`
`
`PRECISE 82RB INFUSION SYSTEM FOR CARDIAC PERFUSION MEASUREMENT
`USING 3D POSITRON EMISSION TOMOGRAPHY
`
`
`
`by
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`
`
`Ran Klein B.A.Sc
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`
`
`A thesis submitted to the
`
`Faculty of Graduate and Postdoctoral Studies
`
`in partial fulfillment of the requirements for the degree of
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`
`
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`Master of Applied Science
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`in Electrical and Computer Engineering
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`Ottawa-Carleton Institute for Electrical and Computer Engineering
`School of Information Technology and Engineering (Electrical & Computer Engineering)
`
`
`Faculty of Engineering
`University of Ottawa
`
`
`February, 2005
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`©2005, Ran Klein, Ottawa, Canada
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`JUBILANT EXHIBIT 1014
`Jubilant v. Bracco, IPR2018-01449
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`

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`82Rb Elution System Control
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`
`
`
`Ran Klein, University of Ottawa
`
`Credits
`
` I
`
` wish to extend my gratitude to Robert deKemp and Andy Adler for guiding me
`through this project. Their mentoring, support, and friendship have made this a memorable
`experience.
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`82Rb Elution System Control
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`
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`Ran Klein, University of Ottawa
`
`Abstract
`Introduction: Quantitative myocardial perfusion measurements using positron
`emission tomography (PET) can be improved by introducing diagnostic tracers at a constant
`rate of activity. 82Rb can be produced cost effectively by eluting a 82Sr/82Rb generator with
`saline; however, it exhibits an undesirable, but reproducible, activity rate variation.
`Previously, a threshold-comparison algorithm controlled saline flow through either generator
`or bypass line using an on/off valve, to simulate constant-activity elutions. Methods: In this
`work a mechanical system and control software is developed to control tracer infusion. The
`valve is cycled at 5Hz and its duty-cycle controlled by a predictive-corrective algorithm in
`order to reduce measurable activity rate fluctuations. Results: Precision increases (RMS
`error improves from >40% to ~14%) as does the range of relative activities that can be eluted
`from the generator. Conclusion: The proposed method demonstrates superior precision and
`flexibility. However, further tests must be conducted to ensure that the precision of the
`system does not deteriorate over time.
`
`
`
`Key Words: Rubidium-82, 82Sr/82Rb generator, cardiac, perfusion, positron emission
`tomography, PET, predictive control.
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`82Rb Elution System Control
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`Ran Klein, University of Ottawa
`
`Table of Contents
`
`........................................................................................................................................................ii
`Credits
`.......................................................................................................................................................iii
`Abstract
`Table of Contents..................................................................................................................................................iv
`Table of Figures....................................................................................................................................................vi
`Table of Tables ...................................................................................................................................................viii
`List of Acronyms..................................................................................................................................................ix
`List of Variables .................................................................................................................................................... x
`Introduction
`........................................................................................................................................................ 1
`Chapter 1:
`Introduction to Molecular Imaging and Dynamic PET................................................................... 4
`1.1 Positron Emission Tomography ................................................................................................................ 4
`1.2 82Sr/82Rb Generator – a Cost-effective Tracer Source............................................................................... 7
`Sr Breakthrough............................................................................................................................................. 9
`1.3 82Rb Elution Profiles ............................................................................................................................... 10
`1.4 Constant-Activity Elution for Quantitative Perfusion Measurement in the Left Ventricle of the Heart . 11
`1.5 Quantitative Perfusion Measurements Using 82Rb.................................................................................. 14
`Chapter 2: The Second Generation 82Rb Infuser – a starting point................................................................. 16
`2.1 The Daily Protocol and Elution Types .................................................................................................... 17
`2.2 Hardware Description ............................................................................................................................. 19
`2.3 Prototype Performance............................................................................................................................ 25
`2.4 Further Development of the 82Rb Elution System (RbES)...................................................................... 26
`Chapter 3:
`System Design and Conceptual Understanding ............................................................................ 28
`3.1 Requirements........................................................................................................................................... 28
`Functional Requirements............................................................................................................................. 28
`Non-Functional Requirements..................................................................................................................... 29
`Other Requirements..................................................................................................................................... 30
`3.2 Initial Design Considerations .................................................................................................................. 32
`Safety........................................................................................................................................................... 32
`Process Monitoring...................................................................................................................................... 33
`Hardware Modifications .............................................................................................................................. 34
`Software packages ....................................................................................................................................... 36
`3.3 Flow Hardware Layout Justification ....................................................................................................... 39
`Pump Speed Variation ................................................................................................................................. 40
`Bypass Ratio Control................................................................................................................................... 41
`3.4 Design of Physical Processes .................................................................................................................. 43
`Run sequence............................................................................................................................................... 44
`Calibration ................................................................................................................................................... 45
`Breakthrough Activity Measurement........................................................................................................... 50
`Elution Tests................................................................................................................................................ 52
`3.5 Software Design...................................................................................................................................... 53
`Pre-Run Stage and the GUI-Sequence......................................................................................................... 53
`Post-Run Stage ............................................................................................................................................ 55
`Real-Time Sequence.................................................................................................................................... 56
`Physical Sequence ....................................................................................................................................... 58
`3.6 Error Detection........................................................................................................................................ 64
`Pressure Errors............................................................................................................................................. 66
`Pump Communication and Operation Errors............................................................................................... 66
`Computer Resources.................................................................................................................................... 67
`Positron Detector Errors .............................................................................................................................. 67
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`82Rb Elution System Control
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`Ran Klein, University of Ottawa
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`Dose Calibrator Communication Errors ...................................................................................................... 67
`Maintenance................................................................................................................................................. 67
`Software Errors............................................................................................................................................ 68
`Warnings...................................................................................................................................................... 68
`Outlier Highlighting .................................................................................................................................... 68
`3.7 System Refinement ................................................................................................................................. 69
`Dose Calibrator Spike Removal Algorithm................................................................................................. 69
`3.8 Summary ................................................................................................................................................. 70
`Chapter 4: Elution Profile Control.................................................................................................................. 71
`4.1 Threshold Comparison Algorithm with Auto-tuning Hysteresis Correction (HC-TC) ........................... 73
`4.2 Variable Flow Control............................................................................................................................. 74
`Cycling Valve Control................................................................................................................................. 74
`Transient State Control................................................................................................................................ 74
`Implementation of the Variable Flow Control............................................................................................. 75
`Valve Response Measurements ................................................................................................................... 76
`Modeling of Valve Response....................................................................................................................... 79
`PWM Valve Life Span................................................................................................................................. 80
`4.3 Variable Flow Control Algorithms.......................................................................................................... 81
`PID Control.................................................................................................................................................. 82
`Forgetful PID Controller.............................................................................................................................. 85
`Predictive Control........................................................................................................................................ 85
`Predictive Corrective Control ...................................................................................................................... 88
`Initial Error Removal................................................................................................................................... 89
`Setting the Saline Flow Rate........................................................................................................................ 90
`Automatic Parameter Tuning....................................................................................................................... 91
`Summary...................................................................................................................................................... 96
`Chapter 5: Testing and Characterization......................................................................................................... 98
`5.1 Safety Testing.......................................................................................................................................... 98
`The Worst Case Scenario............................................................................................................................. 99
`5.2 Test Cases.............................................................................................................................................. 100
`User Interface Testing................................................................................................................................ 102
`Functional Testing ..................................................................................................................................... 102
`Error Handling Testing.............................................................................................................................. 103
`5.3 Testing in a Routine Clinical Setting..................................................................................................... 103
`Computer Crash Issue................................................................................................................................ 104
`5.4 Calibration Characterization.................................................................................................................. 106
`Calibration Constant vs. Flow Rate ........................................................................................................... 107
`Summary of Calibration Analysis.............................................................................................................. 109
`5.5 Analysis of the Self-Tuning Model....................................................................................................... 110
`Variation in Valve Model Parameters with Requested Elution Parameters............................................... 112
`Analysis of Tuned Valve Response........................................................................................................... 114
`5.6 Elution Tests.......................................................................................................................................... 116
`Range of Relative Activities as a Function of Elution Duration................................................................ 120
`5.7 Generator Life Span .............................................................................................................................. 121
`Breakthrough Sr Activity........................................................................................................................... 122
`Activity Curves.......................................................................................................................................... 123
`5.8 Benefits of 82Rb Constant-Activity Elutions ......................................................................................... 124
`Comparison of 82Rb and 13N-ammonia for Measurement of Perfusion in 3D PET ................................... 124
`Optimized Perfusion Measurements.......................................................................................................... 126
`5.9 Critical Analysis and Future work......................................................................................................... 127
`Chapter 6: Conclusion .................................................................................................................................. 130
`List of References.............................................................................................................................................. 133
`Appendix A: Test Cases ................................................................................................................................... 137
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`82Rb Elution System Control
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`Ran Klein, University of Ottawa
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`Table of Figures
`Figure 1-1 – Positron emission tomography......................................................................................................... 5
`Figure 1-2 – 82Rb uptake images for measurement of myocardial perfusion. ...................................................... 6
`Figure 1-3 – 82Sr/82Rb decay sequence. ................................................................................................................ 8
`Figure 1-4 – 82Rb activity during recharging of a generator............................................................................... 10
`Figure 1-5 – Generator activity/volume curves with different flow rates and at different times........................ 11
`Figure 1-6 – Dynamic 82Rb imaging of a canine heart. ...................................................................................... 12
`Figure 2-1 – Daily protocol flow chart. .............................................................................................................. 19
`Figure 2-2 – Hardware component diagram of RbES......................................................................................... 19
`Figure 2-3 – Photograph of the assembled RbES and its components................................................................ 24
`Figure 2-4 – Photograph of top cover of the RbES............................................................................................. 24
`Figure 2-5 – Elution of 50% bolus activity within 30 s using a simple threshold comparison algorithm. ......... 25
`Figure 3-1 – Electro-optic level switch operation............................................................................................... 35
`Figure 3-2 – Response of transport of activity through a fixed volume line at a fixed flow rate........................ 40
`Figure 3-3 – Flow control through generator using a bypass line maintains a constant flow rate through all
`other lines. .................................................................................................................................................. 41
`Figure 3-4 – Flow control through the generator using a variable pinch valve on the generator line................. 42
`Figure 3-5 – Flow control through the generator using a double sided pinch valve on the bypass line and
`generator line. ............................................................................................................................................. 43
`Figure 3-6 – Schematic of the activity counter relating some of the factors that contribute to its efficiency
`measure....................................................................................................................................................... 46
`Figure 3-7 – Dose calibrator chamber measurement diagram. ........................................................................... 47
`Figure 3-8 – Sample calibration run results........................................................................................................ 48
`Figure 3-9 – Aperture response of the dose calibrator as a function of distance along the saline line from
`the vial. ....................................................................................................................................................... 49
`Figure 3-10 – Example of a constant-flow test run without (top) and with (bottom) a Gaussian aperture
`correction.................................................................................................................................................... 50
`Figure 3-11 – Opening message screen. ............................................................................................................. 53
`Figure 3-12 – Various screenshots...................................................................................................................... 54
`Figure 3-13 – Sequence, data, and control, flow and structure diagram of software.......................................... 56
`Figure 3-14 – The Hardware_Interface model.................................................................................................... 57
`Figure 3-15 – Flow Chart for all elution types. .................................................................................................. 59
`Figure 3-16 – Inputs to the Physical_Sequence M-file S-Function block. ......................................................... 62
`Figure 3-17 – Calibration results with and without the dose calibrator peak removal algorithm. ...................... 70
`Figure 4-1 – Elution of 50% bolus activity within 30 s using a simple threshold comparison algorithm. ......... 72
`Figure 4-2 – Pulse-width-modulation control of a solenoid valve to simulate a variable pinch valve. .............. 74
`Figure 4-3 – Activity vs. time curves as measured with the generator valve cycling at 15 Hz at various
`generator valve duty-cycles. ....................................................................................................................... 76
`Figure 4-4 – Valve response curves at υvalve = 2, 5, 15, and 100 Hz................................................................... 77
`Figure 4-5 – Elutions at valve flow ratio ≈ 50% produced by cycling the generator valve at 2, 5, and
`15 Hz. ......................................................................................................................................................... 78
`Figure 4-6 – Valve response (υvalve = 5 Hz) with the swapped axes, allows to determine the duty-cycle
`needed to achieve a desired valve flow ratio. ............................................................................................. 79
`Figure 4-7 – Closed loop controlled system using a PID controller................................................................... 83
`Figure 4-8 – Affects of PID controller parameters on system response. ............................................................ 83
`Figure 4-9 – Sample simulation results of a PID controlled elution................................................................... 84
`Figure 4-10 – Modified PID correction implementing a “forgetful” proportional component........................... 85
`Figure 4-11 – Block diagram of the predictive-corrective control of a PWM valve. ......................................... 88
`Figure 4-12 – Simulation of perfect control with erroneous activity concentration prediction due to a
`slight volume shift. ..................................................................................................................................... 89
`Figure 4-13 – Analyzed errors of a constant-activity elution with flow ratios spanning a large range. ............. 93
`Figure 4-14– Analyzed errors of a constant-activity elution with flow ratios only in the lower range. ............. 93
`Figure 4-15 – Demonstration of an elution in which the entire bolus activity has been eluted. ......................... 95
`Figure 5-1 – Sample test case layout. ............................................................................................................... 102
`Figure 5-2 – Calibration constant over the course of a generator life............................................................... 106
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`82Rb Elution System Control
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`Ran Klein, University of Ottawa
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`Figure 5-3 – Correlation of calibration constant to generator activity.............................................................. 107
`Figure 5-4 – Calculated calibration constant over the range of flow rates. ...................................................... 108
`Figure 5-5 – Calibration constant dependence on flow rate in the case of a high flow resistant generator
`column. ..................................................................................................................................................... 109
`Figure 5-6 – Progress of accelerated self-tuning of the valve response model over three successive
`elutions at 30% over 30 s.......................................................................................................................... 111
`Figure 5-7 – Evolution of parameters G and L during self-tuning through repeated runs of 30% relative
`activity over 30 s....................................................................................................................................... 112
`Figure 5-8 – Parameters G and L evolving during a 30% relative activity over 30 s training session. ............ 112
`Figure 5-9 – Example activity rate error measurements used for valve response model parameter tuning
`that could lead to conflicting adjustments based on how the data is treated............................................. 113
`Figure 5-10 – Adaptation of parameter L over a repeated sequence of 50% relative activity over 30 s
`elutions revealed that the adaptation law is flawed................................................................................... 114
`Figure 5-11 – Valve response correction curve used to determine the PWM duty-cycle required to achieve
`a desired valve flow ratio.......................................................................................................................... 115
`Figure 5-12 – Comparison of performance measures of elutions [n=10] over 30 s at 10, 30, 50, and 70%
`relative activity. ........................................................................................................................................ 118
`Figure 5-13 – Activity rate at patient outlet calculated based on the activity counter readings and dose
`calibrator readings. ................................................................................................................................... 119
`Figure 5-14 – Range of relative activities that can be achieved using the HC-TC method and the PCC-
`PWM method without significantly influencing the precision. ................................................................ 121
`Figure 5-15 – Breakthrough ratio progression over time.................................................................................. 122
`Figure 5-16 – Normalized activity rate vs. time curves measured during calibration runs over the life span
`of a generator............................................................................................................................................ 123
`Figure 5-17 – Example of 82Rb and 13N-ammonia blood curves. ..................................................................... 126
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`82Rb Elution System Control
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`Ran Klein, University of Ottawa
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`Table of Tables
`Table 1-1 – Commonly Used Positron-Emitting Isotopes [ 1] .............................................................................. 6
`Table 2-1 – Minimum PC Requirements............................................................................................................ 20
`Table 3-1 - Software Environment ..................................................................................................................... 38
`Table 3-2 – Elution parameter values for each run type..................................................................................... 60
`Table 3-3 – Physical_Sequence states and their termination conditions. As long as a termination condition
`is not met, the state is maintained unchanged............................................................................................. 63
`Table 3-4 - Detectable errors and their corresponding flags............................................................................... 65
`Table 4-1 - Comparison of elution time accuracy using the threshold comparison algorithm with (HC-TC)
`and without hysteresis correction. .............................................................................................................. 74
`Table 4-2 - Parameters used by the prediction algorithm. .................................................................................. 92
`Table 5-1 – Canadian Standards Association (CSA) field evaluation for electro-medical equipment results
`for two RbES systems................................................................................................................................. 99
`Table 5-2 - Test classification codes and their descriptions. ............................................................................ 101
`Table 5-3 - List of global structures and their contents. ................................................................................... 105
`Table 5-4 – Typical constant-activity elution profiles for various relative activities and over 30 s. ................ 117
`Table 5-5 - Comparison of Performance measures for HC-TC and PCC-PWM 30 s Elutions [n=10]............. 118
`Table 5-6 - Dynamic scan time frame durations for 82Rb and 13N-ammonia perfusion measurements............ 125
`Table 5-7 – Rest study results comparing perfusion measurements in a dog at varied 82Rb constant-
`activity elution time durations and activities show that similar results are obtained regardless of these
`elution parameters..................................................................................................................................... 127
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`82Rb Elution System Control
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`Ran Klein, University of Ottawa
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`List of Acronyms
`
`
`DAQ
`DLL
`FDG
`FOV
`GUI
`HL
`K
`Kr
`LCD
`LOR
`MSE
`MRI
`NI
`PET
`PID
`PWM
`QA
`Rb
`Sr
`UPS
`UOHI
`
`
`Data Acquisition Card
`Dynamically Linked Library
`Fluorodeoxyglucose
`Field of View
`Graphical User Interface
`Half Life
`Potassium
`Krypton
`Liquid Crystal Display
`Line of Response
`Mean Squared Error
`Magnetic Resonance Imaging
`National Instruments
`Positron Emission Tomography
`Proportional Integral Derivative
`Pulse Width Modulation
`Quality Assurance
`Rubidium
`Strontium
`Uninterruptible Power Supply
`University of Ottawa Heart Institute
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`82Rb Elution System Control
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`Ran Klein, University of Ottawa
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`List of Variables
`Dose calibrator aperture response
`a(d)
`A82Rb, A82Sr, A85Sr Activity of delivered 82Rb, 82Sr, 85Sr (MBq)
`ACal
`Activity eluted during calibration run (MBq)
`ÂBreakthrough
`Activity measured at dose calibrator for breakthrough calculation (MBq)
`ÂP(t)
`Measured activity at point P at time t (MBq)
`AP(t)
`Activity at point P at time t (MBq)
`AReq
`Requested activity (MBq)
`
`Desired activity rate at point P (MBq/s)
`PA&
`
`Desired activity rate at activity counter (also referred to as the set point) (MBq/s)
`CA&
`(t)Aˆ
`Measured activity rate at activity counter (MBq/s)
`C&
`~
`Activity rate error at activity counter (MBq/s)
`(t)A
`C&
`CC(v)
`Activity concentration vs. eluted volume