(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2007/0213848 A1
`deKemp et al.
`(43) Pub. Date:
`Sep. 13, 2007
`
`US 20070213848A1
`
`(54) RUBIDIUM ELUTION SYSTEM CONTROL
`(75) Inventors: Robert A. deKemp, Ottawa (CA); Ran
`Klein, Ottawa (CA)
`Correspondence Address:
`OGLVY RENAULT LLP
`1981 MCGILL COLLEGE AVENUE
`SUTE 16OO
`MONTREAL, QC H3A2Y3 (CA)
`(73) Assignee: Ottawa Heart Institute Research Cor
`poration, Ottawa, ON (CA)
`(21) Appl. No.:
`11/372,149
`
`(22) Filed:
`
`Mar. 10, 2006
`
`Publication Classification
`
`(51) Int. Cl.
`G05B I3/02
`
`(2006.01)
`
`
`
`(52) U.S. Cl. ................................................................ 700/32
`(57)
`ABSTRACT
`
`A method of controlling an SrfRb elution system having
`a generator valve for proportioning a flow of saline Solution
`between an SrfRb generator and a bypass line coupled to
`an outlet of the generator Such that Saline solution traversing
`the bypass line will merge with eluted saline solution
`emerging from the generator to provide an active saline
`Solution. During each elution run, a plurality of Successive
`concentration parameter values are obtained at predeter
`mined intervals. Each concentration parameter value is
`indicative of a respective instantaneous activity concentra
`tion of the active saline solution. Respective error values
`between each concentration parameter value and a target
`activity concentration value of the elution run are computed.
`Error databased on a plurality of the computed error values
`is accumulated. Between Successive elution runs, at least
`one performance parameter of the elution system is adjusted
`based on the accumulated error data.
`
`Controller
`
`User interface
`
`JUBILANT EXHIBIT 1033
`Jubilant v. Bracco, IPR2018-01449
`
`

`

`Patent Application Publication Sep. 13, 2007 Sheet 1 of 8
`
`US 2007/021.3848A1
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`Patent Application Publication Sep. 13, 2007 Sheet 2 of 8
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`US 2007/021.3848A1
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`Patent Application Publication Sep. 13, 2007 Sheet 3 of 8
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`Patent Application Publication Sep. 13, 2007 Sheet 4 of 8
`
`US 2007/021.3848A1
`
`- 10
`40
`1. d Patient
`Outlet
`
`Figure 6a
`
`
`
`Figure 6c
`
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`28
`
`

`

`Patent Application Publication Sep. 13, 2007 Sheet 5 of 8
`
`US 2007/021.3848A1
`
`Figure 6d
`
`
`
`Saline
`Supply
`
`28
`
`10
`Patient
`Outlet
`
`

`

`Patent Application Publication Sep. 13, 2007 Sheet 6 of 8
`
`US 2007/0213848A1
`
`Figure 7a
`
`No
`
`Figure 7b
`
`Figure 7c
`
`
`
`
`
`Open
`Generator
`Valve
`
`Close
`Generator
`Valve
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`to
`
`t
`
`t
`
`time
`
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`t
`
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`time
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`

`

`Patent Application Publication Sep. 13, 2007 Sheet 7 of 8
`
`US 2007/021.3848A1
`
`Compute
`CM(t)
`
`
`
`Predict
`Flow Ratio,
`Duty Cycle
`
`S2
`
`S14
`
`
`
`Increase
`DutyCycle
`
`
`
`NO
`
`No
`
`S26
`
`Decrease
`DutyCycle
`
`Figure 8a
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`Figure 8b
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`
`
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`time
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`

`Patent Application Publication Sep. 13, 2007 Sheet 8 of 8
`
`US 2007/021.3848A1
`
`Figure 8a
`
`
`
`
`
`S28
`
`
`
`
`
`No
`
`Figure 8b
`
`
`
`Figure 8c
`
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`
`Predict
`Flow Ratio,
`Duty Cycle
`
`Increase
`DutyCycle
`
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`
`S26
`
`Decrease
`DutyCycle
`
`time
`
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`
`time
`
`

`

`US 2007/021.3848 A1
`
`Sep. 13, 2007
`
`RUBDIUM ELUTION SYSTEM CONTROL
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`0001. This is the first application filed for the present
`invention.
`
`MICROFICHEAPPENDIX
`0002) Not Applicable.
`
`TECHNICAL FIELD
`0003. The present application relates in general to nuclear
`medicine and, in particular, to a rubidium elution control
`system.
`
`BACKGROUND OF THE INVENTION
`0004 As is well known in the art, Rubidium (Rb) is
`used as a positron emission tomography (PET) tracer for
`non-invasive measurement of myocardial perfusion (blood
`flow).
`0005 Recent improvements in PET technology have
`introduced 3-dimensional positron emission tomography
`(3D PET). Although 3D PET technology may permit more
`efficient diagnosis and prognosis in patients with Suspected
`coronary artery disease, the sensitivity of 3D PET requires
`very accurate control of the delivery of Rb activity to a
`patient being assessed.
`0006 FIGS. 1 and 2 illustrate a conventional rubidium
`elution system used for myocardial perfusion imaging. As
`may be seen in FIG. 1, the elution system comprises a
`reservoir of sterile saline solution (e.g. 0.9% Sodium Chlo
`ride Injection), a pump, and a strontium-rubidium (Sr/
`Rb) generator. In operation, the pump causes the saline
`solution to flow from the reservoir 4 and through the
`generator 8 to elute the Rb. The active solution output
`from the generator 8 is then Supplied to a patient (not shown)
`via a patient outlet 10.
`0007 When the system 2 is not in use, the amount of
`Rb within the generator 8 accumulates until a balance is
`reached between the rate of Rb production (that is, Sr
`decay) and the rate of Rb decay. As a result, the Rb
`activity level in the active Saline emerging from the genera
`tor 8 tends to follow a “bolus' profile 12 shown by the solid
`line in FIG.2a. In particular, at the start of an Rb elution
`“run”, the activity level rises rapidly and peaks, as accumu
`lated Rb is flushed out of the generator 8. Thereafter, the
`activity level drops back to a Substantially constant value.
`The maximum activity level A (bolus peak) obtained
`during the run is dependent on the amount of accumulated
`Rb in the generator 8, and thus is generally a function of
`the systems recent usage history, principally: the current
`Rb production rate; the amount of accumulated Rb (if
`any) remaining at the end of the previous elution run; and the
`idle time since the previous run. The generally constant level
`of the bolus tail is dependent on the rate offRb production
`and the saline flow rate produced by the pump 6.
`0008. As is well known in the art, Rb is generated by
`radioactive decay of the Sr. and thus the rate of Rb
`production at any particular time is a function of the mass of
`remaining Sr. As will be appreciated, this value will
`diminish (exponentially) through the useful life of the gen
`
`erator 8. The result is a family of bolus curves, illustrated by
`the dashed lines of FIG. 2a, mapping the change in elution
`system performance over the useful life of the generator 8.
`0009. Because of the high activity level of Rb possible
`in the generator 8, it is desirable to limit the total activity
`dosage delivered to the patient during any given elution run.
`The total elution time required to reach this maximum
`permissible dose (for any given flow rate) will therefore vary
`over the life of the Sr charge in the generator 8, as may be
`seen in FIG.2b, where the total activity dose, represented by
`the area under each curve, is equal in both cases.
`0010) A limitation of this approach, particularly for 3D
`PET imaging, is that the delivery of a high activity rate over
`a short period of time tends to degrade image quality. Low
`activity rates supplied over a relatively extended period are
`preferred. As a result, the user is required to estimate the
`saline flow rate that will obtain the best possible image
`quality, given the age of the generator and its recent usage
`history, both of which will affect the bolus peak and tail
`levels. This estimate must be continuously adjusted through
`out the life of the generator 8, as the Sr decays.
`0011) Accordingly, techniques for controlling an Rb
`elution system that enable a desired activity level to be
`Supplied over a desired period of time, independently of a
`state of the Sri Rb generator, remain highly desirable.
`SUMMARY OF THE INVENTION
`0012. Accordingly, an object of the present invention is to
`provide techniques for controlling an Rb elution system.
`0013 The present invention therefore provides a method
`of controlling an SrfRb elution system having a genera
`tor valve for proportioning a flow of saline solution between
`anSrfRb generator and a bypass line coupled to an outlet
`of the generator Such that saline solution traversing the
`bypass line will merge with eluted saline Solution emerging
`from the generator to provide an active saline solution.
`During each elution run, a plurality of Successive concen
`tration parameter values are obtained at predetermined inter
`vals. Each concentration parameter value is indicative of a
`respective instantaneous activity concentration of the active
`saline Solution. Respective error values between each con
`centration parameter value and a target activity concentra
`tion value of the elution run are computed. Error databased
`on a plurality of the computed error values is accumulated.
`Between successive elution runs, at least one performance
`parameter of the elution system is adjusted based on the
`accumulated error data.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`0014 Further features and advantages of the present
`invention will become apparent from the following detailed
`description, taken in combination with the appended draw
`ings, in which:
`0015 FIG. 1 is a block diagram schematically illustrating
`principal elements of a conventional Rubidium elution sys
`tem;
`0016 FIGS. 2a and 2b are graphs illustrating represen
`tative performance of the elution system of FIG. 1;
`0017 FIG. 3 is a block diagram schematically illustrating
`principal elements of a Rubidium elution system in accor
`dance with an embodiment of the present invention;
`
`

`

`US 2007/021.3848 A1
`
`Sep. 13, 2007
`
`0018 FIG. 4 illustrates a pinch-type valve arrangement
`usable in the elution system of FIG. 3;
`0.019
`FIG. 5 schematically illustrates a positron detector
`usable in the elution system of FIG. 3;
`0020 FIGS. 6a-6d schematically illustrate respective
`operating states of the Rubidium elution system of FIG. 3;
`0021
`FIGS. 7a-7c schematically illustrate a first algo
`rithm for controlling the Rubidium elution system of FIG. 3;
`and
`0022 FIGS. 8a–8c schematically illustrate a second algo
`rithm for controlling the Rubidium elution system of FIG. 3.
`0023. It will be noted that throughout the appended
`drawings, like features are identified by like reference
`numerals.
`
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENT
`0024. The present invention provides a Rubidium (Rb)
`elution and control system in which the Rb activity rate
`delivered to a patient can be controlled substantially inde
`pendently of the condition of the SrfRb generator. Rep
`resentative embodiments are described below with reference
`to FIGS. 3-8.
`0025. In the embodiment of FIG. 3, the elution system
`comprises reservoir 4 of sterile saline solution (e.g. 0.9%
`Sodium Chloride Injection); a pump 6 for drawing saline
`from the reservoir 4 at a desired flow rate; a generator valve
`16 for proportioning the saline flow between a strontium
`rubidium (SrfRb) generator 8 and a bypass line 18 which
`circumvents the generator 8; a positron detector 20 located
`downstream of the merge point 22 at which the generator
`and bypass flows merge; and a patient valve 24 for control
`ling Supply of active saline to a patient outlet 10 and a waste
`reservoir 26. A controller 28 is connected to the pump 6.
`positron detector 20 and valves 16 and 24 to control the
`elution system 14 in accordance with a desired control
`algorithm, as will be described in greater detail below.
`0026. If desired, the strontium-rubidium (SrfRb) gen
`erator 8 may be constructed in accordance with Applicants
`co-pending U.S. patent application Ser. No. 11/312,368
`entitled A Rubidium Generator For Cardiac Perfusion Imag
`ing And Method Of Making And Maintaining Same, filed
`Dec. 21, 2005. In such cases, the pump 6 may be a
`low-pressure pump Such as a peristaltic pump. However,
`other types of generator may be used. Similarly, other types
`of pump may be used, provided only that the pump selected
`is appropriate for medical applications and is capable of
`maintaining a desired saline flow rate through the generator.
`0027. The generator and patient valves 16, 24 may be
`constructed in a variety of ways. In principal, the generator
`valve may be provided as any Suitable valve 16 arrangement
`capable of proportioning saline flow between the generator
`8 and the bypass line 18. If desired, the generator valve may
`be integrated with the branch point 30 at which the saline
`flow is divided. Alternatively, the generator valve 16 may be
`positioned downstream of the branch point 30, as shown in
`FIG. 3. In embodiments in which flexible (e.g. Silicon)
`tubing is used to convey the saline flow, the generator valve
`16 may be provided as one or more conventional "pinch”
`valves of the type illustrated in FIG. 4. The use of pinch
`
`valves is beneficial in that it enables saline flow to be
`controlled in a readily repeatable manner, and without direct
`contact between the Saline Solution and components of the
`valve. Factors associated with the design of the patient valve
`24 are substantially the same as those discussed above for
`the generator valve 16, with the exception that the saline
`flow through the patient valve 24 is (or must be assumed to
`be) carrying radioactive Rb. Accordingly, while any suit
`able valve design may be selected for the patient valve 24,
`it is particularly beneficial to avoid direct contact between
`the active saline Solution and valve components. For this
`reason, pinch valves are preferred for the patient valve 24.
`0028. As may be seen in FIG. 5, the positron detector 20
`may conveniently be provided as a scintillator 32 disposed
`immediately adjacent to a feed-line 33 carrying the active
`saline Solution; a photon counter 34 optically coupled to the
`scintillator 32; and a radiation shield 36 surrounding the
`scintillator 32 and photon counter 34. The scintillator 32
`may be provided by a length of fluorescent optical fiber,
`which absorbs Beta (e-) radiation generated by Rb decay
`to produce a photon. The photon counter 34 (which may, for
`example be an H7155 detector manufactured by
`Hamamatsu) detects incident photons, and generates a
`detection signal 38 corresponding to each detected photon.
`The shielding 36, which may be constructed of lead (Pb),
`serves to shield the scintillator 32 and photon counter 34
`from ambient Gamma and Beta radiation. In some embodi
`ments, the radiation shield 36 is approximately /2 inch thick
`in the vicinity of the scintillation fiber 32, and may extend
`(in both directions) at least 5-times the feed-line 33 outer
`diameter from the scintillation fiber 32. This arrangement
`effectively suppresses ingress of ambient Gamma and Beta
`radiation along the channel through which the feed-line 33
`passes. As a result, spurious photons are Suppressed, and the
`rate at which photons are counted by the photon counter 34
`will be proportional to the Rb activity concentration of the
`active saline solution adjacent to the scintillator 32. In the
`illustrated embodiments, the number of photons detected
`within a predetermined period of time is counted (e.g. by the
`controller 28), and the count value C is used as an activity
`parameter which is proportional to the Rb activity con
`centration. If desired, a proportionality constant K between
`the activity parameter Ce and the Rb activity concentra
`tion can be empirically determined.
`0029. In operation, the pump 6 and valves 16, 24 can be
`controlled to route saline solution through the system 14 in
`accordance with various modes of operation, as may be seen
`in FIGS. 6a-6d. Thus, for example, in a “Bypass-to-waste'
`mode of the system illustrated in FIG. 6a, the generator and
`patient valves 16, 24 are positioned to route the entire saline
`flow through the bypass line 18, and into the waste reservoir
`26. This mode of operation is suitable for initializing the
`system 14 immediately prior to beginning an elution run.
`0030 FIG. 6b illustrates a “patient line flush” mode of the
`system 14, in which the generator and patient valves 16, 24
`are positioned to route the saline flow through the bypass
`line 18 and out through the patient outlet 10. This mode of
`operation may be used prior to an elution run to prime (that
`is, expel air from) the patient line 40 in preparation for
`insertion of the patient outlet into, for example, a vein of a
`patient. At the end of an elution run, this mode may also be
`used to flush any Rb activity remaining within the patient
`
`

`

`US 2007/021.3848 A1
`
`Sep. 13, 2007
`
`line 40 into the patient, thereby ensuring that the patient
`receives the entire activity dose required for the PET imag
`ing.
`0031 FIG. 6c illustrates a “waiting for threshold” mode
`of the system 14, in which the generator and patient valves
`16, 24 are positioned to route the saline flow through the
`generator 8, and into the waste reservoir 26. This mode of
`operation is suitable during the beginning an elution run,
`while the Rb concentration is increasing from zero, but has
`not yet reached desired levels. Flushing this leading portion
`of the Rb bolus 12 to the waste reservoir 26 avoids
`exposing the patient to unnecessary Rb activity and allows
`the total activity dosage delivered to the patient to be closely
`controlled.
`0032 FIG. 6d illustrates an “elution” mode of the system
`14, in which the generator valve 16 is actively controlled via
`a control loop 42 from the positron detector 20 to proportion
`saline flow through both the generator 8 and the bypass line
`18. The generator 8 and bypass saline flows are then
`recombined (at 22) downstream of the generator 8 to pro
`duce an active saline solution having a desired Rb activity
`concentration. The patient valve 24 is positioned to direct
`the active saline solution to the patient outlet 10.
`0033. In the foregoing description, each operating mode
`is described in terms of the associated steps in performing an
`elution run to Support PET imaging of a patient. However,
`it will be appreciated that this context is not essential. Thus,
`for example, one or more of the above operating modes may
`be used to facilitate calibration of the system, in which case
`the patient outlet 10 would be connected to a conventional
`dose calibrator (not shown), rather than a patient.
`0034. As will be appreciated from the foregoing discus
`Sion, each of the operating modes of the elution system is
`controlled by the controller unit 28 operating under software
`control. As a result, it is possible to implement a wide variety
`of automated processes, as required. Thus, for example,
`elution runs can be fully automated, based on user-entered
`target parameters, which allows the user to avoid unneces
`sary radiation exposure. Similarly, it is possible to automate
`desired system calibration and Sr break-through detection
`protocols, which ensures consistency as well as limiting
`radiation exposure of users. A further benefit of software
`based elution system control is that data logs from each
`elution run can be easily maintained, which assists not only
`system diagnostics, but can also be used to ensure that the
`elution parameters (e.g. elution concentration and duration)
`specified for PET imaging have been satisfied.
`0035). As described above, in the “elution” mode of
`operation (FIG. 6d), the generator valve 16 is actively
`controlled via a control loop 42 from the positron detector 20
`to proportion saline flow through both the generator 8 and
`the bypass line 18. Recombining the corresponding genera
`tor and bypass saline flows downstream of the generator 8
`produces an active saline solution having a desired Rb
`activity concentration. Preferably, the control loop 42 is
`implemented using Suitable software executing in the con
`troller 28. Representative algorithms for implementing the
`control loop 42 are described below with reference to FIGS.
`7 and 8.
`0036). In the embodiment of FIG. 7, the controller 28
`implements a threshold-based control algorithm, in which
`
`the generator valve 16 is controlled by comparison of
`measured activity concentration to a desired activity con
`centration. If the measured concentration is higher than the
`desired concentration, the generator valve 16 directs saline
`flow to the bypass line 18 rather than the generator 8, and
`Vice versa.
`0037. In general, the elution run is designed to generate
`a target Rb activity concentration which follows a desired
`function in time CM (t). In the embodiment of FIG. 7, CM (t)
`is a square-wave function having a predetermined constant
`activity concentration C and duration (t-t'), as may be
`seen by the dotted line of FIG.7b. These parameters may be
`provided by explicit user input using the user interface 44
`(FIG. 3), or calculated from other user-input parameters,
`Such as a total activity dosage and Saline flow rate. As will
`be appreciated, the target activity profile CM (t) need not be
`a square-wave function, other profiles may be used, such as
`a ramp function, if desired.
`0038. In some embodiments, the target activity profile
`C(t) may define the desired Rb activity concentration at
`the patient outlet 10. In Such cases, an adjusted target profile
`CM (t) may be computed based on the selected flow rate and
`patient supply line length, to account for expected Rb
`decay (and thus loss of activity) in the patient supply line 40
`between the positron detector 20 and the patient outlet 10.
`This arrangement is advantageous in that it allows a user to
`specify an amount of activity (either activity concentration
`or total dose) delivered to the patient, and the control loop
`42 will operate to match this specification, taking into
`account the Rb decay within the system 14.
`0039 FIG. 7a is a flow chart illustrating a representative
`threshold-based valve control algorithm which may be used
`in the embodiment of FIG. 7. For ease of illustration, the
`flow-chart of FIG. 7a only illustrates the control loop.
`Process steps and threshold, related to transitioning between
`various modes of operation are not shown.
`0040. In preparation for an elution run, a user enters
`target parameters for the elution. These parameters may
`include any three of total activity dose, target activity
`concentration, elution duration, and saline flow rate. From
`the entered parameters, the remaining parameter can be
`calculated, and, if desired, an adjusted target profile CM (t)
`obtained (step S2).
`0041 At the start of the elution run, the controller 28
`opens the generator valve 16 (at time to in FIG. 7b) to place
`the elution system 14 into the “Waiting for Threshold
`mode. During this period, the activity level detected by the
`positron detector will begin to ramp up following the leading
`edge of the natural bolus curve 12 (FIG. 2a). During this
`period, the patient valve 24 remains closed, so that any
`activity eluted from the generator 8 is passed to the waste
`reservoir 26. When the detected activity concentration C
`exceeds the target value C, the controller 28 opens the
`patient valve 24 (at time t in FIG. 7b), and shifts to the
`“elution” mode of operation.
`0042. During the elution mode, the controller 28 itera
`tively obtains an updated concentration parameter C (at
`S4), which indicates the instantaneous activity concentration
`at the positron detector. The concentration parameter C is
`then compared to the desired concentration CM. If C is
`below the desired concentration CM (at S6), the generator
`
`

`

`US 2007/021.3848 A1
`
`Sep. 13, 2007
`
`valve 16 is opened (at S8) so that saline flows through the
`generator 8 to elute Rb activity. If C is above the desired
`concentration CM (at S10), the generator valve 16 is closed
`(at S12) so that saline flows through the bypass line 18. As
`may be seen in FIG. 7b, due to delay in response, the result
`of this operation is a saw-tooth activity concentration profile
`46 centered on the target concentration CM (or CM). At the
`end of the elution run (time t in FIG. 7b), the controller 28
`closes the generator valve 16 and places the elution system
`14 into the “Patient line Flush” mode, which terminates
`elution of Rb activity from the generator 8 and flushes any
`remaining Rb activity within the patient line 40 into the
`patient.
`FIG. 7c illustrates the activity concentration profile
`0.043
`delivered to the patient as a result of the above-described
`process. As may be seen from FIG. 7c, no Rb activity is
`delivered to the patient during the “Waiting for Threshold'
`mode (to-t). During the "elution” mode (t-t, the activity
`concentration 46 follows a saw-tooth pattern centered on the
`target concentration CM (or CM). Finally, in “Patient line
`Flush” mode (following t) the activity concentration drops
`rapidly as Rb elution is terminated and residual activity is
`flushed from the patient supply line 40.
`0044 As will be appreciated, the accuracy with which the
`delivered activity concentration follows the target profile
`CM (t) is largely dependent on the line Volume between the
`merge point 22 and the positron detector 20. In some cases
`relatively large excursions from the target profile CM (t) are
`acceptable. However the control loop response is such that
`the difference cannot be reduced past a certain limit. As a
`result, the "error” between the target profile CM (t) and the
`delivered concentration profile 46 (FIG. 7c) cannot be
`eliminated in the embodiment of FIG. 7. A pulse-width
`modulation technique which overcomes this limitation is
`described below with reference to FIG. 8.
`0045. The embodiment of FIG. 8 differs from that of FIG.
`7 primarily in the manner in which the generator valve 16 is
`controlled. In the embodiment of FIG. 7, the generator valve
`16 is opened or closed based on a comparison between the
`detected activity concentration C and desired activity
`concentration. By contrast, in the embodiment of FIG. 8, the
`generator valve is opened and closed continuously at a
`predetermined frequency. Any desired frequency may be
`used, depending primarily on the physical properties of the
`generator valve 16. In some embodiments, a frequency of
`between 1 and 10 Hz (e.g. 5 Hz) may be used. In order to
`control the proportioning of Saline flow between the gen
`erator 8 and the bypass line 18, the duty cycle of the valve
`16 is varied. Thus, for example, a duty cycle of “0” may
`have the effect of directing the entire saline flow through the
`bypass line 18, and a duty cycle of “100' directs the entire
`saline flow through the generator 8. A duty cycle between
`these limits divides the saline flow between the generator 8
`and bypass line 18 in accordance with the duty cycle value.
`The precision with which the saline flow can be divided
`between the generator 8 and bypass line 18 will be deter
`mined by a minimum adjustment step size, which can be a
`programmable value.
`0046) As described above, the amount of Rb eluted
`from the generator 8, for any given flow rate, will depend on
`the recent usage history of the elution system 14, and the
`instantaneous production rate offRb within the generator 8.
`
`Accordingly, it is possible to improve the accuracy of the
`elution system 14 by implementing a predictive control
`algorithm, in which models of the valve 16 and generator
`performance are used to predict the amount of Rb activity
`that will be eluted from the generator 8 for a given duty cycle
`Setting.
`0047. In particular, the generator performance can be
`modeled to predict the amount of Rb activity that will be
`eluted from the generator for a given flow rate, as will be
`described in greater detail below. In some embodiments, a
`dose calibrator (not shown) is used to measure the generator
`performance in terms of, for example, Rb activity con
`centration vs. eluted volume. This data can be used to predict
`eluted fRb activity concentration for any given saline flow
`rate.
`0048. In addition, the generator valve response can be
`modeled to enable a prediction of the flow rate through the
`generator for any given total saline flow rate (as determined
`by the pump control setting) and valve duty cycle. In some
`embodiments, the valve response may be modeled in terms
`of respective parameters defining upper and lower duty
`cycle limits II,
`and II, and a flow ratio vs. duty cycle
`slope L between the upper and lower limits. With this
`arrangement, the upper duty cycle limit II
`represents the
`value beyond which all of the flow is considered to be
`directed into the generator 8. Conversely, the lower duty
`cycle limit II,
`represents the value below which all of the
`flow is considered to be directed into the bypass line 18. The
`flow ratio vs. duty cycle slope L defines the change in the
`ratio between the respective flows through the generator 8
`and the bypass line 18 for duty cycle values lying between
`the upper and lower limits.
`0049. In cases where the valve response is non linear, it
`may be advantageous to replace the flow ratio vs. duty cycle
`slope parameter L with one or more parameters defining a
`mathematical valve response curve.
`0050. At the start of the elution run, the controller 28
`opens the generator valve 16 (at time to in FIG. 8b) to place
`the elution system into the “Waiting for Threshold mode.
`During this period, the activity level detected by the positron
`detector 20 will begin to ramp up following the leading edge
`of the natural bolus curve 12 (FIG. 2a). During this period,
`the patient valve 24 remains closed, so that any activity
`eluted from the generator is passed to the waste reservoir 26.
`When the detected activity concentration reaches the target
`concentration CM (or adjusted target C'M, as applicable), the
`controller 28 opens the patient valve 24 (at time t in FIG.
`8b), and shifts to the “elution” mode of operation.
`0051
`During the elution mode, the controller 28 imple
`ments a predictive control algorithm in which previously
`stored generator performance data is used (at S14) to esti
`mate a flow ratio that will yield the target activity concen
`tration CM (or CM) at the positron detector 20, for the
`selected flow rate of the elution run. This estimated (pre
`dicted) flow ratio is then used to control the duty cycle of the
`generator valve 16. The controller 28 then obtains an
`updated concentration parameter C (at S16), which indi
`cates the instantaneous activity concentration at the positron
`detector 20. The concentration parameter C is then com
`pared to the target concentration CM (or CM) to obtain an
`error function AC (at S18). Based on the value of the error
`function AC, the duty cycle of the generator valve 16 is
`
`

`

`US 2007/021.3848 A1
`
`Sep. 13, 2007
`
`adjusted. If ACC0 (step S20), the duty cycle is increased (at
`S22) so that proportionally more saline flows through the
`generator 8 to elute more Rb activity. If AC>0 (step S24),
`the duty cycle is decreased (at S26) so that proportionally
`more saline flows through the bypass line 18. If neither
`condition is satisfied the duty cycle is maintained at its
`current status (S28). As may be seen in FIG. 8b, the result
`of this operation is a low-error concentration profile 48 that
`closely matches the target concentration CM (or C'). At the
`end of the elution run (time t in FIG. 8b), the controller 28
`closes the generator valve 16 (that is, reduces the duty cycle
`to “0”) and places the elution system 14 into the “Patient line
`Flush” mode, which terminates elution of Rb activity from
`the generator 8 and flushes any remaining Rb activity
`within the patient line 40 into the patient.
`0.052
`FIG. 8c illustrates the activity concentration profile
`48 delivered to the patient as a result of the above-described
`process. As may be seen from FIG. 8c, no Rb activity is
`delivered to the patient during the “Waiting for Threshold'
`mode (to-t). During the "elution” mode (t-t'), the activity
`concentration closely follows the target concentration CM
`(or C'). Finally, in “Patient line Flush” mode (following t)
`the activity concentration drops rapidly as Rb elution is
`terminated and residual activity is flushed from the patient
`supply line 40.
`0053. In practice, the above-described predictive control
`algorithm has been found to produce an Rb activity
`concentration that closely matches the desired target profile
`C(t), except during the first few seconds of the elution,
`where significant prediction errors may occur. In cases
`where all of the activity from the generator must be eluted
`to reach the requested total dosage, this error must be
`tolerated. However, in other cases it is possible to eliminate
`the error by delaying the start of the "elution' mode of
`operation. Thus, for example, during the “waiting for thresh
`old', mode, the detected activity level C can be monitored
`and compared to a thr