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`
`1191 of 1754
`1191 of 1754
`
`
`
`Europilaches Patentamt
`
`*0
`
`9)
`
`European Patent Office
`
`(I) Publication number:
`
`O 160 303
`
`Office europeen des brevets
`
`A2
`
`69
`
`EUROPEAN PATENT APPLICATION
`
`@ Application number: 85105293.5
`
`Omar: A 61 M 5(14
`
`Dateo‘lflling: 30.04.85
`
`(‘9 Date of publication of application:
`06.1 1.85 Bulletin 5145
`
`Designated Contracting States:
`BECI-lDEFflGBITLILUNLSE
`
`Lawrencevme-Prlncoton Road
`Princeton, NJ. WIUSI
`
`® Inventor: Bonner, Brian Clarence
`263 Glenn Avenue
`Lawrencevllle New Jersey oescclusi
`
` Priority: 01.05.34 us 005753
` ® Applicant: ER. Squibb 8! Sons; Inc.
`
`
`
`Hepreeeniativa: Vocal“: Vonlua Tauclmer Heunernann
`
`Hauh
`Siahat‘liltrana 4 PD. Box 86 07 57
`
`D6000 Minchen DEIDE}
`
` i
`
`® Stronflurn-rubkflum infusion system.
`® This novel strontium-rubidium infusion system includee
`means for generating a solution containing Fluhidium-Bz,
`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 iniect a bolus
`containing a large amount of radioactivity directlyr into a
`patient
`in order to perform first pass ventriculogrephy
`studies.
`.0
`
`EP0160303A2
`
`1192 of 1754
`1192 of 1754
`
`ll.
`
`3?
`
`I
`
`:2“
`
`2:
`
`:e
`
`_.
`:-
`czrir'uign
`rllllllt
`
`3°
`
`35
`
`33
`
`as
`
`'
`
`at
`
`3‘
`
`Lo-.
`._°.. aw? .
`llll‘
`I
`3: a}!
`
`“ I!I
`
`_
`
`fa
`
`I 'fi“ LIE-I'l—‘i.
`
`
`901mm“
`w”
`common m“
`
`.- E1”
`to u 3
`' on a
`
`Owen-n Preairig WM Ltd.
`
`
`
`I
`_
`_
`2: 13—605, 758-5
`. Squibb & Sons, Inc.
`
`PATENT anLTe"
`marem.fi:ofin MfiNfiHE-‘IN m.-
`m-nva
`0160303
`
`-1-
`
`STRONTIUM-RUBIDIUM INFUSION SYSTEM
`
`The present invention relates to a
`
`strontiumrrubidium 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-Bz. particularly for first pass ventri-
`
`culography studies. More precisely. the present
`
`invention provides a strontim-rubidium infusion
`
`system comprising:
`(a) means for generating rubidium-B2 in a
`
`solution which can be infused into a patient;
`
`(b)
`
`means
`
`for collecting a predefined
`
`volume of solution containing rubidiumrsz;
`
`for measuring the radioactivity
`(c) means
`in said predefined volume before it is'
`
`‘
`
`present
`
`infused into said patient; and
`
`(d)
`
`means
`
`for
`
`quickly
`
`infusing
`
`said
`
`predefined volume of rubidium—82 into said patient
`
`5
`
`10
`
`15
`
`29
`
`as a single bolus.
`
`The present application is related to
`
`European Patent Application B4301269.1r entitled
`DOSIMETRY SYSTEM FOP. STRONTIUM-RUBIDIUM INFBSION
`
`PUMP, filed February 27, 1984 and published
`
`25
`
`September 5, 1984 under No. EP 0117752 A2.
`
`1193 of 1754
`1193 of 1754
`
`
`
`01 60303
`
`Current statistics show that approximately
`
`one-third of all deaths in the United States are
`relategi
`to coronary artery disease.
`See ,
`for
`
`example. ?ohost, 6., McKusick, 1L, and Strauss, w.,
`
`'Physiologic Basis
`
`and Utility of Myocardial
`
`Perfusion
`
`Imaging“, Proceedings of
`
`the
`
`Second
`
`International
`
`Symposium on Radiopharmaceuticals,
`
`Society of Nuclear: Medicine, New York 1979, pp.
`
`465-473. This fact has prompted extensive research
`
`to rare efficiently diagnose
`
`and manage
`
`this
`
`in radiophamaceutical
`Recent advances
`disease-
`developma-ent and instrument design have established
`
`nyocardi a1
`
`scintigraphy
`
`as
`
`an
`
`important
`
`new
`
`approach for evaluating coronary artery disease and
`
`myocardial perfusion.
`
`See,
`
`for example, Pierson,
`
`3., Friedman,
`
`IL, Tansley,
`
`1L, Castellana, F.,
`
`Enlander,
`
`1).,
`
`and Huang, P”
`
`“Cardiovascular
`
`Nuclear medicine:
`
`An Overview", Sen. Nucl. Med...
`
`. 10
`
`15
`
`1194 of 1754
`1194 of 1754
`
`
`
`0160303
`
`n.3—
`
`9, 224-240 (1979); Leppo, 3., Scheuer, J., Pohost,
`
`G., Freeman, L.,
`
`and Strauss, H.,
`
`"The Evaluation
`
`of
`
`Ischemic Heart Disease
`
`Thallium-ZDJ. with
`
`Cements on Radionuclide Angiography"; Sem. Nucl.
`
`5 Med., 10, 115-126 (1980): Vogel, R., "Quantitative
`
`Aspects of Myocardial Perfusion Imaging",
`
`Sem.
`
`NBC]. . Med. ,
`
`10,
`
`146-155
`
`(1980) r, Chervu,
`
`R. ,
`
`"Radiopharmaceuticals
`
`in Cardiovascular Nuclear
`
`Medicine", Sena. Nucl. Med., 9, 241-256 (1979); and
`10 Pitt, 13., and Strauss, H... "Cardiovascular Nuclear
`
`Medicine", Sem. Nucl. Med., 7,
`
`3—6 (1977).
`
`Myocardial
`
`scintigraphy studies have been
`
`performed with several
`
`isotopes of potassium,
`
`rubidium, cesium,
`
`and thallium (Tl-201), although
`
`15
`
`the usefulness of all of these nuclides is limited
`
`by their non—optimal physical properties.
`
`In spite
`
`of its long half-life and low-gamma energy, Tl-Zol
`
`is
`
`currently the most widely used agent
`
`for
`
`myocardial
`
`imaging.
`
`See,
`
`for example, Poe, N.,
`
`20
`
`"Rationale and Radiopharmaceuticals for Myocardial
`
`Imaging“, Sem. Nucl. Med., 7, 7—14 {1977); Strauss,
`
`H.
`
`and Pitt, 5.,
`
`"Thallium-zol as a Myocardial
`
`_
`
`Imaging Agent", Sem. Nucl. Med.,
`
`'1', 49—53 (1977);
`
`Botvinick, EL, Dunn, R., Hattner, R... and Massie,
`
`25
`
`B.,
`
`"A Consideration of Factors 'Affecting the
`
`Diagnostic Accuracy of TIL-20]. Myocardial Perfusion
`
`Scintigraphy in Detecting Coronary Artery Disease",
`Sem. N'uci. Med., 10, 157-167 (1980); and Wackers,
`F.,
`"Thallium—201 Myocardial Scintigraphy in Acute
`
`3O Myocardial
`
`Infarction and Ischemia",
`
`Sem. Nucl.
`
`Med., 10, 127—145 (1930}.
`
`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
`
`1195 of 1754
`1195 of 1754
`
`
`
`0160303
`
`-4...
`
`together with radiological procedure:
`
`for viewing
`
`internal
`
`organs
`
`of patients.
`
`It
`
`has
`
`been
`
`difficult, however,
`
`to view a heart, because the
`
`radioactive substances which could be used for
`
`5
`
`viewing the heart have had a very long half-life.
`
`Thus, using them with patients has
`
`involved an
`
`element of danger and each use reduces the number
`
`of times that a patient could be infused within
`
`It would,
`any given time period.
`desirable to have
`a diagnostic
`
`therefore,“ be
`apparatus
`and
`
`10
`
`procedure which could be used with relative safety
`
`for viewing .the heart.
`
`Rubiditm—Bz
`
`is a potassium analog.
`
`That
`
`means it acts in a manner similar to potassium when
`
`15
`
`it is infused into a patient. Thus it builds up at
`
`a very rapid rate,
`
`i.e-, within seconds,
`
`in the
`
`patient' 3
`
`heart.
`
`Ruhidiumvaz
`
`also
`
`has
`
`the
`
`advantage
`
`of
`
`having
`
`a very
`
`short halfulife,
`
`approximately 75
`
`seconds.
`
`Therefore,
`
`it decays
`
`20
`
`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—Bz also has
`
`the efivmtage of being observable using a modified
`
`-—“
`
`25
`
`such as a gamma camera of the type
`game “camera,
`manufactured by Searle Radiographics, Inc., called
`
`the BBQ Gama IV. A problem with using Rubidium—Bz
`
`in a patient
`
`involves measuring the amount of
`
`radiation _in£used into the patient.
`
`In viewr of the
`
`30
`
`very
`
`short half—life of Rubidium—az,
`
`it has
`
`heretofore
`
`been
`
`impractical
`
`to measure
`
`the
`
`radioactivity of
`
`a particular dose and to then
`
`infuse
`
`it into the patient using conventional
`
`means. An accurate method. for measuring the amount
`
`35
`
`of radiation being infused into the patient would
`
`1196 of 1754
`1196 of 1754
`
`
`
`-5-
`
`0160303
`
`be
`
`highly
`
`desirable
`
`for
`
`this
`
`particular
`
`application.
`
`The
`
`availability
`
`of
`
`improved
`
`instrumentation has stimulated interest in the use
`
`5
`
`of
`
`the
`
`positron
`
`emitter,
`
`Rubidium-Sz,
`
`for
`
`for example, Belle: 6.,
`See,
`imaging.
`myocardial
`and Smith. T.,
`"Radionuclide Techniques
`in the
`
`Assessment of myocardial Ischemia and Infarction",
`
`circulation,
`
`53
`
`(a,
`
`Supp.
`
`1)
`
`123—125
`
`(1975);
`
`10
`
`Budinger, T., Yano, Y., Derenzo, 5.. et al.,
`
`"Myocardial Uptake of Rubidium-BZ Using Positron
`Emission Tomography",
`J.,
`fiucl. Med.
`20,
`603
`
`(1979); Budinger, T., Yano, 2:, Derenzo, 5., et
`
`al.,
`
`"Infarction Sizing and myocardial Perfusion
`
`15 Measurements Using Rb-BZ
`
`and Positron Emission
`
`Tomography", Amer. J. Cardiol.Jr
`
`4-5,
`
`399
`
`(1980).
`
`Rubidium—az,
`
`an
`
`analog
`
`of
`
`the
`
`alkali metal
`
`potassium,
`
`is rapidly cleared from the blood and
`
`concentrated
`
`by
`
`the myocardium.
`
`The
`
`short
`
`20
`
`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-BZ is produced by the decay of its
`
`25
`
`parent,
`
`strontium—82.
`
`E. R. Squibb and Sons, Inc.
`
`has developed a Rubidium-BZ generator and infusion
`
`system which yields an isotonic saline solution of
`
`Rubidium-BZ
`
`at
`
`physiological
`
`pH
`
`for
`
`rapid
`
`administration.
`
`In animal experiments,
`
`the safety
`
`30
`
`and myocardial uptake of Rubidium—az has been
`
`demonstrated.
`
`Therefore,
`
`this
`
`agent has
`
`been
`
`selected as a candidate for clinical trials.
`
`In the EuroPean patent application identified
`
`above, a system for infusing Rubidiumraz into a
`patient while measuring the dose going into the patient
`
`35
`
`1197 of 1754
`1197 of 1754
`
`
`
`_o1eoaoa
`
`—6-
`
`C
`
`was described. That system is useful in myocardial
`
`scintig-raphy studies.
`
`In a modification to that
`
`system, described herein, a system which permits
`both myocardial scintigraphy studies, as well as
`
`5
`
`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
`
`10
`
`rubiditm-Bz in a solution which can be infused into
`
`a patient-
`
`In particular,
`
`the strontimn—rubidium
`
`generator,
`
`described above,
`
`is typically used.
`
`Generated rubidium—82 is then collected in a piece
`of tubing seeing a predefined volume._ This tubing
`
`15
`
`is called the “dose volume" tubing, and it contains
`
`the dose volume of rubidium—32 solution which is to
`
`be inqued.
`
`'
`
`The system also includes means for measuring
`
`the radioactivity present in the dose volume before
`
`20
`
`the dose volume is infused into the patient and a
`
`wash syringe for quickly infusing the dose volume
`
`into the patient as a single bolus.
`
`' "
`
`In the Drawings:-
`
`25
`
`FIG.
`1
`is an overall schematic diagram of
`strontium—midium infusion system of
`the
`
`the
`
`present invention;
`
`FIG. 2 is a front View of the infusion pump
`
`control' used with the strontium—rubidium infusion
`
`30
`
`system:
`
`is a front View of the dosimetry
`3
`FIG.
`control used with the strontium-rubidium infusion
`
`system;
`
`FIG. 4 is a graph of radioactivity measured
`(on the y-aris) by the dosineter probe versus time
`
`35
`
`1198 of 1754
`1198 of 1754
`
`
`
`9160303
`
`(on the x—axis):
`
`5
`FIG.
`dosimetry probe;
`
`is
`
`a perspective View of
`
`the
`
`I
`
`FIG.
`
`6
`
`is
`
`a
`
`schematic
`
`diagram of
`
`the
`
`5
`
`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
`
`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
`
`15
`
`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
`
`20
`
`Rate
`
`circuit used to provide a display of the
`
`amount of radiation present in the eluate;
`
`FIG.
`
`11
`
`is
`
`a
`
`schematic diagram of
`
`the
`
`Control Circuit which oversees the Operation of the
`
`remainder of. the circuitry; and
`
`25
`
`iFIG.
`
`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
`
`30
`
`piece of tubing 14,
`
`to a T-shaped twoé-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
`
`35
`
`includes a check valve 23 which permits saline to
`
`1199 of 1754
`1199 of 1754
`
`
`
`-3-
`
`0169393
`
`exit
`
`from the check valve 16 into a filter 24
`
`through a
`
`tube 26, but does not
`
`allow it
`
`re-enter the check valve 16 from the tube 26.
`
`to
`
`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 I enters
`a‘
`
`strontium-rubidium generator 28 which is of
`
`the
`
`type
`described more
`fully in- U.
`S. Patent
`4,405,716,
`issued September 27. 1983, entitled
`
`10
`
`32m; sesame ass-moo mm arm. The generator
`
`23 is preferably enclosed in a lead shield 29.
`
`Saline pumped through the strontim—rubidium
`
`15
`
`generator 28 exits the generator 28 through tubing
`
`30
`
`containing Rubidium-BZ.
`
`The
`
`tubing 30
`
`is
`
`connected to 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
`
`20:
`
`diveer valve 32 through a length of tubing 41
`
`which is called the ”dose volume“ tubing 41, which
`
`has a length,
`
`130'.
`
`The length. DV, of the dose
`
`volume
`
`tubing,
`
`times
`
`its cross-sectional
`
`area.
`
`gives its volume, hereinafter referred to as the
`
`25
`
`'dose volume”.
`
`Diverter‘ valve 32 has a first arm 34 which
`
`leads through tubing 38,
`
`an antibacterial filter
`
`through a tube 42, and ultimately to a waste
`40,
`collection container 43.
`The waste collection
`
`30
`
`container
`
`43
`
`is preferably enclosed in a lead
`
`shield 45.
`
`A second am 35 of the diver'ter valve
`
`32 is connected through tubing 44, an antibacterial
`
`filtez: 48,
`
`additional
`
`tubing 50,
`
`and into an
`
`infusion needle 52.
`
`The
`
`infusion needle 52
`
`is
`
`35
`
`typically-inserted into the arm 54 of a patient 56-
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`1200 of 1754
`1200 of 1754
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`
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`-9-
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`0160303
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`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 Schleicher
`
`8: Schull as
`
`their type
`
`F?030/3.
`‘
`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 diver-tar 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 the 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 that point,
`
`the valve 33 is switched to
`
`open the valve between the dose volume tubing 41
`
`and the wash syringe 37 and close the valve leading
`
`through tubing 30 to the generator 23. Similarly,
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`35
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`1201 of 1754
`1201 of 1754
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`
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`0160303
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`_10_
`
`the diverts: valve 32 is switched from the waste
`
`position to the patient position, and the physician
`
`performing the study quickly injects saline from
`
`the wash syringe 37 directly into the patient 56.
`
`5
`
`That operation performs
`
`a number of different
`
`functions.
`
`In particular,
`
`it pushes
`
`the dose
`
`volume of radioactive eluate from the dose volmne
`
`tubing_4l
`radioactive
`
`into the patient as
`bolus.
`Thereafter.
`
`a single highly
`the
`remaining
`
`10
`
`saline in the wash syringe 37 clears the lines 41,
`
`44, 50, purging them of radioactivity.
`
`An advantage of the wash solution clearing
`
`the patient line of radioactivity is that the line
`
`does not "glow” in photos taken of the patient.
`
`15
`
`Such a glowing interferes with data
`
`from the
`
`p