechanism is
activated. A lower threshold would increase the percentage of agent
retrieved, while a higher threshold would minimize the amount of
native fluid retrieved.
[0075] The threshold of agent concentration for activation of
aspiration may be different than the threshold of agent
concentration for deactivation of aspiration. Alternatively, the
rate of aspiration may be a more continuous function of the agent
concentration. For example, higher agent concentrations may
indicate to the controller that the rate of aspiration may be
increased. Alternatively, the rate of aspiration may be a function
of both agent concentration and time.
[0076] Several other parameters can be controlled to optimize the
goals of retrieval and efficiency, depending on the particular
protocol being performed. For example, the injection rate and/or
aspiration rate may be adjusted to produce an optimal
retrieval.
[0077] If the aspiration rate were to be less than the
physiologically relevant flow rate through the targeted region,
then a certain fraction of the introduced agent would flow past the
distal end of the aspiration lumen and not be retrieved.
Conversely, if the aspiration rate were to be greater than the
physiologically relevant flow rate through the targeted region, an
excess amount of native fluid may be aspirated, some of which may
arrive to the aspiration lumen by traveling in a retrograde manner.
Matching the aspiration rate with the physiological flow rate
through the targeted region of retrieval provides, in certain
embodiments, a desirable optimum solution. A sensor for detecting a
flow rate at the distal end of the aspiration lumen may assist in
achieving this optimization.
[0078] Similarly, at the injection site, if more agent is
introduced than can be immediately accepted at the injection site
for antegrade flow, that agent may get diverted to the systemic
circulation and can thus not be collected efficiently at the
targeted collection region. This situation may be seen to occur
under fluoroscopy as angiographic dye is injected near coronary
ostia, wherein the excess dye flows back into the aorta and is
essentially wasted for diagnostic purposes, while still increasing
the system concentration of the agent. However, if less agent than
can be immediately accepted for antegrade flow is injected into the
injection site, the agent will be diluted with native fluid. This
early dilution will worsen the efficiency of retrieval of the agent
at the target site, since more native fluid will have to be
aspirated in order to retrieve a fixed targeted volume of the
agent. A sensor for detecting the flow rate at the site of
injection is employed, in certain embodiments, to achieve this
optimization.
[0079] Furthermore, the controller may incorporate a dynamic
component in its control algorithm (i.e., it may be an adaptive
controller) whereby the percentage of agent retrieved during a
cycle of injection/aspiration is sensed, and the controller adjusts
parameters for the cycle, such as, but not limited to, a
concentration threshold for aspiration and/or the injection rate
and/or aspiration rate and/or the duration of aspiration. These
adjustments can be made iteratively over consecutive cycles in an
attempt to optimize the parameters of injection and aspiration for
subsequent cycles.
[0080] Optional Detector Components
[0081] A number of different detector components may be employed
with the subject devices. Possible detectors or instruments that
would be generally external to the body include EKG leads,
fluoroscopic images, an automated injection system and/or a
manually triggered signal from a technician. The controller could
then execute a profile of aspiration over time based on the time
from injection or manual triggering. Such a profile may be timed
over a number of cardiac cycles or over conventional time. The
pattern and/or density of pixels in the fluoroscopic images could
also be used to recognize the injection and/or migration of
material that produces imaging contrast.
[0082] In yet other embodiments, detectors of interest include
fiber-optic based sensors, temperature sensors, acoustic sensors,
pH detectors, capacitance-based detectors, fluid velocity
detectors, conductivity detectors and detectors able to detect
changes in ferro-electromagnetism or magnetic susceptibility (see
e.g., Blood, 1 Jan. 2003, Vol. 101, No. 1, pp. 15-19).
[0083] EKG Inputs
[0084] In certain embodiments, signals from EKG electrodes are used
to provide a physiologically based timer wherein the controller
incorporates a delay between the time of injection of material that
is based in part or in entirety according to the number of cardiac
cycles that have elapsed rather than using absolute time measured
in seconds. The two measures of time are combined, in certain
embodiments, to develop an algorithm to trigger the pattern of
aspiration relative to the time of injection. For example, the
algorithm may cause aspiration to begin based after either a preset
number of cycles (e.g. 3.5 cardiac cycles) has elapsed, or an
absolute amount of time (e.g. 8 seconds) has elapsed, whichever
comes first. The use of cardiac cycles is of interest in many
embodiments because it is related to the degree of blood flow in
most organs. The heart rate may also be used to determine the peak
rate of aspiration and the time-course over which the aspiration is
active. A more rapid heart rate may indicate that aspiration could
be optimized by having the aspiration occur more rapidly and/or
over a shorter period of time.
[0085] The EKG leads may be either externally placed on the skin,
as in conventional EKG and/or may be delivered intracorporally, as
done in many electrophysiology studies. In the case of the
intracorporal leads, these leads may be incorporated in a guidewire
or catheter, such as those used to deliver the aspiration lumen
and/or detector to the target site. By incorporating the EKG leads
with a catheter and/or guidewire already used in the system, the
system of the current invention becomes more seamless, with a
lesser dependence on external components.
[0086] Imaging-Based Inputs
[0087] Algorithms applied to image sequences, such as fluoroscopic
image sequences, may be employed to identify the time of injection
of a material that produces contrast in an image sequence. A
representative embodiment of such an algorithm is one that detects
a substantial change in the histogram of the density of pixels in
each frame over time. The rate at which the contrast diffuses is
subsequently calculated based on the rate of restoration of the
histogram of pixel densities to its approximate baseline
distribution (as per prior to injection of material). These two
parameters are used to develop inputs into the controller of the
aspiration mechanism. Other representative algorithms that may be
applied include, but are not limited to: texture-based,
histogram-based, derivative-based and motion-estimation algorithms.
The employed algorithms may be dependent on the region of the
anatomy that is imaged and may also accept EKG and/or respiratory
signals as inputs to help the algorithm take into account any
effects of motion of the region between image frames over the
cardiac and/or respiratory cycles. Such algorithms may be deployed
in real-time, or may be performed using post-processing on one of
the first injections of the material that produces image contrast
to help optimize the aspiration parameters for subsequent
iterations of the removal of injected material. The advantage of
the latter system is that it would have lower hardware requirements
than a real-time system, but it would not produce information to
the aspiration controller necessary for the iteration during which
the optimized aspiration parameters were produced. The
computational capabilities and interface circuitry necessary for
the rapid optimization of aspiration parameters may not necessarily
be incorporated directly into the aspiration controller itself, but
may be incorporated in a software and/or hardware system that is
either incorporated in the image acquisition device, or directly
connected thereto. In this case, the system that detects the time
of injection and/or rate of dispersion of the injected material may
be configured to send input signals to the aspiration controller
that describe its estimates or calculations of one or more of: the
time of beginning of injection, the time of end of injection, the
amount injected, time-course over which the injection occurred, the
rate of dispersion of the material, the region to which the
material flowed, the velocity of the leading edge of the material
and other parameters. Alternatively, the input signals may directly
tell the aspiration controller the time at which to begin
aspiration, end aspiration and/or the degree to which aspiration
should occur during that time period at either a uniform or
variable rate. In this instance, a substantial part of the
aspiration controller may be embedded in the system that does the
image processing, and the cost of the aspiration controller, which
may be a disposable component, can be minimized. Aside from
fluoroscopic-based image sequences, similar algorithms could be
applied using ultrasound images, computed tomography, magnetic
resonance images and other modalities capable of rapidly sequential
images over time (image acquisition rate rapid enough to observe
the migration of the injected material), as long as the material
injected contained a component that produces image contrast in the
particular modality of imaging used.
[0088] Fiber-Optic Based Inputs
[0089] Certain embodiments of the system use one or more
fiber-optic based sensors to detect the presence of the introduced
material. Fiber optics are extremely cheap, versatile, disposable,
biocompatible and non-conducting, making them an ideal material to
use for an intracorporeal sensor. One or more fiber optics are
delivered separately to the vicinity of the region from which
material is to be aspirated, either via the one or more aspiration
lumens, or alongside them. Alternatively, the fiber optics are
incorporated into one or more of the aspiration lumens, or are
delivered via lumen(s) included in the catheter(s) carrying the
aspiration lumen(s). Regardless of the specific construction and
mode of delivery of the fiber optic strand(s), a variety of modes
of optically assaying the blood or other fluid in the vicinity of
the region from which material to be aspirated can be used. Light
of the visible or infrared wavelengths can be transmitted down a
fiber optic strand and used to illuminate a region near the distal
end of the fiber. The interaction of light with the fluid in that
region can then be measured in several ways to provide information
indicative of the composition of the fluid. Scattered or reflected
light can be collected down either the same fiber or via another
fiber. The scattered or reflected light may change in intensity or
its composition in the electromagnetic spectrum or both and such
changes can be detected by detectors at the proximal end of the
fiber. An alternative embodiment would be to use one fiber to
collect light that is emitted from another fiber and use the
changes in the light's properties during transmission through the
intervening fluid to assess the fluid composition.
[0090] Accordingly, a variety of different optic based detection
systems or elements may be employed in the devices and protocols of
the subject methods, where the optic based detection systems may
evaluate transmitted and/or absorbed light in order to determine or
evaluate a property, e.g., presence of target agent, in a fluid. As
such, in certain embodiments one may perform a spectral analysis of
light transmitted through and/or absorbed by a fluid.
Alternatively, one may perform a spectral analysis of
reflected/scattered light. In certain embodiments, the spectral
analysis may be made at one or more finite number of wavelength
ranges, e.g., from about 300 microns to about 5000 microns, from
about 700 microns to about 2000 microns, from about 900 microns to
about 1900 microns, etc. The detection system may include a single
fiber optic embodiment or multi-fiber embodiment, where the system
may include a reflective component.
[0091] Normal blood or other physiological fluid will have a
measurable interaction with the emitted light that can either be
known prior to the use of the device, or calibrated once the fiber
optics are put in place, prior to the introduction of the material
to be aspirated, so that a more anatomically specific and/or
patient specific assessment of the baseline optical properties of
that fluid is performed without the effects of the material to be
introduced and aspirated. However, once the material to be
introduced enters the region which is assayed by the fiber optic
system, the system will recognize a concentration-dependent change
in the properties of the collected light. That information will be
used as an input to the controller to trigger whether or not the
aspiration is activated, and perhaps the extent of aspiration that
is to occur. A major advantage of this system over a time-based
system is that the ability to detect and use an elevation in the
concentration of the material to be aspirated in order to trigger
the aspiration provides a highly optimized system that removes only
that physiological fluid, such as blood, which contains the highest
concentrations of the material(s) to be removed.
[0092] In some cases, the material to be introduced may be of such
a low concentration, or have optical properties which are difficult
to detect with sufficient sensitivity and/or specificity.
Therefore, it may be desirable to include with the material to be
introduced (first component) for therapeutic or diagnostic purposes
one or more second components that would be introduced at the same
time as the first material. Examples of such second components
would include saline, which is clear in visible wavelengths, or
fluorescent compounds (or other labeled compounds, e.g.,
radiolabeled compounds, chromogenically labeled compounds, etc.)
that produce specific wavelengths when photons of shorter
wavelengths are presented to them, or pigmented compounds. The
second component may be incorporated as a functional component of
one or more of the molecules of the first component at a site that
does not affect the active sites of the first component. The use of
these second compositions is to serve as a tag to help identify
that the batch of fluid which was introduced has migrated to the
targeted region for aspiration by essentially improving the signal
to noise ratio of the detection process. In those cases where it is
known that there is a different mobility of the first and second
components through the vascular beds or other anatomic structures,
it may be necessary to assume a delay between the time at which the
second component is detected and when the first component is
assumed to have reached the target region, and that delay could be
incorporated by the aspiration controller in determining the
appropriate time to begin and end aspiration. In yet an alternative
embodiments, the tag component and agent component may be present
in a compartment or containment element, which compartment or
containment element serves to keep the tag and agent components in
a defined orientation or spatial relationship to each other.
Representative compartment or containment elements in which both
the tag and agent components may be placed or packaged include, but
are not limited to: microbubbles, liposomes, cells, etc.
[0093] Several fiber optic based detectors may be required to
properly assay the target region's composition as it is possible
that one or more of the sensors may appose an anatomical structure
and therefore not be directed towards the fluid within the lumen or
cavity of the structure. The sensors may be placed at an offset
upstream from the distal end of the aspiration ports in order to
provide an earlier indication of when the material to be aspirated
will arrive near the aspiration ports so that the system can more
optimally time its activities via the aspiration controller.
Similar sensors could be placed within the aspiration lumen(s) in
order to assist in the quantification of the amount of fluid that
was successfully retrieved by the system.
[0094] In yet other representative embodiments, temperature
sensors, such as thermocouples and thermoresistors, are employed to
detect the entrance of fluid with a slightly different temperature
into the fluid collection site. In these embodiments, one or more
temperature sensors are delivered to the target region of
aspiration by the same methods as the fiber optics previously
mentioned. The introduced fluid, or a substantial portion of it,
has a temperature different from body temperature as it is
introduced into the body. This temperature difference can be
established by having the fluid at less than body temperature prior
to being introduced, or the fluid could be heated slightly (e.g.,
to <50.degree. C.) within or just prior to entering the
injection catheter. As the introduced fluid travels through the
capillaries or other small conduits between the site of
introduction and the site of aspiration, there will be a
substantial equalization of temperature of the fluid with the
tissue through which it travels. However, the high precision of
available temperature sensors is sufficient to detect the residual
difference in temperature that is expected as the introduced fluid
enters the target aspiration region after its first pass through
the perfused organ.
[0095] A disadvantage of this approach is that fluid, such as
contrast agent, that is allowed to rest for more than a few seconds
within the lumen of the injection catheter within the body would
have sufficient time to equilibrate thermally with body
temperature. This equilibration means that the initial volume of
fluid to be introduced, approximately equal to the volume of the
lumen of the catheter, would not be detectable as it enters the
target aspiration region by thermal means. One method to overcome
this limitation is to replace the column of fluid to be removed
within the injection lumen(s) with a column of less harmful fluid,
such as saline or blood, such that all the potentially harmful
fluid to be introduced, such as contrast agent, would not be within
the portion of the injection lumen(s) that is within the body prior
to the initiation of injection. An alternative method is to heat
fluid within the lumen near the very distal end of the injection
lumen as it enters the body to establish a temperature gradient
with an opposite polarity. This approach could be accomplished by
incorporating an electric heating element in the distal end of the
injection catheter.
[0096] Acoustic Sensors
[0097] In yet other representative embodiments, one or more
ultrasonic transducers are used in place of, or in addition to,
either or temperature-based or fiber-optic based sensor. Such
transducers may or may not have a mechanically rotating or
translating motion capability, or have a phased-array functionality
to control the direction of an emitted acoustic pulse. The
transducers are employed to emit a series of acoustic pulses into
the region near the distal region of the aspiration lumens. One or
more of the transducers can be used to detect either backscattered
or propagated acoustic energy. As blood or other physiological
fluids in their pure forms are replaced with fluids that contain
some of the material introduced upstream, there is a change in the
intensity of the acoustic signals that are backscattered from
and/or propagated through the region. Other changes of interest
include changes in the slope of the frequency spectrum of the
signal or changes in the statistical properties of the signal
envelope. These changes are used to provide an indication of the
presence of fluid laden with the material that was introduced
upstream to trigger the aspiration mechanism via the
controller.
[0098] Other Sensors
[0099] Other sensors of interest include, but are not limited to:
those that detect a change in pH of the fluid; a change in the
dielectric constant between two electrically insulated leads where
the fluid is found between the two electrical leads; a change in
the conductivity of the fluid between two uninsulated leads through
which a very low current is driven through their circuit which
includes the fluid within its path; and changes in the magnetic
properties of the fluid found between two coils or via a magnetic
resonance imaging system; etc.
[0100] Positioning and/or Retaining Mechanisms
[0101] In some embodiments, a non-occlusive positioning and/or
retaining mechanism is incorporated with either or both of the
aspiration lumen and detector at the target region. For the
purposes of this invention, a positioning mechanism is generally
defined as a mechanism that tends to place elements of either an
aspiration lumen or a detector in a more desirable general location
than might otherwise occur. For example, it may center the
aspiration lumen or detector within the target region. Such a
mechanism might reduce the resistance to aspiration by distancing
the one or more aspiration holes from the wall of the target
region. It may improve the accuracy of detection by positioning a
detector in a location that is more completely surrounded by the
fluid in which the agent to be detected will likely be found. The
detector may otherwise have difficulty in detecting the agent to be
removed if the detector were in close proximity to the wall or
other structures of the targeted region. Furthermore, an
expandable, non-occlusive mechanism, may serve the purpose of
helping to retain the distal end of an aspiration lumen and/or
detector within the targeted region of aspiration. Such a mechanism
would assist in assuring the operator that the aspiration lumen
will remain in the target region long enough to achieve the desired
performance.
[0102] Several embodiments for positioning and/or retaining
mechanisms are described, in addition to the non-occlusive
funnel-shaped expandable members previously reviewed above. See
e.g., FIGS. 11 to 13. One such mechanism includes a set of one or
more memory-shaped elements, made of either nitinol, stainless
steel, plastic or other similar material. The memory-shaped
elements may be in one of at least two states. The first state is
in a collapsed form, which enables delivery to the target region.
The memory-shaped elements may be held in this configuration by a
sheath that surrounds them and retains a collapsed configuration.
This sheath may be a separate sheath, or may be the catheter that
contains the aspiration lumen, such that the elements are
substantially placed within the aspiration lumen while in the
collapsed form. Alternatively, the elements may be held in the
collapsed form via tension that is applied along a member that
travels the length of the catheter onto which they are
incorporated, with that member potentially residing substantially
within a separate lumen within that catheter. When the detector
and/or aspiration lumen are delivered to the target region, the
elements may then be allowed to enter an expanded form. Such an
expanded form may be similar to the shape of a whisk (as shown in
FIG. 11), or in a spiral shape (see e.g., FIG. 12), or several
other forms that produce a non-occlusive means of distancing from
surrounding structures, such as one or more loops, or a cage. The
expansion can be allowed to occur by the operator moving elements
at the proximal end of the catheter, or by retracting a sheath or
some other similar mechanism. An alternative embodiment is to have
the structure of the aspiration catheter and/or detector assume a
generally "pig-tailed" shape (see e.g., FIG. 13).
[0103] Flow Modulator Element
[0104] In certain embodiments, the devices include a flow modulator
element for modulating fluid flow through the efferent fluid
collection site, at least during removal of fluid therefrom.
Accordingly, the device may include an element that changes or
alters the nature of fluid flow through the collection site, e.g.,
by lengthening the fluid flow path, by narrowing the fluid flow
path, by changing the velocity of fluid flow through the collection
site, etc. For example, the device may include an expandable or
deployable element, e.g., balloon, that can be deployed when
positioned in the fluid collection site so as to alter a parameter
of fluid flow through the site. Depending on the nature of the
device and particular protocol being performed, the fluid flow
modulation element may be positioned prior to, at substantially the
same place as, or after the aspiration element.
[0105] Fluid Exit Element
[0106] In certain embodiments, the subject devices include one or
more fluid exit ports positioned downstream from the distal end of
the aspiration element at which enters the aspiration lumen, but
still at the distal end of the device. In many embodiments, fluid
flow through the fluid exit port or ports is controlled by a flow
regulator element which can be moved at least between an "open" and
a "closed" position, so that flow of fluid out of the aspiration
element through the one or more exit ports can be controlled. A
variety of different exit portion configurations may be present in
these embodiments, including valves, closable windows, etc.
Representative embodiments are further described below.
Specific Representative Devices
[0107] The devices of the present invention may include one or more
of the above-described features. The following section describes in
further detail various representative embodiments of device that
may be employed in practicing the subject methods.
[0108] In one embodiment shown in FIG. 2, a representative catheter
designed for use in methods of removing agent from the coronary
sinus is depicted. In this representative catheter device 20 is an
extruded catheter 22 with formation of the tip curvature of the
distal end 24 such that it can be more easily delivered to the
coronary sinus 28 is provided. The diameter of the catheter in this
embodiment is less than the diameter of the entrance 26 to the
coronary sinus 28 from the right atrium 21, allowing blood to exit
from the coronary sinus when the aspiration mechanism is not
activated. Typically, the outer diameter of the distal end 24 of
this catheter structure ranges from about 1.0 mm to about 30 mm,
such as from about 2 mm to about 7 mm.
[0109] In certain embodiments, the distal end of the subject
catheter is a simple opening, e.g., as depicted in FIG. 3. In the
distal end of the device depicted in FIG. 3, aspiration lumen 30
ends at its distal end with opening 31. The inner diameter 32 of
the opening ranges from about 1.0 mm to about 30 mm, such as from
about 2 mm to about 7 mm. The outer diameter 33 of the distal end
may range from about 1.1 mm to about 35 mm, such as from about 2.1
mm to about 7.3 mm.
[0110] In a variation of the above embodiments, a catheter device
with a more rounded tip is provided, as depicted in FIG. 4A. In the
representative device shown in FIG. 4A, the distal end 41 of device
40 may have a hole 42 in the distal tip, e.g., for a guidewire to
pass through. In addition, there is typically one or more holes 43,
e.g., fenestrae, for aspiration, i.e., fluid to enter the
aspiration element 40. FIG. 4B provides a depiction of a variation
of the device shown in FIG. 4A, where the distal segment of the
wall of the catheter may also have one or more holes (i.e.,
fenestrae) in it, as shown in FIG. 4B. A plurality of holes allows
for less trauma to occur during aspiration. If the tip or one side
of the distal portion of the aspiration catheter were to be in
contact with the wall of the structure to be aspirated (e.g.
coronary sinus), holes that are not in contact with the wall would
still be able to accept flow from the sinus. This structure
minimizes wall injury from aspiration, as well as allows for a more
reliable aspiration of fluid. The diameter of the holes or
fenestrae 43 may vary widely, but in certain embodiments ranges
from about 100 microns to about 7 mm, such as from about 300
microns to about 3 mm. In these embodiments, the distal end of the
catheter device/aspiration element is typically not expandable.
[0111] In yet another alternative embodiment, such as is shown in
FIG. 5, the aspiration catheter tip 51 of device 50 is expandable
to a shape that changes flow patterns without occluding flow in the
antegrade direction. An example of such an embodiment is an
aspiration catheter that is delivered within a delivery sheath (not
shown). In using such embodiments, once the distal tip of the
aspiration catheter is delivered within the region to be evacuated,
the sheath is retracted. The aspiration catheter of these
embodiments is constructed such that upon retraction of the sheath,
its distal end 51 expands to form the shape of a funnel or similar
geometry, where the diameter 52 of the distal end of the funnel may
vary, and ranges in representative embodiments from about 2.1 mm to
about 50 mm, such as from about 3.0 mm to about 10 mm. This funnel
is sized with a maximum diameter such that it is not intended to
make circumferential contact with the target region's walls 53.
Rather, the funnel is intended to provide a rheological advantage
in a non-occluding manner of constraining the general direction
from which fluid is retracted during aspiration so as to minimize
retrograde flow of blood in the target region upon activation of
the aspiration mechanism. By example, in the coronary sinus, it is
an intention of this invention to capture fluid flowing in an
antegrade direction entering the coronary sinus from the cardiac
veins, but not to induce the retrograde entry of blood from the
right atrium into the coronary sinus. Of note, because of the
non-occluding nature of such a design, blood can flow around the
distal tip of the aspiration lumen and proceed along its normal
path when the aspiration mechanism is not activated.
[0112] Yet another embodiment is a device having a tip that can be
expanded to make contact with the walls of the target region for
aspiration, but does not result in occlusion of flow due to holes
or perforations, e.g., fenestrae, in or near to the distal segment
or tip of the catheter. See e.g., FIGS. 6A and 6B. In the device
depicted in FIGS. 6A and 6B, device 60 includes distal end 62 which
may have a deployable funnel configuration. A plurality of fluid
exit ports 63 or fenestrae are provided to provide exit of fluid
from the device when aspiration is not occurring. As such, this
embodiment helps to create desired flow patterns during aspiration,
without occluding flow when the aspiration mechanism is inactive.
This embodiment can be constructed by using a mesh-like material
for a portion of the funnel-like tip, or by creating holes in a
more impermeable material. Optionally, there may be one or more
flaps 64 covering the holes or meshwork, such that the fenestrae
are sealable. These flaps of this embodiment act as one-way valves,
wherein they create minimal resistance to forward flow when the
aspiration mechanism is inactive, but provide considerable
resistance to retrograde flow when the aspiration mechanism is
activated, as they substantially close the holes or pores during
aspiration. This closing action occurs primarily as a result of the
creation of negative pressure within the region distal to the tip
relative to the region outside of the aspiration lumen, proximal to
the tip. FIG. 6A shows the device in the absence of aspiration,
where blood flows into the distal end of the device and out of the
fenestrae or windows, as shown by the arrows. FIG. 6B shows the
device during aspiration, where flaps 64 seal the windows 63,
causing blood flowing in the distal end of the device to remain in
the device and flow in the direction of the arrow to the proximal
end of the device and eventually out of the body.
[0113] Another embodiment of a device of the present invention
which employs a one-way valve mechanism is illustrated in FIGS. 21A
and 21B. The catheter device includes an aspiration lumen 170
having one or more fenestrae 172 at a distal end thereof. Lumen 170
is extendable from and retractable within a delivery sheath 174.
The device further includes a passive, one-way valve mechanism in
the form of a parachute or sail 176 which is attached to the
exterior of aspiration lumen 170 at a distal end 176a and
proximally thereto at a proximal end 178a of parachute ties or
strings 178. As such, the valve mechanism can be retained between
lumen 170 and the interior wall of sheath 174 upon delivery of the
device to the target side and then be selectively deployed from
delivery sheath 174 by either advancing or extending aspiration
lumen 170 in a distal direction or retracting sheath 174 in a
proximal direction. The parachute or sail can be constructed of any
suitable biocompatible material that can is conformable, where
representative materials include, but are not limited to: teflon,
polyethylene, nylon, other polymers and thin-foil metals. In
addition, the parachute or sail may be coated, e.g., with
hydrophobic or hydrophilic coatings, or anti-thrombotic coatings,
etc.
[0114] FIG. 21A shows the device in the absence of aspiration,
where blood flows in an antegrade direction along the distal end of
the lumen 170 and past parachute 176, as shown by the arrows. FIG.
21B shows the device during aspiration, where blood is aspirated
into fenestrae 172 through lumen 170 to the proximal end of the
device and eventually out of the body. Due to the resulting
differential in pressure between the vessel lumen and the
aspiration lumen, blood that has flowed proximal of the fenestrae
172 but is still distal to parachute 176 is also aspirated into
fenestrae 172 in a retrograde direction, as indicated by the
arrows. The negative pressure also causes the sail or chute to
expand or billow, thereby creating a seal with and anchoring the
device to the wall of the anatomical lumen.
[0115] FIGS. 7A and 7B provide yet another embodiment of a device
according to the present invention that may be employed to
selectively remove target agent from the coronary sinus. In the
device depicted in FIGS. 7A and 7B, device 70 includes proximal end
71 and distal end 72. Distal end 72 is shown positioned in the
coronary sinus 73. Positioned at the distal end 72 of device 70 are
a plurality of fluid inlet ports 74, which allow blood to enter the
device upstream of the ostium 75 of the coronary sinus. Positioned
on the device on the atrial side of the ostium 75 in right atrium
78 is detector 76, which can detect the presence of agent in fluid
passing by the detector. Also present on the atrial side of the
ostium 75 is fluid outlet port or window 77, through which fluid
can be controllably allowed to flow depending on whether or not the
device is in a non-aspirating state, as shown in FIG. 7A, or an
aspirating state, as shown in FIG. 7B.
[0116] FIGS. 8A to 8C provide depictions of various embodiments of
the closable exit port or window 77, of device 70. In FIG. 8A,
window 80 is present on a slidable portion 82 which can be moved
into and out of sheath element 84 depending on whether it is
desired for the window to be open closed. Arrow 86 shows the
direction of fluid flow out of the device through window 80 when
the window is in the open position. Arrow 88 shows the direction of
fluid flow through the device when the window is in the closed
position.
[0117] In FIG. 8B, window 80 is present on an internal portion 81
whose position relative to sheath element 84 can be rotated
depending on whether it is desired for the window to be open or
closed, e.g., by rotating internal portion 81 and/or sheath element
84. Arrow 86 shows the direction of fluid flow out of the device
through window 80 when the window is in the open position. Arrow 88
shows the direction of fluid flow through the device when the
window is in the closed position.
[0118] In FIG. 8C, window 80 is present on an internal portion 81
beneath movable flap 85, which flap can be open or closed by
provide negative pressure inside of internal portion 81. Arrow 86
shows the direction of fluid flow out of the device through window
80 when the window is in the open position. Arrow 88 shows the
direction of fluid flow through the device when the window is in
the closed position.
[0119] FIGS. 22A and 22B provide other embodiments of devices
according to the present invention that may be employed to
selectively remove target agent from an anatomical site or chamber
or lumen which has a narrowing or smaller dimension orifice along
the surface of the physiological efferent fluid collection site's
walls. The narrowing or smaller dimension orifice may be due to a
tissue structure or be defined by an ostium into the efferent fluid
collection site, such as the os of the coronary sinus. With these
embodiments, the tissue structure or os facilitates blocking or
occluding fluid flow beyond a target occlusion site where the
occlusion site is substantially external to the target fluid
aspiration site.
[0120] The device of FIG. 22A includes aspiration lumen 180 having
one or more fenestrae 182 at a distal end thereof which allow blood
to enter the device upstream of the ostium 185 of the coronary
sinus. A selectively expandable or inflatable occlusion member or
stopper 184 is provided about lumen 180 at a location proximal to
the fenestrae 182. Stopper 184 is depicted as having a ball shape
but it may have any suitable shape including, but not limited to,
disk-shaped, cone-shaped, etc. Stopper 184 is fixed to lumen 180 at
a position or distance from the distal end of lumen 180 which
positions stopper 184 on the atrial side of the ostium 185 in right
atrium and at a location to prevent blood flow into the right
atrium during aspiration. Here, stopper 184 is shown as an
inflatable balloon which is in communication with an inflation port
186 which extends within aspiration lumen 180. Balloon 184 may be
made of a compliant or non-compliant material as dictated by the
application at hand. Where the anatomy into which the stopper is
positioned is variable in size or landscape, a compliant material
may be more suitable. However, where the size and/or contouring of
the anatomy is known and constant, a non-compliant material may be
most suitable to prevent over inflation of the balloon which may
cause trauma to the tissue. Stopper 184 may alternatively be a
mechanically expandable member that may also be selectively
expandable to accommodate varying or unknown anatomy.
[0121] The device of FIG. 22B also provides a stopper mechanism 194
which may be selectively expandable to control the flow of fluid
past the os 195. Stopper 194 is depicted as having a disk
configuration, but any suitable shape may be employed. Unlike the
stopper of FIG. 22A, stopper 194 is not fixed to the exterior of
aspiration lumen 190 but is selectively translatable or advancable
over lumen 190 by an advancement member 196. Advancement member 196
may be a wire attached to stopper 194 which extends parallely along
aspiration lumen 190 and is controlled by pushing and pulling
actions. Optionally, a loose-fitting sheath 198 may be provided
over aspiration lumen 190 and advancement wire 196, as well as
expandable member 194 to restrain or retain it during delivery.
Expandable member 194 may be made of a firm but compliant material
that can be easily folded about and held against lumen 190 by
sheath 198, and which springs open to an expanded condition upon
release from sheath 198. In certain embodiments, the advancement
member limits the range over which the stopper mechanism may travel
proximally, such that the total range that the stopper may travel
in the proximal to distal direction along the aspiration lumen is
fixed. In yet other embodiments, the stopper may be constructed as
to limit the range of travel of the stopper mechanism between both
a distal limit point and a proximal limit point.
[0122] In yet another embodiment (not depicted in the figures), the
stopper may be connected to the lumen by means of a compliant
material in, e.g., in the form of a string, or sheet that, that
attaches the stopper to the lumen at a defined location and allows
the stopper to travel coaxially along a range of the distal end of
lumen. The range can be defined by either the structure and/or
length of the compliant material, or may alternatively be defined
by flanges or other mechanical limits between the stopper and the
lumen. The stopper inflation/deflation or expansion/recovery
mechanism may be incorporated into the structure that connects the
stopper to lumen, or separate.
[0123] In use, the catheter is advanced until the fenestrae 192 are
ideally positioned within the coronary sinus. As aspiration is
initiated, stopper 194 may be expanded and advanced distally until
the distal side of stopper 194 abuts the os to prevent the flow of
blood there through. However, stopper 194 need not be fully
advanced but placed in close proximity to the os but without
occluding it so as to allow antegrade flow there through. As the
pressure differential between the atrium and the coronary sinus
increases due to aspiration of blood into fenestrae 192, stopper
194 is drawn distally. Notwithstanding the negative pressure
exerted on stopper 194, it cannot travel beyond the position set by
the advancement member 196.
[0124] By occluding or stopping flow proximally to coronary sinus
os (as with the stopper mechanism of FIGS. 22A and 22B),
tributaries within the coronary sinus, including those positioned
very close to the os, will remain in direct fluid communication
with the aspiration ports of the fenestrate of the aspiration
lumen, thus, improving the efficacy of the removal of contrast or
other material from the body.
[0125] To reduce the likelihood of thrombus formation, the stopper
mechanisms of the present invention may be externally coated with
an anticoagulant or the like.
[0126] FIG. 9 provides a depiction of an alternative device for
collection of an agent from the coronary sinus using the methods of
the subject invention. In the device shown in FIG. 9, device 90
includes distal end 92 having sensing element 94. Proximal to the
distal end and positioned inside of the right atrium is collection
element or funnel 96. During aspiration, collection element or
funnel 96 is deployed as shown in FIG. 9, and collects
substantially all fluid flowing out of the coronary sinus through
the ostium.
[0127] FIGS. 14 A to 14C provide depictions of alternative
embodiments of the device shown in FIG. 9 in which fluid collection
occurs at a target site (i.e., right atrium) proximal to the
efferent fluid collection site (i.e., coronary sinus), and
illustrates further that the distal portion of the aspiration lumen
141 need not necessarily reside within the site of convergence,
such as the coronary sinus, but rather, may reside primarily within
a region proximate to the site of convergence, such as the right
atrium 142. In using the devices shown in FIGS. 14A to C, as the
agent to be removed is sensed within the site of convergence, the
aspiration mechanism is activated and the agent to be removed is
aspirated as it exits the site of convergence. In certain
embodiments, the aspiration lumen is one that can be advanced such
that the distal tip of the aspiration lumen enters into closer
proximity to the site of convergence. This motion may occur
secondary to the act of initiating the aspiration mechanism which
would tend to pull the catheter tip forwards, or as the result of a
forced translation of the aspiration lumen. Optionally, a guidewire
or other shaft 144 may reside within the site of convergence and
may contain a sensing element 145. This shaft may have an anchoring
element 144 at its distal such that it can be temporarily anchored
within the convergence site. An example of such a means would be an
expandable member that does not occlude flow, such as a
whisk-shaped nitinol element 144. This shaft would be arranged with
the aspiration lumen in such a way that the advancement of the
aspiration lumen is more effectively directed towards the site of
convergence. For example, the shaft could lie coaxially within the
aspiration lumen, or within a separate lumen that runs coaxially
within the aspiration lumen as part of the aspiration catheter. In
the case where the distal end of the aspiration lumen has an
element, such as a funnel or similarly shaped tip facing towards
the convergence site, whose dimensions are large enough to prevent
it from fully entering the convergence site, the aspiration
catheter can be translated towards the site of convergence such
that the tip forms a temporary seal around an opening into the site
of convergence, such as the os of the coronary sinus. See
particularly FIGS. 14A and 14B. An advantage of a system such as
that shown in FIGS. 14A to 14C wherein the distal tip of the
aspiration catheter is expandable to cover an area larger than the
primary site of convergence is that if there is an additional
conduit 146 in a particular patient or subject through which the
agent to be retrieved could escape into the general circulation,
such as an anomalous middle cardiac vein that emptied into the
right atrium rather than the coronary sinus, the os of both the
coronary sinus and the middle cardiac vein can be generally
enclosable by the distal tip of the aspiration lumen, thus
improving the efficiency of collecting the agent. A further
advantage of such an embodiment is that if some of the conduits
that converge into the fluid collection site do so at a location
very close to the os or exit point of that site, by positioning the
distal tip of the aspiration lumen immediately outside of the site
(as illustrated in FIG. 14C), the amount of agent that leaks from
those conduits that are closest to the os or exit point of the site
is minimized. For example, the more conventional anatomy of the
middle cardiac vein is for it to drain into the coronary sinus at a
point very close to the coronary os. Rather than have the distal
portion of the aspiration lumen within the coronary sinus, it may
be more advantageous in certain embodiments to use the embodiments
described above to have the distal tip of the aspiration lumen in
the right atrium near the coronary os. Once the aspiration
mechanism is activated, the distal tip of the aspiration lumen can
be made to tend to abut against the wall of the right atrium,
enclosing the coronary os and any nearby anomalous points of
cardiac venous return (see e.g., FIG. 14C).
[0128] In a variation of the representative device and its use as
depicted in FIGS. 14A to 14C, FIGS. 15A and 15B provide a depiction
of a device as shown in FIGS. 14a to 14C where the device further
includes a shunting element. In the embodiment of the device shown
in FIGS. 15A and 15B, the aspiration lumen is one that produces a
seal with the structures that define the collection site such that
fluid within the collection site is generally directed to enter
into the aspiration lumen and travel within a distal portion of the
aspiration lumen. In such an embodiment, the aspiration lumen has
one or more exit ports 150 that open into the circulation and would
generally allow the fluid that entered the aspiration lumen at the
distal end to enter back into the circulation at a more proximal
point along the lumen (as described above, e.g., in connection with
FIGS. 8A to 8C. When the aspiration mechanism is activated, the one
or more ports become substantially if not completely closed, thus
directing the fluid that enters the distal tip of the aspiration
lumen to the extracorporeal components of the present invention,
rather than allowing it to directly reenter the circulation from
the aspiration lumen. Mechanisms to substantially or completely
close the re-entry ports include one or more flaps on the external
surface of the lumen that act as one way valves which allow flow to
exit the lumen from these ports when the aspiration mechanism is
not activated, and prevent flow to enter the lumen from these ports
when the aspiration mechanism is activated. Alternatively, an outer
shaft can be placed coaxially around the around lumen, and have
fenestrations in it that, when aligned with the one or more ports
of the aspiration lumen, create a window that allows fluid to
escape the aspiration lumen. By a combination of translating and/or
rotating the outer fenestrated shaft such that the fenestrations do
not align, flow will not able to enter or exit through the re-entry
ports. See FIGS. 15A and 15B.
[0129] In using the devices shown in FIGS. 15A and 15B, the distal
tip 141 of such a system may reside within the collection site 142
and have an expandable element to make a seal with the inner
surface of the collection site, thus directing fluid through the
distal portion of the aspiration lumen. Alternatively, the distal
tip can be made to abut against the tissue external to the os 148
or exit point of the collection site, such as the portion of the
wall of the right atrium near the coronary os. An advantage of this
shunting configuration includes an opportunity to incorporate a
sensor within the aspiration lumen in a highly reliable
configuration that may improve sensor accuracy as compared to the
situation when a sensor may be placed in an anatomical structure.
Yet another advantage is that the portion of the aspiration lumen
through which fluid travels prior to exiting through the distal
exit ports acts as a time-delay circuit, which reduces the
performance requirements of the system by allowing the aspiration
mechanism to take longer to actuate without concern that some of
the agent may have already escaped in the small but finite time
period between the time when the agent was detected and when the
aspiration mechanism was activated.
[0130] In certain embodiments, active shunting is employed, e.g.,
to achieve a desirable pressure profile in the target/efferent
fluid collection site. An embodiment of a device that produces a
reduced pressure at the collection site via active shunting is
depicted in FIGS. 16A and 16B and includes an aspiration lumen 160,
a distal portion 161 of the aspiration lumen through which all
fluid from the collection site 143 tends to travel through, a one
way valve mechanism 162 within that distal portion that generally
only allows fluid to travel in the distal-to-proximal direction of
the aspiration lumen and a re-entry port 164 proximal to the distal
portion with a one way valve mechanism that generally only allows
fluid to escape the aspiration lumen and re-enter the general
circulation. When the proximal end of such an embodiment is
connected to a cyclic pump that aspirates for a certain percentage
of a cycle, and infuses for another percentage of the cycle, the
net result is as follows: 1) during the aspiration portion, fluid
is withdrawn from the collection site, and travels proximal along
the length of the aspiration lumen (a sensor within the aspiration
lumen can optionally detect the presence of the agent to be
retrieved within the distal portion of the aspiration lumen at this
time); and 2) during the infusion portion of the cycle, fluid
proximal to the one-way valve is re-introduced to the general
circulation as it travels in the proximal-to-distal direction back
out the re-entry port. In these embodiments, when the agent is
detected, the infusion portion of the cycle is skipped, allowing
the removal of the fluid containing that agent. In certain
embodiments, the one-way valve or selectively controllable re-entry
port of these embodiments is implemented as described above for the
case of the passive shunting embodiment (e.g., as depicted in FIGS.
15A and 15B). In certain embodiments, the one-way valve within the
distal portion of the aspiration lumen is constructed using an
intraluminal duckbill valve, or a piece of formed flexible plastic
that operates in a manner similar to a bicuspid or tricuspid valve
in the heart. In certain embodiments, a single cusp design is
employed.
[0131] FIG. 10 provides a depiction of an alternative device for
collection of an agent from the coronary sinus using the methods of
the subject invention, where the device includes a fluid-flow
modulating element for modulating blood flow through the coronary
sinus. In FIG. 10, device 100 includes three distinct elements at
its general distal end 102, i.e., an aspiration lumen 104, a
guidewire/sensor element 106 and a spiral balloon element 108.
During use of the device as shown in FIG. 10, the distal end 107 of
guidewire/sensor element 106 is positioned near the ostia of the
cardiac veins so as to provide early detection of agent entering
the coronary sinus. Spiral balloon element 108 spirals around the
central guidewire/sensor element 106 and extends the length of the
coronary sinus. The dimensions of the balloon are such that the
fluid flow path of the coronary sinus is altered so that its length
ranges from about 10 to about 300 mm, such as from about 15 to
about 150 mm, and the diameter of the flow path as it spirals
around the guidewire/sensor element 106 ranges from about 1 mm to
about 50 mm, such as from about 1.5 mm to about 15 mm. The spiral
balloon element 108 provides the ability to modulate the velocity
of fluid flow through the coronary sinus, e.g., where the velocity
of fluid flow may be controlled to range from about 10 ml/sec to
about 500 ml/sec, such as from about 50 ml/sec to about 150 ml/sec.
Several advantages are provided by the device depicted in FIG. 10.
For example, by selecting the appropriate catheter to vessel lumen
ratio, e.g., from about 1% to about 90%, such as from about 10% to
about 70%, the flow of fluid through the coronary sinus can be
controlled at a desirable rate. Furthermore, less negative pressure
may need to be employed to ensure that fluid enters the aspiration
element 104, whose distal end 105 is positioned at the proximal end
of the spiral balloon element 108. Cross-sectional view 109 depicts
the flow path in the coronary sinus and shows how the dimensions
are altered upon deployment of the device. Also, in certain
embodiments such configuration provides advantages as an anchoring
mechanism for the catheter tip to remain in the target vessel for
the duration of the catheterization procedure.
[0132] In an alternative embodiment, a spiral balloon may be
employed without the depicted central guidewire/sensor lumen
depicted in FIG. 10. In these embodiments, the spiral balloon may
serve to anchor the distal end of the device, but maintain a
straight central fluid flow lumen, and therefore not lengthen the
fluid flow may, which feature is desirable in certain
embodiments.
[0133] As indicated, in each of the above embodiments, each
aspiration lumen may optionally incorporate a detector, e.g., where
the detector is integral to the aspiration element/lumen, such as
any of the representative detector embodiments that are described
below.
Systems
[0134] Also provided are systems for use in practicing the subject
methods, where the systems include a device for selectively
removing agent from the efferent fluid collection site, such as the
representative devices described above, and may optionally include
one or more additional components that find use in practicing the
subject methods, e.g., detectors, agent introducers, data
recorders, etc. A representative system is depicted in FIG. 1. In
the system depicted in FIG. 1, the system includes the standard
device components, i.e., an aspiration controller 11 and aspiration
mechanism 12 operatively linked to an aspiration lumen which is
introduced into the subject (body) 13, as well as a number of
additional/optional components, such as an injection/delivery
system 14 for introducing agent into the body at a site upstream of
the target efferent fluid collection site, one or more detector
elements 15 for detecting the presence of agent in the efferent
fluid collection site, and an aspiration recorder/display element
16 for recording data (e.g., fluid flow data, etc.) and displaying
the same to the operator.
Utility
[0135] The subject invention finds use in a wide variety of
different applications, including both diagnostic and therapeutic
applications. Of particular interest is the use of the subject
methods and devices to selectively remove from a subject a locally
administered diagnostic or therapeutic agent, so that the host or
subject is not systemically exposed to the diagnostic or
therapeutic agent.
[0136] In many embodiments, the subject methods are employed to
selectively remove a locally administered diagnostic agent, such
that the diagnostic agent is only contacted with a limited region
or portion of the host to which it is administered, e.g., a
specific organ or portion thereof. A common example of such a
compound is radio-opaque dye. Iodinated forms of such a dye are
used routinely during catheter-based interventional procedures such
as coronary, renal, neurological and peripheral arteriography. The
iodine component has a high absorption of x-rays and therefore
provides a contrast medium for the radiological identification of
vessels when introduced within an upstream artery. However, the use
of such dyes is known to have potential toxic effects depending on
the specific formulation, including direct injury to renal tubule
cells, endothelial injury, bronchospasm, inflammatory reactions,
pro-coagulation, anti-coagulation, vasodilation and
thyrotoxicosis.
[0137] Another representative utility of the subject invention is
in the selective removal from a patient of a locally administered
therapeutic agent, where representative therapeutic agents or
materials that may be introduced locally for desired effects but
whose direct or other effects would be undesired elsewhere include
vasoactive agents, cytotoxic agents, genetic vectors, apoptotic
agents, anoxic agents (including saline), photodynamic agents,
emboli-promoting particles or coils, antibodies, cytokines,
immunologically targeted agents and hormones. Additional agents of
interest include, but are not limited to: cells, enzymes,
activators, inhibitors and their precursors, as well as sclerosing
agents, anti-inflammatories, pro-inflammatories, steroids and
osmotic agents, and the like. As such, another representative
application of the subject methods is to determine the amount of
agent retained at a local area or region of a subject upon local
administration of the agent to the subject. For example, where a
therapeutic agent is locally administered to a region or location
of a subject, e.g., an organ, and blood carrying the agent is
selectively removed from the subject according to the subject
methods, the amount of agent in the collected blood can be used to
determine the amount of agent that was retained by the local region
or area, e.g., organ, of the subject. As such, in those cases where
the present invention is used to retrieve a diagnostic or
therapeutic agent for which a portion of that agent desirably
resides in the region into which it is delivered, and the portion
of the agent collected from the collection represents an amount of
the agent that did not remain resident in that region, the subject
methods may be employed to estimate the effective dosage of the
agent. For example, in the localized delivery of a chemotherapeutic
agent via the afferent branches of a targeted tumor, the present
invention is capable of collecting some of the chemotherapeutic
agent before it is able to enter into the systemic circulation,
thus minimizing its side effects. The difference between the amount
of agent injected and the amount of agent that is retrieved by the
present invention represents the sum of the amount of agent that
was successfully incorporated into the tumor and the amount of
agent that escaped to the systemic circulation. If a goal of the
localized delivery of the chemotherapeutic agent is to attempt to
incorporate a given dosage of the agent into the tumor, it is
possible to use the present invention to better estimate how much
of the delivered agent was successfully incorporated into the tumor
by estimating how much of the agent was retrieved in the collection
site. If a higher than expected amount of agent was retrieved in
the collection site, than a substantial portion of the agent was
not successfully incorporated into the tumor and this may direct
the physician to deliver more agent to the tumor, or consider
alternative strategies for treatment. The higher the efficacy of
the present invention is in terms of retrieving the agent, the more
accurate the estimate of the amount of agent successfully delivered
to the site will become.
Kits
[0138] Also provided are kits for use in practicing the subject
methods, where the kits typically include one or more of the above
devices, and/or components of the subject systems, as described
above. As such, a representative kit may include a device, such as
a catheter device, that includes an aspiration lumen, aspiration
mechanism and aspiration mechanism controller, as described above.
The kit may further include other components, e.g., guidewires,
etc., which may find use in practicing the subject methods.
[0139] In addition to the above-mentioned components, the subject
kits typically further include instructions for using the
components of the kit to practice the subject methods. The
instructions for practicing the subject methods are generally
recorded on a suitable recording medium. For example, the
instructions may be printed on a substrate, such as paper or
plastic, etc. As such, the instructions may be present in the kits
as a package insert, in the labeling of the container of the kit or
components thereof (i.e., associated with the packaging or
subpackaging) etc. In other embodiments, the instructions are
present as an electronic storage data file present on a suitable
computer readable storage medium, e.g. CD-ROM, diskette, etc. In
yet other embodiments, the actual instructions are not present in
the kit, but means for obtaining the instructions from a remote
source, e.g. via the internet, are provided. An example of this
embodiment is a kit that includes a web address where the
instructions can be viewed and/or from which the instructions can
be downloaded. As with the instructions, this means for obtaining
the instructions is recorded on a suitable substrate.
[0140] The following example is offered by way of illustration, and
not by way of limitation.
[0141] I. Contrast Retrieval From The Coronary Sinus During
Coronary Angiography--An Experimental Study
[0142] A. Methods:
[0143] A 10 F guiding catheter was placed in the coronary sinus of
a porcine animal model just distal to the azygous vein. The
external diameter of the guiding catheter was sub-occlusive for the
target segment of the porcine coronary sinus, such that the sheath
permitted flow to observably varying degrees. A coronary guiding
catheter was placed at the ostium of the left coronary arterial
system.
[0144] Aspiration was enabled using a "bleed-back mechanism"
wherein a valve along the proximal portion of the aspiration lumen
was controlled by a human operator. The proximal end of the
aspiration lumen emptied into a small container with graduated
volume markings. The mechanical driving forces for aspiration was
provided via a combination of gravity and the pressure difference
between the venous system and the ambient environment. The volume
of the lumen of the aspiration lumen was measured to be 4 cubic
centimeters.
[0145] 10 cubic centimeters of contrast agent were injected into
the left coronary arterial system. These injections were given
slowly to minimize regurgitation of contrast into the aorta, which
would result in contrast being injected that could not be retrieved
from the coronary sinus. The migration of contrast agent towards
the coronary sinus was observed fluoroscopically by the human
operator. As the contrast was visualized to enter the anterior
interventricular vein, just upstream of the coronary sinus, the
human operator opened the valve of the aspiration lumen. The first
4 cc of fluid was collected in one container, corresponding to
fluid that was resident in the aspiration lumen prior to opening
the valve. The following 10 cc of fluid was then collected in a
second container.
[0146] The hematocrit of the second container was then measured
using standard laboratory techniques and compared with the
hematocrit of the systemic circulation of the animal which was
measured 5 minutes after the injection of contrast agent.
[0147] The process of injecting contrast agent, followed by
aspiration from the coronary sinus into 2 containers and comparison
of the hematocrit of the second container with that of the systemic
circulation was repeated 5 times.
[0148] B. Results:
[0149] The efficiency of removal of contrast was estimated as
follows:
[0150] The hematocrit of the aspirated fluid can be represented as:
Hct = RBC_volume plasma_vol + RBC_vol + contrast_vol ( 1 ) ##EQU1##
where the denominator is known to be 10 cc, making it easy to
calculate RBC_volume by the following: RBC_volume=Hct*10 cc
[0151] Furthermore, the plasma volume can be expressed as RBC
volume multiplied by a factor calculated from the baseline
hematocrit: Baseline = RBC_volume RBC_volume + plasma_volume
##EQU2## which can be rearranged to: plasma_volume = RBC_volume
.times. ( 1 - baseline ) baseline ##EQU3## (1) can further be
rearranged to express contrast_volume as a function of hematocrit
as follows: contrast_vol = RBC_vol Hct - ( plasma_vol + RBC_vol )
##EQU4## Using this latter equation, the volume of contrast agent
retrieved can be estimated, which can directly be expressed as a
percentage of the original 10 cc of contrast injected. For the 5
iterations of this illustrative experiment, the percentages of
original contrast injected that was successfully retrieved were
calculated to be 62.5%, 51.5%, 33.8%, 58.4%, 37.3%.
[0152] It should be noted that this experiment was performed for
proof of concept purposes only and the demonstrated efficiencies of
contrast retrieval likely understate the results achievable. The
incorporation of automated detection, as well as optimization of
injection and aspiration parameters (e.g. volumes, rates) will most
certainly improve these results. Furthermore, improved results
within humans are more likely, given that the coronary sinus in
porcine models also receives flow from the azygous vein, which is
not the case in humans.
[0153] II. Representative Protocols for Selective Removal of
Contrast Agent from the Coronary Sinus:
[0154] A. First Representative Protocol
[0155] 1. The patient is prepared for conventional cardiac
catheterization procedure, including field sterilization, draping
and any necessary medications.
[0156] 2. The physician uses catheterization techniques, such as
the Seldinger technique, and catheterization tools, such as
guidewires and guiding catheters, to access a left-sided coronary
artery via an entry point at the femoral artery near the groin
[0157] 3. The physician uses catheterization techniques, such as
the Seldinger technique, and catheterization tools, such as
guidewires and guiding catheters, to access the coronary sinus via
an entry point at the femoral vein near the groin.
[0158] 4. A catheter for inserting contrast agent into the coronary
artery is advanced to the site at which contrast is to be
introduced.
[0159] 5. An aspiration lumen is advanced to the coronary sinus,
along with a fiber optic that is incorporated in the aspiration
lumen.
[0160] 6. The aspiration controller is turned on so that the fiber
optic can be used to detect a decrease in the concentration of
blood in the coronary sinus (and hence an increase in concentration
of contrast agent).
[0161] 7. A bolus of contrast agent is injected at the site to
which contrast is to be introduced.
[0162] 8. As the bolus of contrast agent migrates through the
arterial system, followed by the myocardial capillaries and
eventually enters the coronary sinus, it is detected by the fiber
optic detector within the coronary sinus.
[0163] 9. The aspiration controller responds to the entry of
contrast agent into the coronary sinus by activating an aspiration
mechanism at the proximal end of the aspiration lumen.
[0164] 10. As the concentration of contrast agent decreases in the
coronary sinus, the detector approaches a threshold at which it
signals the controller to cease aspiration.
[0165] 11. Steps 7 through 10 can be repeated several times to
remove contrast during subsequent cycles of contrast injection.
[0166] 12. Upon completion of use, the aspiration lumen is
withdrawn from the body. The aspirated fluid will contain a
significant portion of the contrast agent introduced during the
procedure.
[0167] B. Second Representative Protocol
[0168] The protocol is performed substantially as described in
II.A. above, with the exception that presence of the agent in the
coronary sinus is detected by cycling small samples of fluid from
the distal tip of the device and then returning the fluid back out
into the circulation if.
[0169] C. Third Representative Protocol
[0170] The protocol is performed substantially as described in
II.A. above, with the additional step of temporarily stenting the
small cardiac vein to get better collection from the right side of
the heart.
[0171] D. Fourth Representative Protocol
[0172] The protocol is performed substantially as described in
II.A. above, with the additional step of covering the AV ridge to
prevent contrast from leaking back into the right atrium from the
small cardiac vein (SCV), thus redirecting that fluid to travel
through the SCV into the CS.
[0173] III. Catheter Based Detection of Radiocontrast Media
[0174] A. Introduction
[0175] Several conditions in the coronary artery injection of
radiocontrast media, such as injection volume (10 cc), time of
injection (1-2 sec), and the high viscosity of the radiocontrast
media, account for limited mixing of the radiocontrast media with
the blood in the coronary artery. The radiocontrast media
consequently tends to flow through the vasculature as a bolus. The
red blood content in the radiocontrast bolus is reduced compared to
the blood prior to the radiocontrast injection. Hematocrit
measurement therefore is an indirect method of detecting
radiocontrast media in blood. One means of hematocrit measurement
is sensing the reflectance properties of red blood cells. A pair of
send and receive optical fibers incorporated in the catheter distal
tip to detect red blood cell backscattered light are employed in
the following experiment. Prior to radiocontrast injection, the
blood is expected to produce the largest reflected light and the
signal is expected to diminish due to a drop in red blood content
as the concentration of radiocontrast media increases.
[0176] B. Sensor
[0177] FIG. 17 is a cross sectional view of the distal tip of an 8
Fr catheter with a pair of 500 .mu.m emitter and detector glass
fibers. The light emitter is a near infrared LED of 950 nm
wavelength, because it is a very efficient emitter, and because
photodetectors are intrinsically well matched to this wavelength.
The 950 nm light is emitted axially from the distal tip of the
catheter and the fibers are positioned so that there is no overlap
in the emitting zone and receiving zones enabling reflectance
measurements as the blood flowed past the distal tip of the
catheter.
[0178] During use, the electronic circuit delivers a pulse of
approximately 500 ma for 100 microseconds with a repetition rate of
120 Hz into the emitter LED. The signal from the photodetector is
conditioned and sampled synchronously with the drive signal, after
the initial transient is complete, approximately halfway through
the pulse. This signal is then low pass filtered and the output
monitored on an oscilloscope.
[0179] C. In Vitro Experimental Results
[0180] Citrated pig blood with a hematocrit of approximately 35%
was pipetted using in 1 ml increments, and added to a container
with the appropriate amount of normal saline to make the required
dilutions. Saline was used as diluant to mimic the effects on red
blood cell volume when radiocontrast media is administered in the
course of coronary angiography. Measurements were made from 0%
blood to 100% blood by inserting the tip of the catheter in the
blood samples and monitoring the output voltage. The results
obtained from this proof of concept experiment are shown in FIG.
18.
[0181] D. In Vivo Experimental Results:
[0182] Calibration was performed on the bench in advance of the
animal experiment, using citrated pig blood and the Isovue 370
radiographic contrast medium. Static calibrations were non-linear,
perhaps due to settling of blood cells or formation of rolleau.
Dynamic experiments with flowing blood with injection of blood
diluted with contrast demonstrated a linear relationship between %
blood and intensity of backscattered light. The response was linear
for blood in the range of 100% to about 40% blood as shown below in
FIG. 19. Since the starting blood sample had a hematocrit of about
35%, the linear response range corresponded to a change in
hematocrit from 35% to roughly 14%.
[0183] A pig, approximately 4 months and 30 kilograms, was
initially immobilized with an intramuscular injection of ketamine
(20 mg/kg) and xylazine (2 mg/kg). Following intubation, the animal
was mechanical ventilated with a mixture of air and 0.5% halothane
to maintain anesthesia during the course of the procedure. A
surgical cut down procedure was performed on the right femoral
artery and a sheath was inserted to create vascular access. A guide
catheter was then inserted through the sheath and advanced under
angiographic guidance into the ostium of the left coronary artery.
A second surgical cut down procedure was then performed on the
right carotid artery followed by insertion of a sheath. A guide
catheter was then inserted and advanced under angiographic guidance
through the right atrium and into the coronary sinus. The catheter
shown in FIG. 17 was then inserted through the guide catheter and
advanced so that the distal tip including the sensing element
extended into the coronary sinus in contact with the venous blood
flow. The venous blood flow in the coronary sinus was not occluded
by the catheter.
[0184] Once positioned in the coronary sinus the detector is
activated and the electronic signal induced by the red blood
reflectance was monitored on an oscilloscope until a stable
baseline signal was achieved. Radiocontrast media (Isovue-370,
Bracco Diagnostics, iopamidol at 755 mg/ml) was power injected over
a 1-2 second interval into the left coronary artery. At the point
of radiocontrast injection, two means of detecting the
radiocontrast were monitored: (a) the change in red blood induced
reflectance by the catheter; and (b) the time of appearance and
subsequent disappearance of the fluoroscopic image of the venous
return of radio-opaque material in the coronary sinus. Five
sequences of radiocontrast injection in the left coronary artery
followed by detection were performed.
[0185] At the end of the procedure the catheters were removed and
the animal was euthanized with an intravenous injection of
pentobarbital.
[0186] When a power injector was used to inject contrast into the
left coronary artery of the pig, the signals observed in five runs
are shown in FIG. 20. The raw signal was displayed as percentage
radiocontrast using the calibration curve above. The injections
were in five consecutive trials: three runs each consisting of 10
cc of radiocontrast media delivered uniformly within 2 seconds, one
run of 5 cc delivered within 1 second, and one run of 1 cc
delivered within 1 second. The lower margin of the chart in FIG. 20
shows fluoroscopic signal markers. The beginning edge of the
markers show the time when the injection began and the time when
the radiocontrast became subjectively visible on the fluoroscope.
Total time for data collection for each radiocontrast injection run
was 15 seconds.
[0187] Results for the 5 and 10 cc injections show a correlation
between the time the catheter senses a change in reflectance in the
coronary sinus and the appearance of the radiocontrast in the
coronary sinus as visualized on the fluoroscope. The data shows
that the sensor measuring radiocontrast induced changes in blood
reflectance is a feasible means of activating catheter based
aspiration of radiocontrast/blood mixtures in the coronary sinus.
The 1 cc injection, although visible on the fluoroscopy, was not
detected with the sensor and represents the sensitivity limit with
the current embodiment of the optical device. Since most
angiographic procedures utilize 5 or 10 cc contrast injections,
failure to detect 1 cc injections does not represent a practical
limitation of the device. Sensitivity can be most readily improved
by reducing electronic noise in the baseline reflectance signal
before contrast injection. It was observed that the greatest source
of the electronic noise was due to the tip of the catheter moving
around in the coronary sinus as the heart was beating and
contacting the wall of the vessel. Means of isolating the sensor to
prevent wall contact would be the most straightforward means to
reduce the electronic noise thus improve sensitivity.
[0188] It is evident from the above discussion and results that the
subject invention provides a significantly improved method of
locally administering an agent, e.g., a diagnostic or therapeutic
agent, to a host. Advantages of using the subject invention to
remove an agent from a fluid collection site include: (a) a
reduction in systemic side effects; and (b) the ability to increase
concentration and/or amount of substance that can be used safely to
achieve desired diagnostic/therapeutic result. Advantages of the
subject non-occlusive methods over occlusive methods include: (a)
minimal structural changes occur while performing the methods so
that complications arising from structural changes (e.g.
morphological changes to coronary sinus may predispose to
arrhythmias and expansion of cerebral veins may induce migraine)
are avoided; (b) the limitation of modulation of flow through the
upstream organ because of minimized changes (e.g. less elevation)
of venous-side pressure is achieved; (c) potentially greater
efficiency with respect to the amount of non-targeted (innocent
bystander) fluid that is removed; (d) less traumatic impact to the
subject than some rapidly expandable implementations of occlusive
members; and (e) more fault-tolerant, as default state is to allow
flow to continue as usual when there is no signal to cause removal
of substances. As such, the subject invention represents a
significant contribution to the art.
[0189] All publications and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference. The
citation of any publication is for its disclosure prior to the
filing date and should not be construed as an admission that the
present invention is not entitled to antedate such publication by
virtue of prior invention.
[0190] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
of understanding, it is readily apparent to those of ordinary skill
in the art in light of the teachings of this invention that certain
changes and modifications may be made thereto without departing
from the spirit or scope of the appended claims.
* * * * *