Note: Descriptions are shown in the official language in which they were submitted.
INFUSION PROCEDURE FOR ENHANCING IMAGE QUALITY
TECHNICAL FIELD
The present disclosure relates to radioisotope elution systems and methods for
imaging using
such systems.
BACKGROUND
Positron Emission Tomography (PET) involves the use of radioisotopes in a non-
invasive manner
for measurement of relative myocardial perfusion and absolute myocardial blood
flow. A
limitation of present PET imaging is that infusion of ultra-short half-life
tracers over a relatively
long period tends to degrade image quality.
U.S. Pub. No. 2015/0228368, assigned to Jubilant Draxlmage Inc. and the Ottawa
Heart Institute
Research Corporation, discloses a rubidium elution system comprising "patient
line flush mode"
in which saline flows through the bypass line and come out through patient
line. This patient line
flush is used prior to elution for expelling air from patient line and after
the elution for removal of
remaining radioactivity and delivery into patient.
U.S. Pub. No. 2017/0172527, assigned to Bayer HealthCare LLC, discloses a
radiopharmaceutical dispensing system comprising intravenous line to inject
the
radiopharmaceutical into the patient. Saline flush is optionally used to
increase 18F-
Fludeoxyglucose (FDG) delivered into the patient.
PCT Publication No. WO 2009/152320, assigned to Bracco Diagnostics Inc.,
discloses a
radiopharmaceutical infusion system for rubidium-82 comprising eluant flush at
higher flow rate
through by-pass line into patient line.
However, these publications, and the prior art generally, have not addressed
ongoing problems
relating to background noise, signal to noise ratio, contrast to noise ratio,
and other issues relating
to image quality, that are associated with conventional nuclear medicine
imaging procedures that
use radioactive materials as contrast agents.
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SUMMARY
Accordingly, an object of the presently disclosed methods is to improve image
quality with low
background noise, higher signal to noise ratio (SNR) and higher contrast to
noise ratio (CNR),
without increasing the total amount (activity) of radioisotope contrast
injection delivered to a
patient, which permits better diagnosis and reduces the need for repeating
infusion and imaging
procedures. This, in turn, reduces exposure of patients to radiation and
maximizes image quality.
Disclosed herein are methods for infusing a radioisotope to a subject using a
system that includes
a controller, an infusion line for delivering fluid under control of the
controller, and a pump that
is communicatively coupled to the controller, the method comprising infusing a
volume of saline
containing a diagnostic dose of the radioisotope from the infusion line into a
peripheral vein of
the subject at a first flow rate; and, using the controller and pump to
deliver a pre-measured
volume of push saline in one or more increments to the peripheral vein at a
second flow rate
Also provided herein are methods for obtaining a diagnostic image of a
subject's heart using a
system that includes a controller, an infusion line for delivering fluid under
control of the
controller, and a pump that is communicatively coupled to the controller, the
method comprising
infusing a volume of saline containing a diagnostic dose of the radioisotope
from the infusion line
into a peripheral vein of the subject at a first flow rate, using the
controller and pump to deliver a
pre-measured volume of push saline in one or more increments through the
infusion line, and to
the peripheral vein at a second flow rate, and, obtaining a diagnostic image
of the subject's heart
using the radioisotope as an imaging agent.
Also disclosed are diagnostic images of a subject's heart that is obtained
using a system that includes a
controller, an infusion line for delivering fluid under control of the
controller, and a pump that is
communicatively coupled to the controller, wherein the image is obtained by
infusing a volume of saline
containing a diagnostic dose of the radioisotope from the infusion line into a
peripheral vein of the
subject at a first flow rate; using the controller and pump to deliver a pre-
measured volume of push
saline in one or more increments through the infusion line, and to the
peripheral vein at a second flow
rate; and, obtaining the diagnostic image of the subject's heart using the
radioisotope as an imaging
agent.
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BRIEF SUMMARY OF DRAWINGS
FIG. 1 illustrates a conventional radioisotope elution system used for
imaging.
DETAILED DESCRIPTION
The present disclosure can be more readily understood by reading the following
detailed
description, including the illustrative embodiments.
As used herein, the term "elution system" refers to a radioisotope infusion
system intended for
generating a solution containing radioisotope, measuring the radioactivity in
the solution, and
infusing the solution into a patient for diagnosis.
As used herein, the term "generator" or "radioisotope generator" refers to a
hollow column inside
a radio shielded container. The column is filled with an ion exchange resin
and radioisotope is
loaded onto the resin.
As used herein, the term "about" preferably means 10% of the indicated
value.
As used herein, the "merge point" refers to a point in a tubing set where a
bypass line and a
generator outlet line intersect each other.
As used herein, the term "patient line" refers to a tubing segment that
connects the merge point to
a patient outlet and is used for infusing the patient with radioactive
solution.
As used herein, the term "radioactive saline" refers to the saline solution
containing radioactive
tracer.
As used herein, the term "controller" refers to a computer or a part thereof
programmed to
perform certain calculations, execute instructions, and control various
activities of an elution
system based on user input or automatically.
As used herein, the term "tubing set" refers to a system of conduits that is
used for carrying fluid
from one point to another. Tubing for use in the tubing set may be formed from
any appropriate
material, including any disposable material or radiation resistant material.
For example, the
tubing may be formed from flexible silicon material.
As used herein, the term "pump" refers to the component that is used to induce
transportation of
elution medium from a source to the inlet of a generator. Generally, a medical
grade peristaltic
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pump or a syringe pump may be used in order to provide control and precise
flow rates from a
generator to a patient infusion line.
As used herein, the term "valve" refers to a component that is used to
alternatively prevent or
permit fluid flow into a portion of the system. Exemplary valves include pinch
valves,
divergence valves, solenoid valves, stop-cock valves, or any combination
thereof.
As used herein, the term "activity detector" refers to a component that is
used to determine the
amount of radioactivity present in eluate from a generator, e.g., prior to the
administration of the
eluate to the patient.
As used herein, the term "transit time" refers to the time required for
radioactive saline to move
from an intravenous access site to a target site within the patient.
As used herein, the term "saline push" refers to the method of flushing the
activity of
radioisotope remaining in the patient line or the patient vein towards the
target organ to quickly
deliver the radioisotope to the target site. The "push saline" can be used to
describe the pre-
measured volume of saline that is delivered as a result of the saline push.
This results in delivery
of higher amount of radioactivity to the target site, which in turn leads to
enhancement of image
quality, high image counts, increase in myocardial uptake factor and
improvement of image
quality measures such as image signal-to-noise ratio (SNR), contrast-to-noise
ratio (CNR), and
coefficient of variance (COV). All these factors contribute to improvement of
image quality.
As used herein, the terms image signal-to-noise ratio (SNR), contrast-to-noise
ratio (CNR), image
count, and coefficient of variance (COV) represent measures of image quality.
As used herein, the term "SNR" refers to signal to noise ratio, which is a
measure of image
quality. SNR can be defined as a ratio of target signal strength to the noise
signal strength.
As used herein, the term "CNR" refers to contrast to noise ratio, which is
also measure of image
quality. CNR can be defined as a difference of target signal strength minus
the background signal
strength, divided by the noise signal strength.
As used herein, the term "image counts" refers to number of radioisotope
disintegrations acquired
per unit time by the PET scanner.
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As used herein, the term "COV" refers to coefficient of variance, which is a
measure of
background noise signal to define image quality. The value of calculated COV
is used for
calculation of SNR and CNR.
The present disclosure provides methods that result in significantly improved
image quality
during radio-diagnosis procedures.
Disclosed herein are methods for infusing a radioisotope to a subject using a
system that includes
a controller, an infusion line for delivering fluid under control of the
controller, and a pump that
is communicatively coupled to the controller, the method comprising infusing a
volume of saline
containing a diagnostic dose of the radioisotope from the infusion line into a
peripheral vein of
the subject at a first flow rate; and, using the controller and pump to
deliver a pre-measured
volume of push saline in one or more through the infusion line, and to the
peripheral vein at a
second flow rate.
Also disclosed are methods for obtaining a diagnostic image of a subject's
heart using a system
that includes a controller, an infusion line for delivering fluid under
control of the controller, and
a pump that is communicatively coupled to the controller, the method
comprising infusing a
volume of saline containing a diagnostic dose of the radioisotope from the
infusion line into a
peripheral vein of the subject at a first flow rate, using the controller and
pump to deliver a pre-
measured volume of push saline in one or more increments through the infusion
line, and to the
peripheral vein at a second flow rate, and, obtaining a diagnostic image of
the subject's heart
using the radioisotope as an imaging agent.
Unless specified otherwise, the following description pertains any of the
methods disclosed
herein.
The second flow rate may be lower than, equal to, or greater than the first
flow rate. In certain
embodiments, the second flow rate is equal to or higher than the first flow
rate. In particular
instances, the second flow rate is higher than the first flow rate.
The pre-measured volume of saline that is delivered through the infusion line
and to the
peripheral vein of the subject may be referred to as "push saline". It may be
so termed because it
functions to push the radioisotope that has been eluted from the generator and
any residual
amount of radioisotope within the elution system tubing set to the subject's
heart. The volume of
CA 3021925 2018-10-23
saline containing the diagnostic dosage of radioisotope may be about 2 mL to
about 40 mL. For
example, the volume of saline containing the diagnostic dosage of radioisotope
may be about 2,
4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, or 40 mL.
If the pre-measured
volume is not delivered in a single bolus, then it may be delivered in two or
more separate
increments. Each increment preferably contains an equal fraction of the pre-
measured volume.
For example, if the push saline is delivered in two increments, then each
increment preferably
contains 50% of the pre-measured volume, and if the push saline is delivered
in three increments,
then each increment preferably contains about 33.3% of the premeasured volume,
and the like.
The second flow rate (the rate at which at least one increment of the pre-
measured volume of
push saline is delivered) may be from about 10 mL/min to about 300 mL/min. For
example, the
second flow rate may be about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120,
140, 150, 160, 180,
200, 220, 240, 250, 260, 280, or 300 mL/min. If the push saline is delivered
in more than one
increment, each increment may be delivered at a discrete flow rate, such that
respective
increments are delivered at the same or different flow rates. For example, if
the push saline is
delivered in two increments, the first and second increments may respectively
be delivered at the
same flow rate or at a different flow rate.
In some embodiments, the volume of push saline that is delivered from the
bypass line is about 2
mL to about 40 mL, and the second flow rate is from about 10 mL/min to 300
mL/min.
In certain embodiments, the volume of push saline that is delivered from the
bypass line is about
2 mL to 40 mL, and the saline is delivered from the bypass line starting
immediately after elution
of the radioisotope from the generator, and continuing over a period of about
0.4 seconds to 4
min following infusion of the radioactive saline. For example, the delivery of
the push saline
may continue for about 0.5 seconds, 1 second, 3 seconds, 5 seconds, 10
seconds, 20 seconds, 30
seconds, 45 seconds, 1 minute, 1.5 minutes, 2 minutes, 2.5 minutes, 3 minutes,
3.5 minutes, or 4
minutes following infusion of the radioactive saline.
As noted above, the present methods yield a significant improvement in image
quality when used
pursuant to a radio-diagnosis procedure. For example, the present methods
involving the delivery
of the push saline as described herein can result in an improvement by about
or at least 5, 10, 15,
20, 25, 30, 35, 40, 45, or 50% in the quality of a diagnostic image of the
subject that is obtained
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following the step of delivering the push saline, as compared to a diagnostic
image that is
obtained pursuant to a method in which push saline is not delivered.
The methods disclosed herein may result in a higher number of image counts
with respect to a
diagnostic image of the subject that is obtained following the step of
delivering the push saline, as
compared to a diagnostic image that is obtained pursuant to a method in which
push saline is not
delivered. For example, the number of image counts for diagnostic images that
are obtained
pursuant to the present methods may be improved by a factor of at least 1.5
times compared to
the number of image counts for diagnostic images that are obtained pursuant to
a method in
which push saline is not delivered. Such improvement may be by a factor of
about 1.5, 1.6, 1.7,
1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3.0, or more.
The methods disclosed herein may result in an increase in image signal to
noise ratio of at least
20% with respect to a diagnostic image of the subject that is obtained
following the step of
delivering the push saline, as compared to a diagnostic image that is obtained
pursuant to a
method in which push saline is not delivered. For example, the image signal to
noise ratio with
respect to a diagnostic image of the subject that is obtained pursuant to the
present methods may
increase by about 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48,
50, 52, 54, 56, 58, 60,
62, 64, 68, or 70% as compared with an image that is obtained pursuant to a
conventional method
in which push saline is not delivered following infusion.
The methods disclosed herein may result in an increase in image contrast to
noise ratio of at least
20% with respect to a diagnostic image of the subject that is obtained
following the step of
delivering the push saline, as compared to a diagnostic image that is obtained
pursuant to a
method in which push saline is not delivered. For example, the image contrast
to noise ratio with
respect to a diagnostic image of the subject that is obtained pursuant to the
present methods may
increase by about 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48,
50, 52, 54, 56, 58, 60,
62, 64, 68, or 70% as compared with an image that is obtained pursuant to a
conventional method
in which push saline is not delivered following infusion.
The methods disclosed herein may result in an improvement in image background
noise by at
least 10% with respect to a diagnostic image of the subject that is obtained
following the step of
delivering the push saline, as compared to a diagnostic image that is obtained
pursuant to a
method in which push saline is not delivered. For example, the improvement in
image
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background noise with respect to a diagnostic image of the subject that is
obtained pursuant to the
present methods may be about 10, 15, 17, 19, 20, 22, 24, 26, 28, 30, 32, 34,
36, 38, 40, 42, 44, 46,
48, 50, 52, 54, 56, 58, 60, 62, 64, 68, or 70% as compared with an image that
is obtained pursuant
to a conventional method in which push saline is not delivered following
infusion. Another way
to express "improvement" in background noise by at least 10% is to say that
background noise is
"reduced" by at least 10%.
The methods disclosed herein may result in an improvement in coefficient of
variance by at least
10% with respect to a diagnostic image of the subject that is obtained
following the step of
delivering the push saline, as compared to a diagnostic image that is obtained
pursuant to a
method in which push saline is not delivered. For example, the improvement in
coefficient of
variance with respect to a diagnostic image of the subject that is obtained
pursuant to the present
methods may be about 10, 15, 17, 19, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38,
40, 42, 44, 46, 48, 50,
52, 54, 56, 58, 60, 62, 64, 68, or 70% as compared with an image that is
obtained pursuant to a
conventional method in which push saline is not delivered following infusion.
Another way to
express "improvement" in coefficient of variance by at least 10% is to say
that coefficient of
variance is "reduced" by at least 10%.
Also provided are diagnostic images that are produced according to any of the
methods described
herein.
The methods disclosed herein may result in a decrease in venous return transit-
time in the
subject, as compared to conventional methods in which push saline is not
delivered. For
example, the venous transit time may decrease by about 5, 10, 15, 20, 25, 30,
35, 40, 45, 50, 55,
or 60% relative to the venous transit time that occurs pursuant to a
conventional method in which
push saline is not delivered following radioisotope elution.
In another aspect, the present methods produce an improvement in image quality
by reducing the
required dose of radioactive material in comparison to a diagnostic procedure
where no saline
flush is used.
In accordance with the present methods, the controller may deliver the push
saline from a bypass
line that can be placed in fluid communication with the infusion line via a
valve, to the infusion
line. As noted below, any suitable valve may be used for this purpose, and in
some
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=
embodiments, the valve for placing the bypass line into fluid communication
with the infusion
line may be a pinch valve.
In certain embodiments, the system further comprises a valve assembly that
includes at least one
valve for diverting fluid among different components of the system, such as
among different
tubing segments of the system. The valve assembly may include any type or
types of valves that
that are suitable for liquid valve systems, such as one or more pinch valves,
diverter valves, stop
cocks, or any combination thereof. In some embodiments, the constant activity
flow is controlled
using one or more pinch valves. For example, the opening of the bypass line in
order to allow the
push saline from the bypass line to the infusion line may be effected by use
of one or more pinch
valves. Control of the valve assembly, such as the opening and closing of
valves, may be via the
controller.
The radioisotope that is used in accordance with the present methods has a
half-life of from about
seconds to 10 hours. The radioisotope may be, for example, 82Rb, 150, 13N,
11¨,
or 18F,
although any suitable PET radiotracer may be used.
The diagnostic dose of the radioisotope within the radioactive saline may be
at least 5 mCi.
The pump that is used in the present methods may be a peristaltic pump, a
syringe pump, a
medical grade pump, or any combination thereof.
The push saline may be delivered using a process that is manual, automated,
semi-automated, or
any combination thereof.
The system may further include an activity detector that is downstream from
the generator for
measuring radioactivity within a fluid that is downstream from the generator,
e.g., that is eluted
from the generator. When the system includes an activity detector, the
activity detector may be a
beta detector, gamma detector, photomultiplier tube, silicon photomultiplier,
positron detector, or
may represent any combination thereof.
Also disclosed herein are diagnostic images of a subject's heart that are
obtained using a system
that includes a controller, an infusion line for delivering fluid under
control of the controller, and
a pump that is communicatively coupled to the controller, wherein the image is
obtained by
infusing a volume of saline containing a diagnostic dose of the radioisotope
from the infusion line
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, -
into a peripheral vein of the subject at a first flow rate; using the
controller and pump to deliver a
pre-measured volume of push saline in one or more increments through the
infusion line, and to
the peripheral vein at a second flow rate; and, obtaining the diagnostic image
of the subject's
heart using the radioisotope as an imaging agent. The characteristics of the
steps of infusing
saline containing a diagnostic dose of the radioisotope and using the
controller and pump to
deliver the pre-measured volume of push saline may be in accordance with any
of the
characteristics described above in accordance with the presently disclosed
methods.
The step of obtaining the diagnostic image using the radioisotope as an
imaging agent may be in
accordance with conventional processes. For example, the diagnostic image by
be obtained using
conventional steps associated with Positron Emission Tomography (PET) or with
Single Photon
Emission Computed Tomography (SPECT) or with planar Gamma Camera (GC) imaging.
FIG. 1 illustrates a conventional radioisotope elution system used for
myocardial perfusion
imaging. The elution system comprises a reservoir for elution medium, a pump,
and a
radioisotope generator. In operation, the pump causes the saline solution to
flow from the
reservoir and through the generator to elute the radioisotope. The active
saline eluted from the
generator is then supplied to a patient via a patient line through patient
outlet. Although
conventional systems may include a bypass line, the bypass line in such
systems are used (1) to
enable the constant-elution activity mode by feedback control of the saline
through the generator,
or (2) to flush radioisotope out of the elution system tubing set after the
desired dose of
radioisotope has been measured by the onboard detector. These uses are
distinguishable from the
presently disclosed methods, pursuant to which the push saline is delivered
from the bypass line
immediately after the conventional elution in order to shorten transit time to
the patient.
While this invention has been described in detail with reference to certain
preferred
embodiments, it should be appreciated that the present invention is not
limited to those precise
embodiments. Rather, in view of the present disclosure, which describes the
current best mode
for practicing the invention, many modifications and variations would present
themselves to
those skilled in the art without departing from the scope, and spirit of this
invention.
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