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`1191 of 1754
`1191 of 1754
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`
`
`
`9
`
`Europaisches Patentamt
`
`European Patent Office
`
`Office européen des brevets
`
`(9) Publication number:
`
`0 160 303
`A2
`
`EUROPEAN PATENT APPLICATION
`
`Application number: 85105293.6
`
`® int.c.: A 61 M 5/14
`
`Date of filing: 30.04.85
`
`@ ®
`
`@) Date of publication of application:
`06.11.85 Bulletin 85/45
`
`Designated Contracting Statas:
`BE CH DE FR GB IT LI LU NL SE
`
` Priority: 01.05.84 US 605758
`
`
`
`
`
`
`@) Applicant: E.R. Squibb & Sons,Inc.
`Lawrenceville-Princeton Road
`Princeton, N.J. 08540(US)
`
`@) Inventor: Bergner, Brian Clarence
`263 Glenn Avenue
`Lawrenceville New Jersey 08540(US)
`
`Representative: Vossius Vossius Tauchner Heunemann
`Rauh
`Siebertstrasse 4 P.O. Box 85 07 67
`D-8000 Miinchen B6{DE}
`
`® Strontium-rubidium intusion system.
`) This novel strontium-rubidium infusion system includes
`means for generating a solution containing Rubidium-82,
`measuring the radioactivity in the solution, and infusing it
`into a patient in order to perform various studies on the
`patient’s heart. The new system includes a wash syringe
`which can be used by a physician to manually inject a bolus
`containing a large amount of radioactivity directly into a
`patient
`in order to perform first pass ventriculography
`studies.
`10
`
`a
`ze
`\/
`P
`fp?
`fe
`te Lad
`oO 1
`
`i
`TIT
`
`24
`cenvna i 33
`PEPrere
`7 7]
`ra
`4
`AD
`
`<
`» 35
`Be
`if
`
`aa
`
`6485 5
`
`EP0160303A2 ANi.
`
`-_
`
`=
`
`ee
`a
`Oe
`ea (m1)
`
`ae
`
`CONTROLLER
`
`DOSIMETRY
`
`PRORSALE
`
`;
`
`"]
`
`i .
`4
`*
`Zz Fig. /
`as
`
`1192 of 1754
`1192 of 1754
`
`Creydon Printing Company Ltd.
`
`
`
`e: A-6 05 758-S
`:
`’
`. Squibb & Sons, Inc.
`
` PATENTMNWALTE
`AIRRPRTETR,4, BONN MONGCHEN ro
`0160303
`
`=-j=
`
`STRONTIUM-~RUBIDIUM INFUSION SYSTEM
`
`The present invention relates to a
`strontium-rubidium infusion system. More specif-
`ically, it relates to a strontium-rubidium infusion
`system which has an in-line, real time dosimetry
`system which can be used to infuse patients with
`Rubidium-82, particularly for first pass ventri-
`culography studies. More precisely, the present
`invention provides a strontiwm-rubidium infusion
`system comprising:
`
`(a) means for generating rubidium-82 in a
`solution which can be infused into a patient;
`(b)
`means
`for collecting a predefined
`volume of solution containing rubidium-82;
`(c) means
`for measuring the radioactivity
`in said predefined volume before it is
`present
`infused into said patient; and
`said
`infusing
`(da)
`means
`for
`quickly
`predefined volume of rubidium-82 into said patient
`as a single bolus.
`
`The present application is related to
`European Patent Application 84301269.1, entitled
`DOSIMETRY SYSTEM FOR STRONTIUM-RUBIDIUM INFUSION
`
`PUMP, filed February 27, 1984 and published
`
`September 5, 1984 under No. EP 0117752
`
`AdZ2.
`
`-
`
`16
`
`15
`
`29
`
`25
`
`1193 of 1754
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`
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`
`0160303
`
`Current statistics show that approximately
`one-third of all deaths in the United States are
`related to coronary artery disease.
`See,
`for
`example, Pohost, G., McKusick, K., and Strauss, W.,
`"Physiologic Basis
`and Utility of Myocardial
`Perfusion
`Imaging", Proceedings of
`the
`Second
`International
`Symposium on Radiopharmaceuticais,
`Society of Nuclean Medicine, New York 1979, pp.
`465-473. This fact has prompted extensive research
`to more efficiently diagnose
`and manage
`this
`disease.
`Recent advances
`in radiopharmaceutical
`development and instrument design have established
`myocardial
`scintigraphy
`as
`an
`important
`new
`approach for evaluating coronary artery disease and
`myocardial perfusion.
`See,
`for example, Pierson,
`R., Friedman, M., Tansley, W., Castellana, F.,
`Enlander, D.,
`and Huang, P.,
`“Cardiovascular
`Nuclear Medicine:
`An Overview", Sem. Nucl. Med.,
`
`5
`
`- 10
`
`15
`
`1194 of 1754
`1194 of 1754
`
`
`
`0160303
`
`-3—
`
`9, 224-240 (1979); Leppo, J., Schever, J., Pohost,
`G., Freeman, L.,
`and Strauss, H.,
`"The Evaluation
`ef
`Ischemic Heart Disease Thallium-201 with
`
`Comments on Radionuclide Angiography"; Sem. Nucl.
`5 Med., 10, 115-126 (1980); Vogel, R., "Quantitative
`Aspects of Myocardial Perfusion Imaging",
`Sem.
`Nucl. Med.,
`10,
`146-156
`(1980); Chervu, R.,
`“Radiopharmaceuticals
`in Cardiovascular Nuclear
`Medicine", Sem. Nucl. Med., 9, 241-256 (1979); and
`10 Pitt, B., and Strauss, H., "Cardiovascular Nuclear
`Medicine", Sem. Nucl. Med., 7, 3-6 (1977).
`Myocardial
`scintigraphy studies have been
`performed with several
`isotopes of potassiun,
`xubidium, cesium,
`and thallium (T1-201), aithough
`the usefulness of all of these nuclides is limited
`
`15
`
`20
`
`25
`
`In spite
`by their non-optimal physical properties.
`of its long half-life and low-gamma energy, T1-201
`is
`currently the most widely used agent
`for
`myocardial
`imaging.
`See,
`for example, Poe, N.,
`"Rationale and Radiopharmaceuticals for Myocardial
`Imaging", Sem. Nucl. Med., 7, 7-14 (1977); Strauss,
`H.
`and Pitt, B.,
`"Thallium-201 as a Myocardial
`Imaging Agent", Sem. Nucl. Med., 7, 49-58 (1977);
`Botvinick, E., Dunn, R., Hattner, R., and Massie,
`B.,
`"A Consideration of Factors Affecting the
`Diagnostic Accuracy of T1-201 Myocardial Perfusion
`Scintigraphy in Detecting Coronary Artery Disease",
`Sem. Nucl. Med., 10, 157-167 (1980); and Wackers,
`Poe
`"“Thallium-201 Myocardial Scintigraphy in Acute
`30 Myocardial
`Infarction and Ischemia”,
`Sem. Nucl.
`Med., 10, 127-145 (1980).
`In diagnostic procedures in which the heart
`is involved, it is desirable for a diagnostician to
`be able to view a patient's heart. Heretofore,
`various
`radioactive materials
`have
`been
`used
`
`35
`
`=
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`1195 of 1754
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`0160303
`
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`tegether with radiological procedures for viewing
`internal
`organs
`of patients.
`It
`has
`been
`difficult, however,
`to view a heart, because the
`radioactive substances which could be used for
`viewing the heart have had a very long half-life.
`Thus, using them with patients has
`involved an
`
`@lement of danger and each use reduces the number
`ef times that a patient could be infused within
`any given time period.
`It would,
`therefore, be
`desirable to have
`a diagnostic
`apparatus
`and
`procedure which could be used with relative safety
`for viewing the heart.
`That
`Rubidium-82 is a potassium analog.
`means it acts in a manner similar to potassium when
`it is infused into a patient. Thus it builds up at
`a very rapid rate,
`i.e., within seconds,
`in the
`patient's
`heart.
`Rubidium-82
`also
`has
`the
`advantage
`of
`having
`a very
`short half-life,
`approximately 76 seconds.
`Therefore,
`it decays
`after a very short period of time following entry
`into the body,
`thereby allowing numerous procedures
`to be performed within a relatively short
`time
`period in a given patient. Rubidium-82 also has
`the advantage of being observable using a modified
`gamma camera,
`such as a gamma camera of the type
`manufactured by Searle Radiographics, Inc., called
`the PHO Gamma IV. A problem with using Rubidium-82
`in a patient
`involves measuring the amount of
`radiation infused into the patient.
`In view of the
`very
`short half-life of Rubidium-82,
`it has
`heretofore
`been
`impractical
`to measure
`the
`radioactivity of
`a particular dose and to then
`infuse
`it into the patient using conventional
`means.
`Amn accurate method for measuring the amount
`of radiation being infused into the patient would
`
`5
`
`10
`
`15
`
`20
`
`am 25
`
`30
`
`35
`
`1196 of 1754
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`0160303
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`
`desirable
`
`for
`
`this
`
`particular
`
`highly
`be
`application.
`improved
`of
`availability
`The
`instrumentation has stimulated interest in the use
`of
`the
`positron
`emitter,
`Rubidium-82,
`for
`myocardial
`imaging.
`See,
`for example, Beller G.,
`and Smith, T.,
`“Radionuclide Techniques
`in the
`Assessment of Myocardial Ischemia and Infarction",
`Circulation,
`53
`(3,
`Supp.
`1)
`123-125
`(1976);
`Budinger, T., Yano,
`Y¥., Derenzo, S., et al.,
`"Myocardial Uptake of Rubidium-82 Using Positron
`Emission Tomography",
`J., Nucl. Med.
`20,
`603
`(1979); Budinger, T., Yano, Y., Derenzo, S., et
`al., “Infarction Sizing and Myocardial Perfusion
`15 Measurements Using Rb-82
`and Positron Emission
`Tomography", Amer. J. Cardiol., 45,
`399
`(1980).
`Rubidium-82,
`an
`analog
`of
`the
`alkali metal
`potassium,
`is rapidly cleared from the blood and
`concentrated
`by
`the myocardium.
`The
`short
`half-life of the Rubidium-82 (76 sec) offers the
`unique advantage of permitting repeat perfusion and
`blood flow studies
`in patients whose clinical
`status is rapidly changing.
`Rubidium-82 is produced by the decay of its
`parent, strontium-82.
`E. R. Squibb and Sons, Inc.
`has developed a Rubidium-82 generator and infusion
`system which yields an isotonic saline solution of
`Rubidium-8&2
`at
`physiological
`pH
`for
`rapid
`administration.
`In animal experiments,
`the safety
`and myocardial uptake of Rubidium-82 has been
`demonstrated.
`Therefore,
`this
`agent has
`been
`selected as a candidate for clinical trials.
`
`5
`
`10
`
`20
`
`25
`
`30
`
`In the European patent application identified
`above, a system for infusing Rubidium-82 into a
`patient while measuring the dose going into the patient
`
`35
`
`1197 of 1754
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`0160303
`
`-6—
`
`+=
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`was described. That system is useful in myocardial
`scintigraphy studies.
`In a modification to that
`system, described herein, a system which permits
`both myocardial scintigraphy studies, as well as
`first pass ventriculography studies,
`is described.
`
`In accordance with the present invention, a
`strontium-rubidium infusion system is described.
`The
`system includes
`means
`for
`generating
`rubidium-82 in a solution which can be infused into
`
`the strontium-rubidium
`In particular,
`a patient.
`is typically used.
`described above,
`generator,
`Generated rubidium-82 is then collected in a piece
`of tubing having a predefined volume. This tubing
`is called the “dose volume” tubing, and it contains
`the dose volume of rubidium-82 solution which is to
`be infused.
`
`The system also includes means for measuring
`the radioactivity present in the dose volume before
`the dose volume is infused into the patient and a
`wash syringe for quickly infusing the dose volime
`into the patient as a single bolus.
`
`In the Drawings:-
`FIG.
`2
`is an overall schematic diagram of
`strontium-rubidium infusion system of
`the
`the
`present invention;
`FIG. 2 is a front view of the infusion pump
`control: used with the strontium-rubidium infusion
`
`system;
`
`is a front view of the dosimetry
`3
`FIG.
`control used with the strontium-rubidium infusion
`
`5
`
`10
`
`15
`
`29
`
`25
`
`30
`
`system;
`
`35
`
`FIG. 4 is a graph of radioactivity measured
`{on the y-axis) by the dosimeter probe versus time
`
`-*
`
`1198 of 1754
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`
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`0160303
`
`-J=
`
`is
`
`a perspective
`
`5
`
`{on the x-axis);
`FIG.
`5
`dosimetry probe;
`FIG.
`6
`is
`a
`schematic
`diagram of
`the
`interface between the dosimetry probe of FIG. 4 and
`the dosimetry control circuitry;
`FIG. 7 is a schematic diagram of the circuit
`for the Single Channel Analyzer used to convert and
`
`view of
`
`the
`
`.
`
`shape the raw pulses from the dosimetry probe of
`
`10
`
`FIG. 4;
`
`FIG. 8 is a schematic diagram of the circuit
`for the Multiply-Divide circuit used to carry out
`the formula which converts pulses from the Single
`Channel Analyzer
`into radioactivity present
`in
`front of the dosimetry probe;
`FIG. 9 is a schematic diagram of one of the
`Display Controller circuits used to interface the
`switches and the displays to the other circuitry;
`FIG. 10 is a schematic diagram of the Dose
`circuit used to provide a display of the
`Rate
`amount of radiation present in the eluate;
`the
`FIG.
`11
`is
`a
`schematic diagram of
`Control Circuit which oversees the operation of the
`remainder of the circuitry; and
`‘FIG.
`12 is a schematic diagram of a valve
`driver circuit.
`
`Referring now to FIG. 1, a saline bag 10 is
`connected,
`through a bullet nose fitting 12 and a
`piece of tubing 14,
`to a T-shaped two-way check
`valve 16 having three arms.
`A first arm 20 is
`attached to a one-way valve 21 which permits saline
`to enter the check valve 16, but does not allow it
`to exit back into the tubing 14.
`A second arm 22
`includes a check valve 23 which permits saline to
`
`15
`
`20
`
`25
`
`30
`
`35
`
`aaa
`
`1199 of 1754
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`
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`0169303
`
`«~§=
`
`exit
`
`from the check valve 16 into a filter 24
`
`through a
`
`tube 26, but does not
`
`allow it to
`
`re-enter the check valve 16 from the tube 26.
`
`An
`
`automatic syringe 18, connected to the check valve
`16 fills from the saline bag 10
`and pumps out
`through the tubing 26 into the filter 24.
`Saline
`pumped
`through
`the
`filter
`24
`enters
`a
`strontium-rubidium generator 28 which is of
`the
`type
`described more
`fully in. U.
`Ss. Patent
`4,405,716,
`issued September 27, 1983, entitled
`8225 GENERATING METHOD AND ELUENT. The generator
`28 is preferably enclosed in a lead shield 29.
`
`Saline pumped through the strontium-rubidium
`generator 28 exits the generator 28 through tubing
`30
`containing Rubidium-82.
`The
`tubing 30
`is
`connected te a diverter valve 33 having a first arm
`35 which connects
`to a manually operated wash
`syringe 37. The remaining arm 39 is connected to a
`@iverter valve 32 through a length of tubing 41
`which is called the “dose volume" tubing 41, which
`has a length, DV.
`The length, DV, of the dose
`volume
`tubing,
`times
`its cross-sectional
`area,
`gives its volume, hereinafter referred to as the
`“dose volume".
`Diverter valve 32 has a first arm 34 which
`
`an antibacterial filter
`leads through tubing 38,
`40,
`through a tube 42, and ultimately to a waste
`collection container 43.
`The waste collection
`
`10
`
`is
`
`20,
`
`25
`
`30
`
`container
`shield 45.
`
`is preferably enclosed in a lead
`43
`A second arm 35 of the diverter vaive
`
`32 is connected through tubing 44, an antibacterial
`filter 48,
`additional
`tubing 50,
`and into an
`infusion needle 52.
`The
`infusion needle 52
`is
`typically inserted into the arm 54 of a patient 56.
`
`35
`
`1200 of 1754
`1200 of 1754
`
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`
`.
`
`-9-
`
`0160303
`
`In
`
`the
`
`preferred
`
`embodiment
`
`of
`
`the
`
`invention,
`
`the check valve 16 is a dual back check
`
`valve of the type made by Beckton Dickenson Inc.,
`and the antibacterial filters 24, 40, 48 are of the
`type made by Schieicher & Schull as
`their type
`
`FP030/3.
`"In the operation of the device to perform
`first pass ventriculography studies,
`the amount of
`radioactivity in the
`saline
`eluted from the
`strontium-rubidium generator 28 must be measured.
`Accordingly,
`a
`dosimetry probe
`58
`is
`placed
`adjacent
`to the tubing 30 where it measures
`the
`radioactivity of the rubidium-containing saline as
`it enters the the diverter valve 33. The diverter
`
`valve 33 is a three-part valve which permits flow
`from either the generator to the diverter valve 32
`or from the wash syringe 37 to the diverter valve
`32.
`
`The diverter valves 32, 33 are connected to
`
`a dosimetry controller 62 for automatic operation.
`The operation of the dosimetry controller 62 will
`be further explained hereinafter. Based upon the
`signal sent by the dosimetry controller 62 to the
`valves 32, 33,
`the elution from the generator 28 is
`directed through thd valves 32,
`33 and the dose
`volume tubing 41 into the waste container 43 until
`
`such time as the minimum dose rate is met. Once
`
`the minimum dose rate for a first pass study has
`been reached,
`the dosimetry controller 62 starts
`
`integrating patient volume and dose to fill the
`dose
`volume
`tubing 41 with highly radioactive
`eluate. At tha