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Precise 82 Rb Infusion System For Cardiac Perfusion Measurement

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1. eee 95 Figure 5 1 Sample test case layout 0 s ccsceccsecescecnessssecosessesevssesonshenvesosbagesssshevensecuoteceesasenenedbasesancnereuveses 102 Figure 5 2 Calibration constant over the course of a generator life eee eceseeeeseceeeeceeeeceeeeeeaeeeeeneens 106 vi Rb Elution System Control Ran Klein University of Ottawa Figure 5 3 Correlation of calibration constant to generator activity ceeceecesecesecesececeseeeecseecseeeseeneeenes 107 Figure 5 4 Calculated calibration constant over the range of flow rates ec eeceseessesecneeseeeceeeeeceeerceaeenees 108 Figure 5 5 Calibration constant dependence on flow rate in the case of a high flow resistant generator EEEa oli BEA PTEE E TRN E AEA AETA LRtL Bea Toe Oh ees Se thle es LENE E Ct oy 109 Figure 5 6 Progress of accelerated self tuning of the valve response model over three successive lutions at 30 OVERS OSs daira rr steel coisas cas Nes agde cade ag ues etsy tdesbu ae AA A Biig A AE EA 111 Figure 5 7 Evolution of parameters G and L during self tuning through repeated runs of 30 relative activity over 3O Senecio iecerei ii initi ee E E lets saveddecuedecdvssssnccvesesvdeesdacsidicesseueeeedenddlecsdibeneetentivees 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 tu
2. Figure 1 3 Sr Rb decay sequence Half lives are in Rb T 1 2 76s parentheses Kr stable Sr is produced using large cyclotrons capable of creating high energy protons 80MeV for beaming on metallic Rb or RbCl solutions 14 Only a few specialized organizations such as the Los Alamos Research Labs and the TRIUMF cyclotron operated by MDS Nordion are capable of producing Sr However high yields and the long half life of PSr makes the production manageable and cost affective As a side product Sr T2 64 8 days is also produced but is not beneficial for Rb production and is difficult to separate from Sr The manufacturer includes a measure of the ratio of Sr to Sr typically 1 1 ratio with each production Rb can be supplied using a Sr Rb generator at a relatively low cost as there is no need for an onsite cyclotron The generator consists of a tin oxide SnO 2 ion separation column which strongly binds Sr isotopes The generator must be loaded roughly every two months with Strontium 82 Sr which has a half life of 25 5 days 15 As the Sr decays to Rb its chemical properties change due to the shift from a column two element to a column one element on the periodic table Rb binds to the tin oxide column much more weakly than Sr When the column is flushed with a solution such as 0 9 NaCl saline the Rb is displaced by Na sodium and the Rb is eluted in the form of RbCI elu
3. Sigmoid Scaling G The sigmoid component of the valve response model 18 was added to account for the increased slope in the low flow ratio range The input to the sigmoid is scaled using parameter G which can be tuned to control the slope of the response in the lower range Since the sigmoid function has an asymptote to 1 as the input tends to infinity the higher range of flow ratios is almost unaffected by this parameter To tune parameter G the activity rate errors corresponding to valve position in the lower flow rate region 0 lt r lt r are selected and a linear fit to the error vs flow ratio is conducted as shown in Figure 4 13 and Figure 4 14 by a solid line The slope of this line is represented by S in 29 which computes the change to the G parameter AG If the slope is negative for example the activity rate error decreases as the valve is opened This is corrected for by decreasing the scaling on the sigmoid as a result the duty cycle on the lower region of flow ratio will be decreased The goal is to have no change in activity rate error as the flow ratio is modified AG y5G S 29 The upper limit of the lower flow ratio range r is computed as the flow ratio at which the slope of the valve response model Figure 4 6 is twice the linear slope diI dr 2 L At flow ratios above this point the significance of parameter G is diminished while at the range below this point the sigmoid shape is dominant 92
4. Termination 59 Rb Elution System Control Ran Klein University of Ottawa Table 3 2 Elution parameter values for each run type Paramete Flush Calibratio Constant Constant Constant Constant Constant Constant r n Activity Time Flow Activity Time Flow Test Test Test Prime U D U D U D U D U D U D U D U D patient line Elution 00 00 U D U D U D U D U D U D Activity Elution 15 15ml min Calc Calc U D Calc Calc U D Flow Rate ml mi n Maximum 50ml 15ml 30 ml 15 ml 30 ml 30 ml 15 ml 30 ml Elution Volume Elution 200s 60s U D U D 60s U D U D 60s Time P t 00 ve Calc j Calc S Threshold 0 0 5 0 0 5 0 Activity Calg MBq s Fale MBq s Rate Overshoot 0 0 0 075 ml 0 25 ml 0 25 ml 0 075 ml 0 25 ml 0 25 ml Volume Calibrated no yes no no no yes yes yes run Calculate no yes no no no no no no Calibratio n Constant Legend Calc Calculated U D User Defined The real time sequence is based on a state machine composed of eleven discrete states Figure 3 15 not including the initialization and termination of the component The Physical_Sequence was implemented as an M file S function which is a Simulink block that is implemented in Matlab code Although execution req
5. clean 20 Rb Elution System Control Ran Klein University of Ottawa A 17 inch liquid crystal display LCD resistive touch screen was chosen 3M M S0 Large buttons as part of the graphical user interface GUI allow easy operation while a simple display allows viewing from across a room Connections to a PC through a standard VGA cable for display and a D type 9 pin RS232 serial cable for touch screen inputs Included in the package are the drivers required for manipulating the mouse cursor via the touch screen Although the screen is not waterproof it will withstand a few droplets Data Acquisition Board DAQ The National Instruments PCI 6035E data acquisition board is used to both acquire readings from sensors and control actuators National Instruments has a good reputation in the field of data acquisition and is widely supported by development platforms Both Matlab Simulink and Labview have drivers integrated into their packages without the need of further purchase The PCI 6035E boasts a variety of input and output capabilities including 8 Digital I O Channels 8 Analog Inputs 16 bit 160 kHz A D converter 2 Analog Outputs 16 bit 160 kHz D A converter 2 General Purpose 24 bit Counters Timers Flow Control Valves The flow control valves are solenoid powered pinchers that squeeze the silicon tubing to a seal They are controlled by an operating signal of 0 or 12 VDC polarity does not matter Each valve is a doub
6. of LU 2 0 20 40 60 Figure 4 15 Results from an elution in which the entire bolus activity was eluted The valve upper bound parameter Imax can be adjusted based on the region where the valve is fully opened and the correction algorithm attempts to further increase the duty cycle In this case the activity does not rise further so Imax will be slightly decreased 95 Rb Elution System Control Ran Klein University of Ottawa Valve Lower Bound II in As opposed to the other model parameters the lower bound duty cycle was found to have little significance on measured error This can be reasoned through observation that the predicted flow ratio never falls below 20 As a result modeling in the range 0 20 need not be optimized and in fact cannot be optimized since relevant data cannot be measured It was decided to avoid the automatic tuning of this parameter and fix it to zero This corresponds to zero duty cycle to achieve zero flow through the generator Summary In an effort to develop a control system capable of delivering a constant rate of activity from a Sr Rb generator various considerations had to be taken into account These include the decay of activity during transport in the lines the variation in activity concentration from the generator during an elution and the slow response in feedback especially in comparison to typical elution times These difficulties were addressed through the developm
7. Activity Time T Time Figure 3 2 Response of transport of activity through a fixed volume line at a fixed flow rate However if the flow rate is not constant computation of the delay time becomes more difficult as one must integrate the flow rate over time to determine the transport delay T For each infinitely small slice of the radioactive liquid in the line a different delay would result and therefore a different amount of decay This can be expressed in a closed form integral as in 5 which can be solved numerically based on discrete time measurements One could numerically integrate finite products of flow rate and time slice duration backwards in time until achieving the line volume The sum of the corresponding time slices would represent T v f t d de Variation of flow rate would make prediction of activity at the end of a line difficult and potentially inaccurate To avoid computational errors and increase simplicity one would like to have a constant and known flow rate throughout the entire delivery time This concept serves as the key to choosing the ideal saline hardware layout from the following possible solutions Pump Speed Variation The flow through the generator could be varied by control of the flow rate via the pump Although this would seem like a simple and effective design there are two main complications involved This would make computation and control of activity at the patient output complicated
8. S Beanlands J Vincent Manufacture of strontium 82 rubidium 82 generators and quality control of rubidium 82 chloride for myocardial perfusion imaging in patients using positron emission tomography Appl Radiat Isot Vol 50 pp 1015 1023 1999 G F Knoll Radiation detection and measurement Second Edition 1989 by John Wiley and Sons Inc ISBN 0 471 81504 7 Matlab 6 5 1 User Manual Real Time Windows Target Introduction Real Time Kernel A P Johnson M W S Macauley High precision timing within Microsoft Windows Threads scheduling and system interrupts Microprocessors and Microsystems Vol 25 No 6 pp 297 307 2001 University of Ottawa Heart Institute Investigator s Report 2003 Capintec CRC 15R User Manual Capintec Inc The American Heritage Dictionary of the English Language 3 Edition 1992 by Houghton Mifflin Company Provided through Microsoft Bookshelf 1999 T Imaizumi O Oyama Yoshimitsu T Study of pneumatic servo system employing solenoid valve instead of proportional valve by keeping the solenoid valve plunger to be floating Flucom Symposium Proceedings article 076 2000 E Kreyszig Advanced engineering mathematics 8 edition 1999 by John Wiley and Sons Inc ISBN 0 471 15496 2 K J Astrom B Wittenmark Adaptive Control ph edition Addison Wesley 1995 K S Narendra A M Annaswamy Stable Adaptive Systems Prentice Hall 19
9. Since the two photons formed during a decay are created at the same time and travel in opposite directions at the speed of light they should be detected almost simultaneously i e coincidence by detectors on opposite sides of the event If two coincident photons are detected by the scanner it can be assumed that the decay occurred along the line of response LOR connecting the two detectors These collected coincidence counts can be processed through various mathematical algorithms such as filtered back projection to reconstruct a tomographic image of the scanner field of view FOV as shown below 511keV gt y ray Coincidence gt Detector Isotope Nucleus Electron 511keV y ray Figure 1 1 Positron emission tomography The positron discharge followed by annihilation with an electron producing two collinear photons y rays on the left The projected line of response based on a detection of coincident events by the scanner is shown on the right The image is a cross section of the chest with red depicting tracer uptake in the heart muscle A transmission image is fused in gray showing the lungs and arms for anatomical reference PET tracers must be labelled with a positron emitting isotope A major advantage of PET over other molecular imaging modalities is that oxygen carbon and nitrogen which are common building blocks in organic chemistry have positron emitting isotopes with practical half lives Table 1
10. and started Once the start command is issued to the RTWT the GU Sequence terminates On completion of the real time process a termination function is called which executes the post run operations Program Hardware_Interface Result Screens Sequence GUISequence e FinalElutionScreen Physical_Sequence e Emergency Stop l e Error_screen I Sensors Actuators Legend Seauence gt Daa gt Control gt Figure 3 13 Sequence data and control flow and structure diagram of software The Hardware_Interface model consists of several layers At the lowest layer the Hardware_Interface itself communicates with the hardware sensors and actuators At the next layer the Physical_Sequence model controls the sequence of elution steps acting as a state machine At the topmost layer the Data_Log stores data from the Hardware_Interface to global variables These data are used for computations in the Physical_Sequence saving 56 Rb Elution System Control Ran Klein University of Ottawa of records to file producing elution reports as part of the post run stage and calibration of the system Figure 3 13 demonstrates the flow of control data and sequence of a full elution sequence Hardware Interface The Hardware_Interface shown in Figure 3 14 is a wrapper for the entire Simulink model which runs the real time sequence The model collects readings from the activity counter pressure sensor overflow switch and
11. operational order calibrated and meets all guidelines to ensure patient and operator safety The protocol consists of a system flush and a calibration run Although the outline remains 17 Rb Elution System Control Ran Klein University of Ottawa unchanged the protocol was slightly modified to remove operator intervention where automation was introduced The daily protocol begins with replacement of the saline supply and of the patient line and emptying of the waste container A flush run is initiated by the operator to flush and prime all lines with 0 9 NaCl saline The generator is then flushed with 50 ml saline in order to remove air bubbles and any Sr breakthrough from the system The generator is then allowed to completely recharge by stopping saline flow for at least 10 minutes A calibration run follows to recalculate the calibration constant of the activity detector and measure the activity vs volume curve of the generator Calibration is performed by eluting at a constant flow rate 15ml min over 60 seconds to an external dose calibrator which serves as a reference The activity in the dose calibrator is registered 30 minutes after the end of the elution to compute the breakthrough Sr and Sr activity Only after a calibration run with low Sr breakthrough has been successfully completed can patient elutions be carried out The calibration constant is a measure of the positron counter s efficiency and is therefor
12. performance measures may improve once a newer generator is obtained for research use Replacement of this generator was not scheduled until late January 2005 therefore this hypothesis could not be tested The life span of Sr Rb generators has been determined until now by the risk of Sr breakthrough and minimum patient activity 2000 MBq The results of Figure 5 16 pose yet another constraint on the life span of the generator the bolus width which limits the accuracy of constant activity elutions Fortunately these constraints do not contradict each other As the Sr isotopes migrate along the tin oxide column they not only increase the risk of Sr breakthrough but also make constant activity elution harder to achieve 5 8 Benefits of Rb Constant Activity Elutions Since this project was started the RbES has been used in several studies which are in their initial phase Some of the relevant initial results are included here to demonstrate the benefits of the constant activity rate Rb elutions All the studies mentioned within have been conducted with approval of the University of Ottawa Heart Institute Research Ethics Board Comparison of Rb and N ammonia for Measurement of Perfusion in 3D PET With the RbES capable of producing constant activity elutions one can address the larger issue Do constant activity elutions of Rb enable perfusion measurements with similar quality to those obtained using N ammonia Althoug
13. 0 3 4 oO 19 tb ob S 02 7 202 4 ammonia ammonia 0 1 rubidium 0 1 rubidium 0 0 0 0 5 1 1 5 0 0 5 1 1 5 Time min Time min Figure 5 17 Represantative graph of Rb and N ammonia activity concentration in the blood over time for the same patient show similar curves Left is under rest condition while Right is under dipyridamole induced stress condition The variation in blood activity vs time curve shapes using constant activity Rb is similar to intra patient variations for repeated ammonia studies The key benefit appears to be that the intra patient blood activity curve with constant activity Rb studies is less variable than with constant time elutions The reason is that the activity rate profiles using constant activity elution are similar regardless of the generator age Optimized Perfusion Measurements A second study being performed at UOHI aimed to create more controlled experimental conditions by performing the studies in dogs PET images of dogs are higher quality than those of humans as the small tissue mass introduces less attenuation and scatter The entire procedure is carried out with the dog under full anaesthesia and respiratory monitoring As with the human study perfusion scans were conducted under rest and dipyridamole induced stress condition using constant activity Rb During a rest study the activity 40 300 MBq and the duration 15 240 s of the PCC PWM elutions were varied in order to
14. 0 4 045 0 5 0 55 06 0 65 0 7 0 75 Desired Flow Ratio 40 0 Figure 5 9 Example activity rate error measurements used for valve response model parameter tuning to illustrate conflicting adjustments based on how the data are treated With this adjustment conflict in mind it is interesting to know what values parameter L would converge to with each adjustment scenario This was attempted through repeated runs of 50 relative activity over 30 s but was aborted as a second problem with the L parameter adaptation law was revealed Figure 5 10 113 Rb Elution System Control Ran Klein University of Ottawa If a high relative activity is requested the generator bolus activity may be exhausted before the end of the elution resulting in large negative error at very high valve flow ratios Adjusting parameter L based on the slope rule results in producing constant activity rate elutions with a bias This is a result of the slope rule attempting to achieve a constant level of error throughout the range of valve flow ratios Since negative errors are inevitable if the bolus activity is exhausted the end result is negative errors throughout the range of valve flow ratios Valve Response Valve Response Valve Response Valve Response 1 02 1 01 1 1 0 95 g a g 1 B 0 95 3 h i g i 3 R h 0 9 i
15. 13 ammonia J Nucl Med Vol 37 pp 1701 1712 1996 M L Beauchesne T D Ruddy R A deKemp M T Aung N Levesque T Alvarez Diez T K Vickers B A Aubrey R S B Beanlands Reproducibility of myocardial perfusion measurements with rubidium 82 PET imaging abstract Circulation 98 I 222 1998 R A deKemp T D Ruddy T Hewitt M M Dalipaj R S B Beanlands Detection of serial changes in absolute myocardial perfusion with Rb PET J Nucl Med Vol 41 pp 1426 1435 2000 R R Raylman J M Caraher G D Hutchins Sampling requirements for dynamic cardiac PET studies using image derived input functions J Nucl Med Vol 34 pp 440 447 1993 D L Bailey H Young P M Bloomfield S R Meikle D Glass M J Myers T J Spinks C C Watson P Luk A M Peters T jones ECAT ART a continuously 135 Rb Elution System Control Ran Klein University of Ottawa 29 30 31 32 33 34 39 36 37 38 39 40 rotating PET camera performance characteristics initial clinical studies and installation considerations in a nuclear medicine department Eur J Nucl Med Vol 24 1 pp 6 15 1997 Y Yano J L Cahoon T F Budinger Precision flow controlled Rb 82 generator for bolus or constant infusion studies of the heart and brain J Nucl Med Vol 22 11 pp 1006 1010 1981 T M Alvarez Diez R A deKemp R
16. 15 and 100 Hz indicate the valve flow ratio r resulting from PWM duty cycle IT As the cycling frequency is increased the valve response becomes less linear and more similar to a step function In the case of 100Hz cycling frequency the flow ratio changed from fully opened to fully close in a very small duty cycle interval less than 1 Although in 37 Imaizumi demonstrates a linear response of a solenoid valve using a transient state control these results could not be reproduced It is possible that the discrepancy in results is due to the valve s mechanics In our application the return spring applies a large force so as to pinch the tubing when no current is fed through the solenoid Imaizumi used a single pincher valve and therefore had no need for such a powerful return spring Due to this undesired response the transient control approach was not explored 77 Rb Elution System Control Ran Klein University of Ottawa further leaving the cycling valve approach as the choice alternative to emulate a variable flow valve The PWM response at 2 Hz seems to be the best choice of the set demonstrated in Figure 4 4 since it presents the mildest slope leading to the largest dynamic range of duty cycles thus small variation in duty cycle have less effect on the effective valve flow ratio However examination of the activity vs time curves at approximately 50 valve flow ratio Figure 4 5 revealed that the low cycling frequen
17. 3 ose 2 o 3 o9 Tos 0 96 0 98 0 85 0 8 0 4 0 6 0 8 1 0 4 0 6 0 8 1 03 04 05 06 07 08 0 4 0 6 0 8 Variation in Error v s Valve Flow Ratio Variation in Error v s Valve Flow Ratio Variation in Error v s Valve Flow Ratio Variation in Error v s Valve Flow Ratio 40 T FF 40 40 T Ari 20 Py i 20 20 5 l pe 20 r a l pe 1 o i o Ah T Ols op palmet Mmraap PaA O al Ba amao ER tyes t 40 i AL 0 407 AL 0 40 Aga Ma AL 0 00076225 Mo et alo 0 I AG 0 11633 Si AG 0 22759 60 bid AG 0 37729 ol AG 0 28301 0 4 0 6 0 8 1 0 4 0 6 0 8 1 03 04 05 06 07 08 0 4 0 6 0 8 Desired Flow Ratio Desired Flow Ratio Desired Flow Ratio Desired Flow Ratio Instantaneous Activity Rate at Patient Outlet I intaneous Activity Rate at Patient Outlet Instantaneous Activity Rate at Patient Outlet Instantaneous Activity Rate at Patient Outlet P 04 G04 P 08 P 08 a a a o3 RMS 49 6851 03 RMS 55 7499 o6 o6 o g o o 0 2 0 2 04 0 4 g 4 g d RMS 50 7615 0 1 S 0 1 0 2 0 2 2 6 zo 2 o o o 20 40 60 fo 10 20 30 40 5 o 20 40 60 o 20 40 60 Time s Time s Time s Time s 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 The resulting elution curves become flat but biased due to exhaustion of the generator activity This issue does not occur when the alternate mean error rule is used since the lower range w
18. A small change in duty cycle in the high range will result in a much larger change in flow ratio than in the lower range of duty cycles The scaling is performed by multiplying the correction signal from the modified PID by the differential of the valve response at the desired flow ratio dII r dr As a result when the valve is supposed to be wide open the scaling is small corresponding to the high sensitivity of the valve in this range It is important to include this scaling since without it the correction will become over amplified as the valve is opened over the course of the elution 88 Rb Elution System Control Ran Klein University of Ottawa Initial Error Removal Simulations of constant activity elutions with slight shifts in the predicted volume eluted through the generator Figure 4 12 revealed that the first few seconds of the elution are most susceptible to prediction errors In cases where all the activity from the generator must be eluted to reach the requested dose these initial errors must be tolerated However in cases where a much lower dose is requested the initial errors can be avoided by diverting the elution to the waste container The initial error removal mechanism IERM waits for the activity rate to reach a threshold level 90 of the desired activity rate then begins a time delay of Tiem Once Tierm has elapsed the elution is routed to the patient rather than the waste Constant Activity Hution with
19. Analysis of Tuned Valve Response c cccscesssesscesseeseesseeeeceecnsecnsecaecnaeceaecaeecaeecaeeeaeeeeeeeseaeeeseeeneterenatens 114 5 6 Elution Tests xiii cise tet htn een eat ee eared aah cn Se ee 116 Range of Relative Activities as a Function of Elution Duration cc cceeeseesceeceeseecneeeeceseeeeesecaeeeeeneeeres 120 5 7 Generator Life Sp nn nieri eiiie kiii i ii EE AEE i E ie a E iiis 121 Breakthrough Sr Activity 2c 24 a eek oe a eo hae ne ee ek ee TEE 122 AGV CURVES ara e Hoe ae ah i ee ek aR ee A ee ee 123 5 8 Benefits of Rb Constant Activity El0tions cccccccscsssssssesssssssesssssssessesssscsssssssssssevsssessessesessessesesseess 124 Comparison of Rb and N ammonia for Measurement of Perfusion in 3D PET c ccscsscescesseeseseeeees 124 Optimized Perfusion Measurements ssi iniiai rearen A R E R E E AER EE 126 5 9 Critical Analysis and Future Workin iohieierinieio Shek wien A E E wiacikes 127 Chapter 6 Conclusion ia cicccs cecccecicsccceccacs ccesccecs ceding E ii E E ie EE E eee 130 EROA AE A E ice E E E A E E E E EEEE TE 133 Appendix As Test O A A E T A E E 137 Rb Elution System Control Ran Klein University of Ottawa Table of Figures Figure 1 1 Positron emission tomography cccceescescesscesscesecesecenecseecseecaeeeseeeeesceeeenseeaeeaeenaeeeaeceeeneeeneenes 5 Figure 1 2 Rb uptake images for measurement of myocardial perfusion c sscssssssessesssessess
20. Digital Output2 National Instruments L PCI 6035E auto Pulse Signal Tracing Trigger Generator1 gt ValveVibratorDriver Figure 3 14 The Hardware_Interface model 57 Rb Elution System Control Ran Klein University of Ottawa The DAQ general counter 1 GPCTR1 is configured to accumulate on each input rise This input is connected to the activity counter through TTL over coax cable Over a typical elution the 24 bit counter can easily overflow leading to data errors To avoid this problem it is desirable to reset the counter after each reading by the software a feature that is not supported by the Simulink drivers In the prototype system this issue was elegantly solved by connecting the counter external reset to a digital output on the DAQ The Hardware Interface periodically resets the counter in synch with reading of the counter value Other sensors are straightforward to interface the pressure sensor is read by an A D converter and the overflow switch is a binary input The pressure and counter readings are both conditioned through an averaging filter This is achieved through a simple delay line and averaging of all the readings over the past second Since each is read at 20 samples per second the averaging is over 20 samples The pressure sensor readings are converted to PSI units through multiplication by a calibration constant determined to be 580 through empirical calibration with an external gauge Recali
21. Elution System Control Ran Klein University of Ottawa Table 5 5 and Figure 5 12 compare the activity rate RMS error and the elution time error over the range of relative activities The requested elution time is typically achieved using HC TC but fluctuations cause a gt 40 RMS error The PCC PWM control significantly reduces the RMS error over most of the range of relative activities except in at the upper extreme of generator activity 70 relative activity Table 5 5 Comparison of Performance measures for HC TC and PCC PWM 30 s Elutions n 10 Requested RMS Error SD Elution Time Error SD Modeling Accuracy SD Dose HC TC PCC P value HC TC PCC P value HC TC P value relative activity i Elution Time Error Comparison RMS Comparison Time p Error m PCC PWM 10 0 5 0 0 0 oH eh i 709 5 0 l l 10 0 10 30 50 70 Relative Activit Relative Activity lative ACHVIY Figure 5 12 Comparison of performance measures of elutions n 10 over 30 s at 10 30 50 and 70 relative activity The root mean square RMS activity rate error shown on left is an indication of instantaneous precision while the elution time error on the right is an indication of global precision The activity rate is measured at the activity counter and is used to predict the activity rate at the patient outlet To ensure that this
22. M C Chul K S Park Localization of epileptogenic zones in F 18 FDG brain PET of patients with temporal lobe epilepsy using artificial neural network IEEE Trans on Med Imag Vol 19 No 4 Apr pp 347 355 2000 C K Yen Y Yano T F Budinger R P Friedland S E Derenzo R H Huesman H A O Brien Brain tumor evaluation using Rb 82 and positron emission tomography J Nucl Med 23 6 pp 532 537 1982 T Jones Clinical Uses of Sr Rb Generators Appl Radiat and Isot Vol 38 No 3 pp 171 173 1987 R D Finn D J Schyler Production of Radionuclides for PET Principals and Practice of Positron Emission Tomography Lippincott Williams and Wilkins p1 15 2002 M A Green The potential for generator based PET perfusion tracers J Nucl Med Vol 31 10 pp 1641 1645 1999 M R Cackette T J Ruth J S Vincent 82Sr production from metallic Rb targets and development of an Rb generator system Appl Radiat Isot Vol 44 No 6 pp 917 922 1993 Y Yano T F Budinger G Chiange H A O Brien P M Grant Evaluation and application of alumina based Rb 82 generators charged with high levels of Sr 82 85 J Nucl Med Vol 20 pp 961 966 1979 Y Yano Essentials of a Rubidium 82 generator for nuclear medicine Appl Radiat Isot Vol 38 No 3 pp 205 211 1987 V Dhawan Model for 82Sr 82Rb generator elution profiles A second a
23. Response The valve response is important for achieving good flow ratio control Although the collected data demonstrated in Figure 4 4 can be used to calculate the duty cycle needed to achieve the desired valve flow ratio this would entail measuring of the exact valve response of each system In addition recalibration of the response due to changing dynamics of the valves would involve a long and complicated process Developing a model of the response with few free parameters would allow tuning of the valve response more easily For flow control we show the response graph Figure 4 4 with swapped axes Figure 4 6 as we wish to set the duty cycle to achieve a desired valve flow ratio Valve Response Uyaive 5 Hz 0 98 0 97 0 96 0 95 0 94 0 93 0 2 0 4 0 6 0 8 1 Valve Flow Ratio r Figure 4 6 Valve response V aiye 5 Hz with the swapped axes allows determination of the duty cycle needed to achieve a desired valve flow ratio Measured response solid and model dashed fitted in the useful range 20 100 with model parameters I 9 0 997 I min 0 L 0 004 and G 16 A few models were considered leading to a combination sigmoid and linear function 18 The sigmoid accounts for the response in the lower flow ratio range 0 50 while a line models the mild slope in the higher range 50 100 Equation 18 converts the desired valve flow ratio r to valve duty cycle II
24. TE 70 Chapter 4 Elution Profile Controls asi nieras ne r e a a hans EE EE EA EARE SESAR SiS 71 4 1 Threshold Comparison Algorithm with Auto tuning Hysteresis Correction HC TO s esesseessseeessee 73 4 2 Marable Elow omtroll aaae aaae naaa aaa Aa e dup vapid a AEEA sd AAE aOR fens AEAN OSEERE EATER 74 Cycling Valve Control PASEA E E E E E T AEE EA 74 MELTA oaro REEE E E A TA 74 Implementation of the Variable Flow Control eeesesessesessseeeesseseeseseesessrereseesessteresseseseserseeseenessesressesees 75 Valve Response Measurements cccccccesscessesscesscescesecesecaecseecseecseeeneeeaeseeeeeeseeeseenaeeeaeeaecaecnsecaeeaeeenes 76 Modeling of Valve Response cccsccessesssesssesscesrceescesccesecesecssecsaecaeecseeeaeeeseseesseeeseenseceseseeeeenseecaecaeeeaeeenes 79 PWM Valve Tite Spann ssc sie cecssaccbee E cadidecaccesce E A E E E 80 4 3 Variable Flow Control Al gorithms ccccesccesessseesseeseeeseeeeeeeeesecnsecaeesaecnaecaaecaeeeaeeeeeeeeeeesenesneeeseeaees 81 PID Ont ol aise ses iden n eed esc A EEE E A obo babes E bys 82 Forgetful PID Controlletsscscs tee sos E EE E oak ed ebs ce Redd i ade ges seein ede eds 85 Predictive Control EEEE EAA E E E E disables Sovoaban teaese E loletuetys 85 Predictive Cortective Control cgrciec sds niesienia i ai TE E E a E ds 88 Initial Error Removals iiien inie EEE bag deen Paitin AER RER E Ria 89 Setting the Saline Flow Rates iccc c cc csc ccieleccsshevcecteesi
25. Volume Prediction Shift of 0 1 ml 1 5 44 4 Activity Rate Q5heedsskenyssssnsas i 1 L 0 5 10 15 Ee Activity Rate Ob banean ee WS nGceSusneasnsae5s Activity Rate T i 1 1 1 1 1 O55 E foe ee eee dy nepeoepep ene pecorino 1 5 10 15 Volume mi Figure 4 12 Simulation of perfect control with erroneous activity concentration prediction due to a slight volume shift 0 1 ml If the predicted eluted volume is less than the actual eluted volume top a peak of activity is expected A slow rise is expected if the predicted volume is too large bottom The middle curve shows perfect alignment Truncating the first few seconds of an elution should remove the largest prediction error regions Tiem is calculated depending on the relative activity of the elution For relative activities less than 10 the delay is set to 10 s For relative activities above 70 no delay is 89 Rb Elution System Control Ran Klein University of Ottawa used Intermediate relative activities are assigned a delay through linear interpolation between these limits The end result is a truncation of initial errors to improve the elution profile significantly but without affecting the range of activities that can be eluted from the generator Setting the Saline Flow Rate In order to minimize sensitivity to flow ratio error one would
26. actual calibration constant for successive runs K 0 9K 0 1 K 9 Breakthrough Activity Measurement The dose calibrator is used to detect the breakthrough activity as part of the calibration test through measurement of Rb activity Once elution to a vial is complete a high proportion of Rb isotopes are present This activity decays exponentially over time After ten minutes approximately 0 42 of the activity should remain in the vial However as 50 Rb Elution System Control Ran Klein University of Ottawa time progresses an asymptotic equilibrium of activity that is greater than zero may result due to the contribution of amp Rb isotopes from amp 5Sr decay in the vial p y The Sr solution that is loaded onto the generator column is composed of mostly Sr but also contains a large amount of Sr The manufacturer provides the ratio of Sr to Sr in the sample as was measured in the factory so The half lives of Sr and Sr are 25 5 and 64 8 days respectively allowing calculation of their ratios s t at the elapsed time t since measurement by the manufacturer using 10 In 2 t 25 5 _ In 2 t 1 64 8 1 25 5 s t s eo in 2 t 64 8 Age ao The breakthrough of each isotope As2sr As2rb and Agsssr As2rb is calculated as a relative activity ratio of Sr activity to Rb activity delivered as demonstrated in 11 below a A preakthrough dos 1404880 Asse _ gy 4 1 Ty 825r Ay rp Ag
27. as the exact time delay to the outlet must be solved based on the varying flow rate 5 This is further complicated by the chosen pump module Harvard Apparatus model 66 peristaltic pump which does not support changing of flow rate on the fly A stop command must be issued and a new start command must follow resulting in finite and varying pauses in the flow 40 Rb Elution System Control Ran Klein University of Ottawa Bypass Ratio Control The above problems can be resolved by setting a constant flow rate at the start of the elution process and controlling the ratio of the saline that flows through the generator point G in Figure 3 3 The remaining portion of the saline would flow through the generator bypass line The two lines would then be merged point M upstream from the activity counter point C Thus the flow in the combined line remains constant This allows computing of the transport delay from the counter to the patient outlet point O The flow rate only varies in the line volume connecting the generator to the merger Vom based on flow ratio r In order to reduce the variability in transport delay and decay this line volume must be kept to a minimum Ratio 1 r F I l switch pwitch PointG PointM PointC Point P Point O Generator Merging Activity Patient Waste Patient Output Stopcock Counter Valve Outlet EF Figure 3 3 Flow control through generator using a bypass line maintains a const
28. calibration constant over the range of flow rates The same test was repeated with a second generator this time revealing a different trend in results as shown in Figure 5 5 As the flow rate increased the calibration constant decreased almost linearly Further investigation revealed that the line pressure was increasing linearly with the flow rate up to 20 ml min at which point it saturated 10 25 psi compared with 7 15 psi in the previous generator This high pressure was due to saline flow resistance imposed by the second generator This resistance generated a high pressure resulting in backwash through the peristaltic pump head leading to a flow rate lower than expected If calibration constants were corrected for the measured flow rate measured through the saline volume in the vial the calibration constant would have varied less with flow rate demonstrated by the dashed line in Figure 5 5 However the flow rate cannot be measured with the current hardware The high flow resistance introduced by the second generator is due to the tin oxide packing of the generator column during production Tin oxide comes in a powder form and is filtered twice to exclude particles outside a specific size range The filtered powder is then packed to remove large air pockets If the packing is too tight or the size of powder grains is too small one can expect restricted saline flow through the column Once the generator has been loaded with Sr and released for
29. clinical use the flow resistance does not seem to change over time 108 Rb Elution System Control Ran Klein University of Ottawa x10 Calibration Constant vs Flow Rate high flow resistance eo e 8 3 56 oe 4 E 3 e p g 2 54 4 N J l tap Measured Calibration Constant J 1L Corrected Calibration Constant 5 0 54 4 Oo I ji 0 5 10 15 20 25 30 Flow Rate mM min Figure 5 5 Calibration constant dependence on flow rate for generator column with high flow resistance Variation in elution characteristics including flow resistance is expected between generator models In this study two generators of the same model were used Both were custom made at UOHI 30 It is expected that a single generator model be used in any single facility in order to promote reliability and inter changeability To address backwash through the pump head resulting from increased flow resistance two courses are suggested for future work It is preferable for future applications that flow resistance be tested after the building of the column and before loading of Sr to ensure that the saline pressure at the generator input remains below 20 psi at flow rates in the range of 5 25 ml min In addition it is suggested that the pump head rotor be replaced with a model that can sustain higher back pressure without backwash Summary of Calibration Analysis The calibration results helped
30. conflicting parameter adjustments 112 Rb Elution System Control Ran Klein University of Ottawa One reason for the conflicting L parameter adjustments is the two different scenarios through which this parameter may be adjusted To illustrate this Figure 5 9 bottom shows an example activity rate error vs desired flow ratio Since more than 4 data points exist for the higher flow ratio region r lt r lt 1 parameter L is adjusted based on the slope of the line fit to this region dotted line referred to as slope rule As the slope is negative in this case the adjustment of L is positive 0 00021 However if less activity was requested less than 4 data points might be measured in the higher flow ratio region and the mean error in the lower flow ratio region r lt r would be used to adjust L referred to as a mean error rule Since the mean error is clearly negative the slope would be decreased to increase the duty cycle in this range Figure 5 9 top shows the valve response that corresponds to the range of desired flow ratios that were used during the elution and the cut off between the lower and higher range of the response r Valve Response o for Duty Cycle gt S o 4 0 25 0 3 0 35 04 045 05 055 0 6 065 07 0 75 Variation in error v s the valve ratio 0 High threshold adjestment 0 Linear Slope Adjustment 0 00021072 Sigmoid Scaling adjestment 0 050531 4 25 0 3 0 35
31. demonstrate that the RbES using PCC PWM can dramatically improve the precision of constant activity elutions over HC TC if the valve response model 130 Rb Elution System Control Ran Klein University of Ottawa is properly tuned This is noted in the reduction of RMS error as well as in reduction of performance variability as the requested elution parameters change However this work does not clearly determine if the proposed self tuning algorithm is reliably effective during routine clinical use A clinical setting entails routine use of the system as desired by the clinical application and does not include ad hoc training sessions intended for tuning of the valve response model In this work the training sessions span the entire dynamic range of achievable relative activities forcing the self tuning algorithm to converge to global nominal values without biasing towards a specific range of relative activities The risk of biasing the model parameters is very real in a clinical setting as repeated elutions within a limited relative activity range are likely Future work should focus on assessing long term reliability of the current implementation In particular the focus should be on the performance of the self tuning algorithm proposed in this work as well as potential alternatives In addition the sigmoid linear model used to describe the valve response may prove to be overly complicated with too many degrees of freedom However the
32. error reported and no user intervention N 65 Rb Elution System Control Ran Klein University of Ottawa The error flag may receive two identifiers relating to user intervention Error flag code 1 negative one relates to termination and exiting of the software by the operator The software will abort the elution set all actuators to their safe mode and display the exit screen Error flag code 2 negative two corresponds to the user pressing the emergency stop button during an elution The program will likewise terminate and set the actuators to their safe modes and finally present a yellow screen indicating the operator has terminated the elution Pressure Errors Pressure errors are included only for cases when the pressure rises above a threshold 20 PSI 138 kPa for a prolonged period of time over 3 seconds High pressure is an indication of a blockage or pinched line and could result in backwash through the pump head or rupturing of the saline lines When backwash occurs the effective flow rate is lower than expected introducing error to the transport delay and control algorithms Each pressure measurement at the physical sequence level corresponds to an average of 20 hardware readings over the previous one second This mechanism is included to reduce the effect of outliers which could lead to false error detection An appropriate message is generated based on the state of the valves at the time of error detec
33. factors that contribute to its efficiency Not all positrons in the FOV are captured by the scintillator and not all the tubing cross section is necessarily in the FOV The dose calibrator is composed of an ionization chamber that is sensitive to ionizing radiation in the form of high energy photons Although shielding from external radiation is included in the design and is typically added in the form of lead rings radiation from the surroundings is also detected to varying degrees The exact region of measurement of the dose calibrator is unknown and dependent on its geometry Measurements are taken not only of the contents in the vial but also of a portion of the line leading to the vial The exact portion of the line that is measured by the calibrator cannot be easily determined theoretically Empirically the transport delay from the activity counter to the calibrator can be determined through shifting of the measurements for optimal alignment 46 Rb Elution System Control Ran Klein University of Ottawa Figure 3 7 Dose calibrator chamber measurement diagram The integral activity curve referring to the dose at the patient outlet Ao t can be obtained by convolving the instantaneous count rate from the activity counter N t with the Rb decay curve e The convolution function accounts for the accumulation in the vial and simultaneous Rb decay The transport delay between the activity counter and the patie
34. have a favourable effect on quantitative perfusion measurement using PET Preliminary studies at UOHI in a dog demonstrate that similar measurements are obtained regardless of the amount of tracer activity and elution duration in this mode In a second experiment comparing N ammonia and Rb as perfusion tracers in humans both introduced at constant activity rates preliminary results indicate that there is no significant difference in quantitative perfusion measurements obtained using either tracer If these results are confirmed through future work constant activity Rb elutions may serve as a cost effective alternative to N ammonia for quantitative perfusion measurement using PET which could offer cheaper state of the art diagnosis to a wider population 132 Rb Elution System Control Ran Klein University of Ottawa List of References 1 S R Bergmann B E Sobel Positron Emission Tomography of the Heart Futura Publishing Inc 1992 2 L Koike M Ohmura M Hata N Takahashi T Oka I Ogino J Lee T Umezawa K Kinbara K Watai Y Ozawa T Inoue FDG PET scanning after radiation can predict tumor regrowth three months later Int J of Radiation Oncology Biology Physics Vol 57 No 5 p 1231 1238 2003 3 J N Talbot Y Petegnief K Kerrou F Montravers D Grahek N Younsi Positron emission tomography with F FDG in oncology Nucl Inst and Meth in Phys Res Section A Acce
35. in less delay and dispersion of the solution as it travels through a smaller volume to the generator outlet These curves follow the model described by 1 but the model parameters vary with time or total eluted volume Normalized activity curves at various ages of generator 16 01 2004 1 2 30 01 2004 13 02 2004 27 02 2004 07 03 2004 05 04 2004 29 04 2004 14 05 2004 01 06 2004 16 06 2004 29 06 2004 D 08 i H RX SN 13 07 2004 5 WOK 30 07 2004 5 SN 17 08 2004 z Hh RAK ON 31 08 2004 I Iran 18 10 2004 g 0 6 l GI N i 01 11 2004 D TAO x 15 11 2004 01 12 2004 g 13 12 2004 04 o Z l 0 2 f 0 BPA Lo J 1 0 10 20 30 40 50 60 Time s Figure 5 16 Normalized activity rate vs time curves measured during calibration runs over the life span of a generator The significance of these results is that the prediction mechanism is expected to perform better with a new generator than with an old one In the case of an old generator a 123 Rb Elution System Control Ran Klein University of Ottawa small error in the volume through the generator will manifest itself as a large error in the predicted activity concentration and therefore a larger error in the predicted valve flow ratio Since all of the constant activity elution measurements in this work were performed within the last two months of the generator on the research system it is expected that the elution
36. like to use a large range of the valve flow ratios during any given elution In addition one would like to avoid using extreme flow ratios as the valve may saturate Finally the lower range of flow ratios is less sensitive to control error and is therefore the preferred range to use Since the effective activity rate is a product of activity concentration valve flow ratio and saline flow rate the range of flow ratios that will be used during an elution is directly influenced by the saline flow rate The flow rate must be set at the beginning of an elution based on the desired activity rate in relation to the generator activity referred to as relative activity rate o min When conducting a low relative activity elution a low flow rate is desired so that the flow ratios used during the elution are not near the lower saturation point On the other hand the flow rate should not be too low as to avoid long transport delay and Rb decay When conducting high relative activity elutions higher flow rates are desirable so that the generator bolus activity is eluted and minimal Rb decay occurs en route the patient The reproducible flow rates in the Rb elution system are in the range of 5 25ml min At the lower limit 5 ml min flow rates were used for 20 min relative activity rate elutions corresponding to 10 relative activity over 30 s At the upper limit 25ml min flow rate is used for 140 min relative activity rate elutions correspondin
37. 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 gt 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 Rb generator cardiac perfusion positron emission tomography PET predictive control iii Rb Elution System Control Ran Klein University of Ottawa Table of Contents Gredits Aah bicta esa Ma teredad ee ete dees eed oe ered Ret Detach Mera att a tide dale beret Regt eats hd ii Apra i O l a a e a a aaa Miss loud a a a ites RE AE a e etiaes iii able of Contents aisa derea e r EA r E E T ao a E a eee iv Table of Figutess e ated heii E ee Ree a e AA Re e vi Table of Tables maien nii i N ee REA R A ARE RREA e viii IEO a eKO 1h a EAE E E E A E A E EE A E ix Cistof Vara DES aa dee ead a et ata deca ai ate aes le ta A a x Introduction remti stele EE E E AERE OE EIRE EA AE EE EEEO A E Oa 1 Chapter 1 Introduction to Molecular Imaging and Dynamic PET ssssssssssssesssesersrsseessssreresseseesresesseserseeseese 4 1 1 Positr
38. need for a valve response model and self tuning algorithm may be completely avoided by seeking or developing a more suitable flow ratio control mechanism For example a new valve may be found with linear response If it is also fast acting simple to integrate and cost effective the problem can be significantly simplified For this reason it is the recommendation of the author that a first step to future improvement be research into a possible replacement for the generator valve that exhibits faster transition response than the current model Additional work should concentrate of preparing the system for distribution to external facilities by improving robustness and protection of intellectual property This would include transporting the software to a proven real time operating system in place of Microsoft Windows 98 In addition the software should be compiled to binary code which would both hide the source code and simplify the system Byte code would eliminate the use of both the virtual machine and interpreter in the current application thus reducing the consumption of computer resources and potentially improving the robustness of the system In contrast the current market does not seem to justify the development of new hardware components confirming the decision to utilize off the shelf components 131 Rb Elution System Control Ran Klein University of Ottawa Current theories suggest that constant activity elutions may indeed
39. plastic lid covers the lines to reduce positron exposure Finally the LCD touch screen was mounted on an adjustable support arm so that the operators can adjust its angle for ideal height and visibility Bicron BCF 10 blue scintillator optimized for diameters gt 250um Both the CRC 15R and CRC 15PET models were tested and used during this research 23 Rb Elution System Control Ran Klein University of Ottawa LCD Touch Screen Dose Calibrator Interface Dose Calibrator Ionization Chamber High Density Plastic Lid Waste Container Shielded Generator Personal Computer Patient Linc High Density Plastic Lid Peristalti Generator eristaltic Salve pump Head Figure 2 4 Photograph of top cover of the Rb elution system 24 Rb Elution System Control Ran Klein University of Ottawa The PC printer and power isolation transformer were mounted on the lower tray An interface box was constructed for mounting below the top cover and included the pump interface board valve driver circuitry and DAQ I O connector block Finally the waste container was mounted on the top shelf inside a lead container with a lid 2 3 Prototype Performance In 18 Epstien et al presented initial results with the RbES The reported results include simulation data as well as elution measurements Elutions in the range of 10 70 generator bolus activity
40. practice the dynamics of the system are not expected to change very quickly and therefore some robustness can be maintained using small learning coefficients as demonstrated in chapter 4 In order to assess the stability and robustness of the self tuning algorithm both analytical and empirical analyses were performed The first was included in the design process and is described in the previous chapter At the characterization stage the performance of the self tuning algorithm was assessed by monitoring the elution profiles and the associated model parameters In order to speed up the tuning process for demonstration purposes the learning parameters YL ys and yr listed in 29 30 and 31 respectively were increased by an order of magnitude X10 Figure 5 6 shows the activity rate vs time bottom and error vs valve flow ratio top for three successive elutions 30 relative activity over 30 s The linear slope and sigmoid scaling are adjusted based on the lower range of valve duty cycle r lt r As the parameters converge their adjustments decrease in magnitude The improvement in precision can be both noticed visually as a decrease in error slope and by the gradual decrease in root mean square RMS elution error from 24 5 to 14 7 110 Rb Elution System Control Ran Klein University of Ottawa Variation in Error v s Valve Flow Ratio Var
41. prediction is accurate a comparison with the dose calibrator was made and a modeling accuracy factor Table 5 5 was calculated for each relative activity relating to flow rates 5 25 ml min The modeling accuracy was calculated as the ratio between the integrated rate of activity based on both activity counter and dose calibrator readings 34 demonstrated by Figure 5 13 The activity counter readings were corrected for transport delay to the patient outlet while the calibrator readings were 118 Rb Elution System Control Ran Klein University of Ottawa deconvolved with the Rb decay curve to convert accumulated activity readings to activity rate measurements Ideally the area ratio should be equal to 1 indicating perfect modeling As Table 5 5 shows using both HC TC and PCC PWM resulted in model accuracy 1 throughout the entire range of relative activities with a significant improvement with PCC PWM in the 10 30 relative activity range The PCC PWM results indicate modeling error that is typically less than 10 with a slight underestimation of activity at the patient outlet in the 30 50 relative activity range Aca t edt Neu t T Teo T K f e ecoa dt corr Instantaneous Activity at Patient Outlet Model Accuracy 34 T g l i Detector Delayed Sp Calibrator Deconolved i 2p 2 20 0 Time s Figure 5 13 Activity rate at patient outlet cal
42. rate from the generator decreases 119 Rb Elution System Control Ran Klein University of Ottawa below the set point as the bolus of activity is exhausted This is seen in the decrease of activity rate in the final 5 s of the elution in the mentioned figure Since the generator valve is already fully opened at this point nothing more can be done to increase the activity rate These reasons combine to set the upper limit of relative activity that can be expected from a constant activity elution At 70 relative activity the mean elution time error achieved by PCC PWM is less than with HC TC p 0 002 However the variability of elution time error is similar for both control modes p gt 0 45 for 10 30 70 with exception of 50 relative activity p 0 022 At 70 relative activity PCC PWM seems to experience more variability in the elution time error compared to lower relative activity elutions This is partially due to late registration of the activity rise phenomenon as discussed above Due to the higher saline flow rate gt 20 ml min used in high relative activity rate elutions a fast rise of activity over time results as the bolus is flushed from the generator Detection of a rise in activity is needed to synchronize the prediction algorithm with the actual eluted volume by solving for V If this rise is not sampled early enough for the prediction algorithm to take effect an initial overshoot results which will lead to early
43. run but include data collection from the dose calibrator A data analysis follows the elution by producing activity rate and integral activity graphs as is done with calibration runs A correspondence between the sets of theoretical and measured curves is the ultimate indication of accurate modeling of the system If the curves agree it can be deduced that the model of the system reliably determines the activity profile injected to the patient Elution tests can be treated as a cross between a calibration run and a patient elution Data collection from the dose calibrator and analysis reports are identical to calibration however the calibration constant is not recalculated The elution sequence dictated by the elution parameters should be identical to regular patient elutions 52 Rb Elution System Control Ran Klein University of Ottawa 3 5 Software Design A complete run sequence is composed of three main stages pre run real time sequence and post run The real time sequence stage was the main focus of the development and therefore will be covered in greater detail while the other two stages will be briefly explained and demonstrated Pre Run Stage and the GUI Sequence The pre run stage is controlled by the GU Sequence function which runs through a series of steps to interact with the user and collect relevant information to initiate the elution The only interaction with external hardware is to test communication and s
44. set point and the actual output Properly tuned the controller will affect the plant actuators to reduce the output error over time The proportional factor serves to quickly adjust the actuator based on current errors If the proportional gain is too small the error will decrease slowly however if it is too large overshoots can occur leading to oscillations around the set point The integral component serves to reduce steady state errors and speed up the reduction of error The derivative component serves to reduce overshoot due to over correction by the controller Refer to Figure 4 8 for an example of these affects 82 Rb Elution System Control Ran Klein University of Ottawa Control Input Desired Output Output 4 Desired me C PE DEO if Edr Output fee e set point ETA Steady state error gt Time Figure 4 8 Affects of PID controller parameters on system response In the case of the RbES building of a state space model is complicated by the changing feedback delay for different flow rates Even if this were accomplished a linear PID type controller cannot model and therefore correct for a pure feedback delay 38 39 40 In addition the activity curve continuously changes making a pure feedback control system inadequate as it will always lag in response These assumptions were confirmed through a series of simulations of a PID feedback loop controlling the flow ratio ide
45. to patient line patient is Else Slow Drip flushed to the Bypass to patient Patient Slow Drip A slow drip to Continue button is Threshold Calibration Cumulative Bypass to the patient line pressed activity or flush run Time Waiting Patient until the exists Else Cumulative continue button Activity is pressed Waiting Else Waiting for Threshold Waiting for Elutes from Threshold activity Calibration or flush run Cumulative Threshold generator to rate is reached Time Waiting waste until the Else elution or test Cumulative threshold Activity activity is Waiting reached or the Threshold not reached timed out Error is set time has Termination expired follows Cumulative Elute activity Requested time has passed Bypass Patient 63 Rb Elution System Control Ran Klein University of Ottawa Time Waiting from the Flush generator for a given time Cumulative Elute the Requested dose reached Bypass Patient Activity activity until the Flush Waiting required dose is Requested dose not reached timed out Error is set reached or time Termination expires follows Bypass to Flush the Enough time has Flush or patient run Exit Patient Flush remaining elapsed to flush activity in the activity from lines Else calibration or elution Extra line to the test Calibrator patient Data Extra Gather Enough measurement Calibration run Wait for Calibrator additional
46. to the merge using an additional activity counter however this has the drawback of increased cost and complexity to the system and the need to know the exact flow ratio set by the generator valve An alternative approach capitalizes on the fact that the activity concentration is almost entirely dependent on the volume eluted from the generator If one knows the exact volume that was eluted through the generator and the time delay to the merging point M one can estimate the activity concentration just upstream to the merge Cy t The main advantage of this alternative is that no hardware modifications such as addition of another positron detector are required The predicted valve ratio r t can be computed based on the predicted activity concentration just upstream from the merger Cy and the set point A 23 Since the prediction is for point M and the set point is calculated for point C one must account for the decay during transport Dmc The activity concentration Cy is converted from activity concentration MBq ml to activity rate MBq s by factoring the flow ml s A r t 23 Duc f Cy The activity rate at the activity counter is equal after a transport delay Tmc to the activity rate at the merger ee decayed during transport by Dmc 24 The rate of activity at the merger ae is a product of the actual activity concentration Cy and the flow rate through the generator path f it Ac t T
47. up front Although many considerations should be taken into account a few dominant aspects made this choice clear We were looking for a simple and mature operating system which would be compatible with all our hardware and provide many services so as to reduce the development time In addition we wanted to work with a flexible environment 36 Rb Elution System Control Ran Klein University of Ottawa which would allow future development as needed Finally the realization that a familiar environment would eliminate the initial learning curve brought forth the decision to use a Microsoft Windows operating system to complement the PC platform Debate over the development environment RT Rational Rose National Instruments LabView and Matlab Simulink was easily resolved based on our extensive experience with Matlab and the wide features it supports The development environment of choice was Matlab with a real time windows target for Simulink Simulink allows drawing real time applications through an extremely high level language of connecting blocks Combined with the optional real time windows target RTWT one can compile the program to executable code for optimized performance Matlab is a high level interpreter language that provides powerful mathematical and graphical tools The computational overhead incurred with an interpreter language could potentially be overcome by later compiling the scripts into stand alone executable programs
48. using an optional package To compile the Simulink models to executable code a supported C compiler must be provided The Watcom C compiler is an accepted and proven compiler that is available without charge In addition this compiler is continually being developed and is supported by Matlab The RTWT runs as a CPU ring zero application same privileges as the operating system OS kernel and is driven by the PC hardware clock for accurate timing The RTWT is triggered by a hardware timed interrupt and handles the application before triggering the OS kernel As a result compiled applications are guaranteed execution in a real time fashion with the highest processing priority possible 32 However higher level services such as graphics rendering and higher level interpreters are still provided by the operating system A debate over which Windows version to use arose within our group On the one hand we had a long and relatively good experience with Windows 98 However this operating system suffers from a reputation of being unstable and having poor real time capabilities Due to licensing issues our alternative was windows 2000 which is based on NT technology and is supposed to address the above mentioned concerns After experimenting with both operating systems and an ongoing correspondence with Mathworks technical support team we concluded that Matlab RTWT had a compatibility issue with 37 Rb Elution System Control Ran
49. vials must be changed between elutions which cannot be automated without the use of elaborate manipulators Considering these complications and that the entire system could be tested within two work days it did not seem worthwhile to set up an automated testing environment The tests were organized in a MS Access database for easier management and editing Each of the 49 tests was classified under one of three groups as shown in Table 5 2 The cases are implemented in such a manner so as to test as many software branches as possible in order to shorten testing time An example case is included in Figure 5 1 while the complete test list is included in Appendix A Table 5 2 Test classification codes and their descriptions Test Code Test Type Description E Error Handling Tests relating to error detection handling and reporting mechanisms F Functionality Tests relating to the functioning of the application such as functionality of elutions and functions triggered by user input U User Interface Tests relating to the user interface such as handling of invalid inputs operation University of Ottawa Heart Institute Rb Rubidium Chloride Injection Investigator Brochure 101 Rb Elution System Control Ran Klein University of Ottawa estName 3a Dump Stalled Fault Des cription est that a pump stall is detected and reported correctly Start any operation Once the real
50. was estimated as the interval between initial rise and peak activity A series of calibration elutions was conducted for each cycling frequency with the duty cycle II varied to sample the dynamic range of the response as shown in Figure 4 3 for cycling at 15 Hz The calibration runs were identical to a regular calibration run 15 ml min saline flow rate except that the generator valve was set to cycle at a given frequency and duty cycle rather than remaining fully opened In addition the elution was performed over 120 s instead of the standard 60 s so as to measure the longer rise times The rise time for each elution was measured as the interval between initial rise and peak activity The rise 76 Rb Elution System Control Ran Klein University of Ottawa time of a regular calibration run duty cycle set to 100 was used as the reference to which all other rise times were compared The ratio of rise time for a given duty cycle and the reference rise time indicates the effective ratio of saline that flows through the generator referred to as valve flow ratio r The valve flow ratio vs duty cycle curves for the set of cycling frequencies were plotted in Figure 4 4 The inverse of these curves allow one to determine the duty cycle needed to achieve an effective flow ratio Comparison of Valve Response to Vyaive Figure 4 4 Valve response curves at Vyaive 2 5
51. 1 These isotopes give the potential to synthesize almost any organic compound as a PET tracer Rb Elution System Control Ran Klein University of Ottawa Various tracers have been developed to image different organs and tissue Increased glucose consumption for example is used for detection of cancerous tumours 2 3 4 and distinguishing between hibernating live and necrotic dead tissue in the heart using Fluorodeoxyglucose FDG 5 6 7 In neuroscience FDG has been used to locate hypoactive and hyperactive regions in the brain to diagnose disease such as epilepsy 8 9 Another application used PET imaging to asses the integrity of the blood brain barrier 10 using Rb as a tracer Table 1 1 Commonly Used Positron Emitting Isotopes 1 Isotope Half Life T12 min Mean distance to annihilation mm Cyclotron O oxygen 15 2 1 1 1 Produced PN nitrogen 13 10 0 0 72 1C carbon 11 20 3 0 56 ISE fluorine 18 110 0 35 Generator Rb rubidium 82 1 27 2 4 Produced Ga gallium 62 67 8 1 1 Blood flow perfusion studies are of interest in cardiac medicine as they can indicate vascular stenosis a clogging of the arteries due to plaque build up that restricts the flow of blood Perfusion measurement can be achieved by introducing a cationic tracer that is similar analogous to potassium K All living cells have mechanisms that extract potassium through the cell membran
52. 30 during a 30 relative activity over 30 s relative activity over 30 s The start point is the training session The grey lines define the manual fit of the curve while the stop point was region of model parameter variation over 17 determined when change to the parameters was subsequent elutions relatively small n 87 The above training process involved 87 repeated elutions which in a typical clinical setting would require several weeks to complete Although a clinical system is not expected to be in a parameter state that is so far from the nominal values this slow learning indicates that the self tuning algorithm will be very slow to accommodate changes in the system The system learning parameters yg and yg can be increased in order to speed up the learning process suggested values could be 0 1 and 0 05 respectively Variation in Valve Model Parameters with Requested Elution Parameters In the above training set the parameters are optimized for the specific requested profile 30 relative activity over 30 s It is expected that these parameters should remain valid over other profiles as well different durations and relative activities but in practice this may not be true as the self tuning mechanism corrects for measured activity rate errors regardless of what their source is Over a set of elutions with variable relative activities this suspicion was confirmed in the sense that changing the relative activity seemed to result in
53. 89 136 Rb Elution System Control Ran Klein University of Ottawa Appendix A Test Cases Merge into here the report from the TestList Database 137
54. A field evaluation for electro medical equipment results fortwo RDES SVStEMs ES E EE EROE S E E E E TEE 99 Table 5 2 Test classification codes and their descriptions eessssesssssesessesseeeessrserssestseestesessteressesesseeeessese 101 Table 5 3 List of global structures and their contents cccccsceesseeceeseeseeeseeeecesecesecesecaecaecseecaeecseceeeneeeaes 105 Table 5 4 Typical constant activity elution profiles for various relative activities and over 30 s 06 117 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 Rb and N ammonia perfusion measurements 125 Table 5 7 Rest study results comparing perfusion measurements in a dog at varied Rb constant activity elution time durations and activities show that similar results are obtained regardless of these elution Parameterss 2c E E EE SESE ee ihsateseees dali ger EA area athe 127 vill Rb Elution System Control Ran Klein University of Ottawa List of Acronyms DAQ Data Acquisition Card DLL Dynamically Linked Library FDG Fluorodeoxyglucose FOV Field of View GUI Graphical User Interface HL Half Life K Potassium Kr Krypton LCD Liquid Crystal Display LOR Line of Response MSE Mean Squared Error MRI Magnetic Resonance Imaging NI National Instruments PET Positron Emission Tomography PID Proportional Inte
55. A A ER 123 Figure 5 17 Example of Rb and N ammonia blood curves scsscssessessessesseesessecscssscsesssssessesesseeseesesees 126 vii Rb Elution System Control Ran Klein University of Ottawa Table of Tables Table 1 1 Commonly Used Positron Emitting Isotopes 1 cccceccesseesseesseeseeeeeeeeeeeeenseeeseeeaeeaeceecseeeaeeeneeees 6 Table 2 1 Minimum PC Requirements 0 cccecccecscesscsssceseceseeecesecesecaecnaecsaecseeeaeeeseeeeeeeeeeeeseeeneeeeeeeenaeenaes 20 Table 3 1 Software Environment ecenin iii o E e EE E EAEE E Ea 38 Table 3 2 Elution parameter values for each run type ssssesssssersssseeeesseseessesersreseesesersrsseenesseeressesessesersesses 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 eccececesecesececeeseeeseeeneeseeeeceeenseceeeeeceeeeaeeeeceaeeeeeeneeses 63 Table 3 4 Detectable errors and their corresponding flags ccccesecsseesseesecseeeseeeseeeeeeeeeeeeeseenseenseenaeenseenaes 65 Table 4 1 Comparison of elution time accuracy using the threshold comparison algorithm with HC TC and without hysteresis correction esanei r e EE N AE O E E RR EEA 74 Table 4 2 Parameters used by the prediction algorithm s sssssesssesssssseserssseeeesstsressesetsrsseenesseeressenesseeseesesses 92 Table 5 1 Canadian Standards Association CS
56. I _10mi min Figure 1 5 15mi mi i somvmin Representative 25min generator activity volume curves with different flow rates at different times 20 from reference Activity MBq ml a N S eet an Sere eee 1 1 il 1 L 10 12 14 16 Volume ml 1 4 Constant Activity Elution for Quantitative Perfusion Measurement in the Left Ventricle of the Heart Diagnosis of cardiac patients and optimization of their treatment is highly dependent on the measurement of perfusion in the left ventricle LV heart muscle As demonstrated in Figure 1 2 the uptake images of a potassium analogue radioisotope can be used to assess perfusion However these images only indicate the relative perfusion with the region of highest uptake serving as the baseline to which all other regions are compared The baseline Rb Elution System Control Ran Klein University of Ottawa is assumed to be a region with normal healthy perfusion Therefore a uniform uptake image is interpreted as a healthy subject In some cases such as diabetes or multi vessel coronary artery disease the uptake may be reduced throughout the entire LV thus resulting in uniform images These cases can be misdiagnosed as healthy when in fact they experience a global reduction in perfusion 21 To address this issue the need for quantitative perfusion measurements has arisen By dividing the imaging time into frames one can image the tra
57. I slot In order to power the buffer board a 12VDC power cord was spliced from the floppy drive power cable Table 2 1 lists the specifications of the PC that was installed A mini tower case was selected due to the physical restrictions of the cart Table 2 1 Minimum PC Requirements Component Specification CPU Intel Pentium HI 1200 MHz RAM 256 MB Hard Drive 40 GB CD ROM Drive 1 USB Ports 4 RS232 Serial Ports 1 2 added with a PCI interface board Case Mini tower PCI slots 2 serial port and data acquisition board Power Supply 350 W An important advantage of using a PC to control the system is the wide range of applications and devices that are readily supported This included off the shelf user interface devices as well as machine interfaces and data acquisition devices In addition a wide range of operating systems and development environments could be chosen from Simply said PCs offer a good performance to price ratio in a flexible package User Interface Medium The user interface was designed to meet the following requirements e Interface with the user must to be simple and intuitive e The technologists must be able to monitor the progress of the elution even from a distance so as to reduce radiation exposure e The technologist must be able to operate the system with a single gloved hand e The input device must be resistant to small amounts of liquid and easy to
58. Klein University of Ottawa Windows 2000 It was finally decided to continue the development in a Windows 98 environment with the hope that the application would later be compatible with other operating systems Windows 98 was designed as a general purpose operating system that shares resources including processor time amongst all running tasks As a consequence it does not meet the requirements of a real time operating system in which tasks are handled with tight time constraints 33 However this is not a limitation in our case as the RTWT operates as a second kernel parallel to that of the operating system and is triggered directly by hardware events As a result the real time model is handled by a real time kernel while higher level services are handled in a less timely constrained fashion by the operating system During the development cycle Matlab and Simulink were used as a development environment The Simulink model was compiled to run on the RTWT The remaining components were implemented in Matlab including the interface and high level control of the real time functionality In this manner the real time components were guaranteed proper time management while the less critical higher layers could be developed with less consideration for system resources Table 3 1 Software Environment Software Type Company and Product Components and Version Operating System Microsoft Windows 98 Windows 98 SE Developm
59. PRECISE RB INFUSION SYSTEM FOR CARDIAC PERFUSION MEASUREMENT USING 3D POSITRON EMISSION TOMOGRAPHY by Ran Klein B A Sc A thesis submitted to the Faculty of Graduate and Postdoctoral Studies in partial fulfillment of the requirements for the degree of Master of Applied Science in Electrical and Computer Engineering Ottawa Carleton Institute for Electrical and Computer Engineering School of Information Technology and Engineering Electrical amp Computer Engineering Faculty of Engineering University of Ottawa February 2005 2005 Ran Klein Ottawa Canada Rb Elution System Control 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 Rb Elution System Control 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 Rb can be produced cost effectively by eluting a Sr Rb 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
60. Rb Elution System Control Ran Klein University of Ottawa Valve Response D N 0 98 Duty Cycle M 0 96 0 25 0 3 0 35 0 4 0 45 0 5 0 55 0 6 Variation in Error v s Valve Flow Ratio 0 65 Error Su 0 3 0 35 0 4 0 45 0 5 0 55 0 6 Desired Flow Ratio r Figure 4 13 Analyzed errors of a constant activity elution with flow ratios spanning a large range The slope of the error points relating to the valve flow ratio lower range r lt r S is used to adjust parameter G while the slope of the error points relating to the higher valve flow ration range 1r lt r lt 0 95 Sy is used to adjust parameter L Valve Response 3 O 95 rt gt Q 0 9 4 0 2 0 25 0 3 0 35 0 4 0 45 0 5 Variation in Error v s Valve Flow Ratio 20 J 3K Sw ae e k O g a 20 E 40 0 2 0 25 0 3 0 35 0 4 0 45 0 5 Desired Flow Ratio r Figure 4 14 Analyzed errors of a constant activity elution with flow ratios in the lower range Parameter G is tuned based on S in the same manner as elutions that span into the higher valve flow ratio range The mean error across all points associated with r lt r EL is used to adjust parameter L 93 Rb Elution System Control Ran Klein University of Ottawa Linear Slope L The linear slope is corrected in one of two ways based on the available data If sufficient error measurements are available for
61. Software Desig Moena r O E E codon ease O E E E A E 53 Pre Run Stageand the GUI Sequin erenn oe O ER EO EE 53 POStERUM Slap Siei enee aaO EERE E AEE OIER E EEEE EREE S 55 Reals Times quence e oe a A O E iinet O eee ec O R O E 56 Physical Seguente nrerin a E E O bea E oe cee 58 3 6 Errot DetectiOh areire ioeo E E Eee E NEEESE EON EN A E E REE i 64 Pressure EOTS isci eoor isee teoriiesri troion een aE E EAE EEEE EIEEE EE E E 66 Pump Communication and Operation ErTorsS ssesseeeeesseseeseeseeseesesresetstssteressrsresreseesteseeressreeessesesesesseeees 66 COMPULET RESOULCES sissccsscccecctocsdeseneys oE iE E AE EAE EAE E E E EE E E 67 Positron Detector Err Orsi c esctays secssehsedsiess eas heptevtantsed a a a ete esaea Sri 67 Rb Elution System Control Ran Klein University of Ottawa Dose Calibrator Communication Errors ccsccessesscesecesecseescecseecseeeseeeseeseeecesseesseenseeaecsenaeeneenaeeneeenes 67 Mathtenaiices AAL T EAE P ETETE E EAN B RAEI EE ET E EEE 67 SOft ware E H ROI Te e222 E PEE E OAE AE ERAR EE E E AE E 68 DOET nT a VE es os E E A AA R E EET E A E EET AA E E eee 68 Outlier Highlighting AA E O EE T Site cade a eats ood saa ce tetacts Ses 68 37 System REMMEMENE x scsoccef ef A odes A A A E A AE 69 Dose Calibrator Spike Removal Al gorithim cccceccesccsseesseesceseecseeeseeeseeseeeeeeeesseenseenseeeaeenaecaeceeeneeenes 69 EEE S0011 0V1 DERA EEEE E A bu cu veh sasegiae Be odtbeds A E AE RIE E E E E
62. The 79 Rb Elution System Control Ran Klein University of Ottawa parameters F G O and L can be tuned to fit the measured response Parameter G scales the sigmoid to match the lower ratio range while the slope L accounts for the slope of the higher ratio range Parameters F and O can be computed through 19 and 20 respectively based on the maximum and minimum effective duty cycles max and Imin The consideration for using Imax and Imin is to use measures that have physically significant meaning upper and lower saturation duty cycles respectively l e F Max T nin L 19 e 0 5 O T rin F 2 20 The measured data reveals that at duty cycles higher than Imax 0 997 the valve is effectively fully open to flow through the generator upper saturation point Similarly at duty cycles below Imin 0 25 the valve is effectively closed lower saturation point A manual model fit of the curve was estimated with Imax 0 997 Tmin 0 L 0 004 and G 16 and plotted with dashed lines in Figure 4 6 The useful range of valve flow ratios 20 100 is well represented by the sigmoid linear model where the sigmoid accounts for the knee shape of the response curve and the line models the higher range 50 100 The extremely low response range r lt 20 is not used and was ignored during the fit Modification of the free parameters of the model allows improving the fit in one region potentially at the expense of other r
63. aborted by the user using the Emergency Stop button in which case an appropriate message screen should be displayed In the case of a successful run the information presented to the user will vary based on the run type Figure 3 12f With the exception of daily flush runs a view toggle button is presented on the bottom bar which enables to toggle between text results and a graphical report Figure 3 12g Two graphs are included of the instantaneous activity rate at the patient outlet and of the integral activity at the patient outlet as discussed in the calibration section 55 Rb Elution System Control Ran Klein University of Ottawa If the termination of the real time sequence was a result of an error or an emergency stop a window coloured red Figure 3 12a or yellow respectively is displayed Error messages are as specific as possible given the available information The messages include a description of the error and suggestions on how to resolve the issue After the post run message has been displayed to the user the option of restarting the program is displayed The program is completely restarted after each run through a call back function which clears the entire workspace and restarts the software for the next operation Real Time Sequence The real time process is started by confirming the elution settings by the user The Hardware _ Interface model is loaded to the RTWT initialized with all the relevant parameters
64. acesce ca ee E A E E E E E 90 Automatic Parameter TUNDE issnin isi iiini EEE EEEE E ii 91 SUMMIT t AONA EAEE N E AAE O E O EE 96 Chapter 5 Testing and Characterization c cesccssccssesesececeesseeseesseesceesccnseceseeeeensecaeceaecnaecaaecaeseseseneeneeensenes 98 Dall Safety Vestn EEEE E E E ER IAE E E 98 hes WOrst AO Ii oa Eea O AAEE EE E E ER EE EA EE ET 99 oA E E CASCS A EET ST E E T E E E E E E T Weer Interface KA a A A E A A E E io ocszehstie BO Functional Testing Error Handling Testing 53 Testing in a Routine Clinical Setting cccccc cc cccccccccecccc ci ceseesevesecs see cancecdeccadedcecsteudevsuedecesseesdeeducessedeacedGeevece 103 Computer Crash ISsire meneceri ieir seii Ei E EEE Soy deessedecdu ceeded ducdaesete casa EE is 104 54 Calibration Characterization c cccsccccccss ceccescucciecacusctccieesevesaceseecancacdeccsdedcucsteudcesdededeeceesecduaveiessteedeeesece 106 Calibration Constant vs Flow Rate cccecccessessscesecesecesecscecaeeeneceseeseceeeeseeesecseceaeceaecnaecaeeeaeeeaeeseeeaeeeneeaes 107 Summary of Calibration Amalysis s c cc ccccccscccacescecsecescecencedcvcsececdesctceceecadctcescedsaceedasdecesdaddnesededstseteedeeceese 109 5 5 Analysis of the Self Tuning Model ccceeccecscesscesecesecssecseecsecenecaeeeseeeseeeeeseeeeeneeenseenaeeaeceaeeaenaeenaes 110 Variation in Valve Model Parameters with Requested Elution Parameters cscccsccsceesteeseeteeteeeeeees 112
65. activity at the dose calibrator after calibration The bottom graph shows the actual and estimated activity rate at the activity counter The cyan line refers to the beginning of elution threshold activity OMBq s is passed The red line indicates the end of the elution generator valve is closed while the black line indicates the overshoot volume that is flushed to the calibrator 48 Rb Elution System Control Ran Klein University of Ottawa The calibration process was validated over various flow rates and showed close correlation of the integral activity curves However at low flow rates larger variations were noticed This is partially explained by the aperture response of the dose calibrator demonstrated in Figure 3 7 As activity enters the aperture the sensitivity increases The shape of the response is unknown but was estimated to be Gaussian at the edges as demonstrated by Figure 3 9b The prototype system assumed the aperture to be a step response to the line distance Figure 3 9a Once the activity is in the chamber the sensitivity is highest and is assumed equal throughout The undetermined distance that relates to the region of full sensitivity is depicted by the flat portion of Figure 3 9a and right and is accounted for by solving for a b Full Sensitivity Sensitivity Sensitivity 17 chamber Gaussian yee response at edge of aperture 0 Distance from vial 0 Distance from vial along saline line along saline lin
66. akthrough activity measurement remained a manual function e The interface lacked sufficient real time feedback to the technologists about the state of the system e Although the electronic reports and logs of the elutions were mature a paper report which is needed to be filed in patient charts was not available 26 Rb Elution System Control Ran Klein University of Ottawa e The system contained no measures to avoid electrical ground leakage This issue had to be addressed especially since the cart is made of stainless steel contains electrical equipment and connects to the patient with saline which is conductive e No protection against overflow of the waste container was implemented in the prototype system If overflow was to occur this could potentially lead to damaging of the system components or developing of a shock and fire hazard The hardware design of the prototype system addressed many of the prototype system requirements and could therefore be used as a platform for further work The software on the other hand was in an incomplete state with many requirements left unaddressed The prototype system served as a starting point from which the state of the art could be understood and as a reference to which future developments could be compared The remainder of this document describes the research development and testing that was carried out to bring the system from a prototype stage to a mature system full
67. al valve response The transport volume from the valve to the activity counter was set to 0 13 ml and the controller rate was set to 20 Hz which are characteristic values The PID parameters were tuned through trial and error Parameter D was always set to zero PI controller since it resulted in amplified activity fluctuations Three sample results are included in Figure 4 9 83 Rb Elution System Control Ran Klein University of Ottawa Constant Activity Elution with PID Control 70 R Act over 30 s 9 0 04 T T T T T T T v P 0 2 D oosl S e ee eass 004 gt l D E Oe ere res ha po alee fies Jare E E E E S EE EE E S 5 0 5 10 15 20 25 30 35 40 Time s po Constant Activity Elution with PID Control 30 R Act over 30 s 5 0 02 T T T T T T T T v i aea a eef ee ee STE 2 oe i l gt 5 I 0 0017143 gO Da aa ial E mene ee ee a ee ee j 1 4 4 5 0 5 10 15 20 25 30 35 40 45 Time s 9 6 T T T T T 5 P 0 005 0 0007 D 4p D 077 gt ae i es ee ae 2L ee eer es ae ee ae betel a g i o 0 10 20 30 40 50 60 Figure 4 9 Sample simulation results of a PID controlled elution with an activity transport delay from the valve to the activity counter 0 3 ml and a high controller refresh r
68. ant flow rate through the other lines M O Variation in flow rate is only in section G M As a result of the layout an overshoot of activity may be expected due to the volume between point M and point C If the elution is terminated based on accumulated activity measured by the activity counter this overshoot of activity must be taken into account Therefore the stopping threshold should be reduced to the requested dose minus the expected overshoot The overshoot of activity can be derived from the activity curve measured during the day s calibration run and is dependent on the eluted volume and the overshoot volume Vac The ratio between the two lines can be controlled through various valve types Variable Pinch Valve It is expected that with a variable pinch valve an exact flow ratio through the generator can be controlled Ideally this would allow absolute control of the amount of activity that can be extracted from the generator Similar to Kirchhoff s law in electricity the 41 Rb Elution System Control Ran Klein University of Ottawa pinch on one line increases the resistance thus forcing more current through the alternative route Various implementations of such valves exist A common valve implementation includes a stepping motor coupled to a screw thread which moves the pinchers In order to vary the pinch to a large extent the motor must be rotated over many steps This results in a long response time In add
69. apart On each occasion either a N ammonia or Rb constant activity using HC TC perfusion scan was conducted under rest and stress condition In total four scans were performed on each patient with 220 MBq introduced over 30 s The studies were performed with a Siemens CTI ART 3D scanner using a dynamic protocol with time frames as shown in Table 5 6 The N ammonia acquisition was over a longer time since the slower decay permits longer uptake measurements Table 5 6 Dynamic scan time frame durations for Rb and N ammonia perfusion measurements Rb dynamic scan time frames N ammonia dynamic scan time frames 12x 10s 12x 10s 2x 30s 2x 30s 1x 60s 1x 60s 1x 120s 1x 120s 1x 240s 1x 240s 2x 300s Total Scan Time 10 min 20 min Figure 5 17 gives results from a representative study showing a comparison of blood activity vs time curves under both rest left and stress right conditions The curves are shift corrected to minimize the mean squared error and are corrected for the activity decay of each tracer In addition the curves are normalized by the peak activity The blood curves in this case are similar in shape and magnitude 125 Rb Elution System Control Ran Klein University of Ottawa i Rest Study j Stress Study 0 9 0 9 sn 0 8 ors 3 3 0 7 70 7 a m Q 0 6 N06 z 5 a 0 5 RMS 0 38482 0 5 RMS 0 53891 O O O 8 0 4 D 0 4 pei 5 J HM 03 4
70. assess the variation in perfusion measurements If the tracer kinetic model is accurate one would expect similar perfusion measurements 126 Rb Elution System Control Ran Klein University of Ottawa regardless of these parameters The results in Table 5 7 confirm this expectation as the standard deviation in perfusion measurements average across entire LV is 8 1 These results are well within range of typical test retest variability 15 using constant time elutions Variable Activity time 30 s Variable Time Activity 150 MBq Activity Relative Median Perfusion ml min g Time s Median Perfusion ml min g MBq Activity n 2x576 n 2x576 40 9 1 0 57 15 0 68 75 17 0 0 60 30 0 63 150 34 0 0 64 60 0 60 300 68 0 0 64 120 0 59 240 0 67 Table 5 7 Rest study results comparing perfusion measurements in a dog at varied Rb constant activity elution time durations and activities show that similar results are obtained regardless of these elution parameters 5 9 Critical Analysis and Future work Although experience with the system instilled confidence in its design the self tuning algorithm seems to be the potential weak point in the entire PCC PWM control concept The main concern is that repeated elutions at a given relative activity rate may result in model parameters that are not suited to other relative activity rates While there is no evidence to suggest t
71. ate For this reason the generator is referred to as an ion exchange column Various vendors Bracco 2004 formerly Squibb and research teams have manufactured Sr Rb generators that are all similar in design A shielding casing made of depleted uranium TRIUMF 1993 lead Bracco 2004 or tungsten is used to absorb Rb Elution System Control Ran Klein University of Ottawa radiation produced by decay in the generator thus reducing exposure to patients and personnel During loading Sr and Sr impurity is pumped into the column through the input line resulting in binding of most of the Sr within the first few mm of the tin oxide column After numerous quality assurance tests of the eluate for pyrogens sterility and metal breakthrough the generator can be used clinically In addition these runs ensure that the Rb yield is sufficiently high Once the Sr decays to levels that cannot yield sufficient amounts of Rb the generator must be reloaded or replaced A typical life span of a generator is 1 2 months and is primarily determined by the amount of Sr that was loaded and the Rb activity required for imaging The activity is often measured compared to the generator production capability If a complete generator flush will yield 2000 MBq and an injected activity of 500 MBq is desired one would refer to 25 relative activity Over time the relative activity needed for imaging will increase as the ge
72. ate 20 Hz Even in the best case scenario the simulations demonstrate some shortcomings of using a PID controller The activity curves vary throughout the elution due to lagging behind the change in activity concentration This is especially noticeable in the 10 relative activity elution bottom where delay is longest due to the slow saline flow rate In all the cases overshoot is noticeable in the first few seconds of the elution as the activity concentration changes fastest in the early bolus volume Testing of this implementation on the system revealed far worse results probably due to poor modeling of the valve response at the time slower controller refresh rates and random noise in the feedback 84 Rb Elution System Control Ran Klein University of Ottawa Forgetful PID Controller One of the drawbacks of a conventional PID is that noise in the error measurements can result in large changes in the control signal Since noise is characterized by fast changes in measurements it is mostly amplified by the differential component and the proportional component It is common to set the differential gain to zero in order to reduce the effect of noise but the proportional component cannot be removed as the resulting controller will become very slow The conventional PID controller was modified to create a forgetful PID controller by converting the proportional gain into a forgetful integral with a forgetting factor as is sh
73. bration after 1 year showed no significant change in this calibration constant Physical Sequence All the elution types comprising the daily protocol are composed of similar physical steps as shown in Figure 3 15 A single physical sequence that is controlled by the parameters of each elution is desirable The parameters in Table 3 2 dictate the physical sequence of the elution 58 Rb Elution System Control Ran Klein University of Ottawa Patient Elution Initialization Calibration Initialization Wait for Pump Start Option Prime Patient Prime Patient Line Prime Patient Line Prime Patient Line Cumulative Time Waiting Bypass to Patient Flush Slow Drip Bypass to Patient Start Elution Waiting for Threshold Slow Drip Bypass to Patient Start Elution Cumulative Time Waiting Termination Cumulative Activity Waiting Bypass to Patient Flush Bypass to Patient Flush Extra Calibrator Data Wait for Breakthrough Reading Termination Termination Figure 3 15 Flow Chart for all elution types The similarity in form justifies the implementation of a single physical sequence state machine Test Elution Initialization Wait for Pump Flush Bypass to Option Prime Patient Prime Patient Line Slow Drip Bypass to Patient Start Elution Waiting for Threshold Cumulative Activity Waiting Bypass to Patient Flush Extra Calibrator Data
74. cer distribution as a function of time This is referred to as dynamic imaging and enables to measure the rates at which a process of interest develops In the case of quantitative perfusion measurement dynamic images can be used to capture the rate of tracer uptake from the blood into the myocardium A tracer kinetic model is fit to this uptake rate in order to estimate perfusion in absolute units ml min g 22 Figure 1 6 Series of dynamic Rb images of a dog heart Just after injection Rb is in the RV blood pool F3 F4 Subsequent images show the LV F4 F5 and the LV blood pool F5 F6 dispersion through the body F7 F11 and the resulting retention in the heart muscle F12 F17 with most of the activity in the LV horseshoe shape To demonstrate this idea a study on a dog performed at the University of Ottawa Heart Institute UOHI using a Rb dynamic PET scan is shown in Figure 1 6 A series of sequential images non uniform time frames shows the tracer entering the right ventricle 12 Rb Elution System Control Ran Klein University of Ottawa blood pool RV F3 The activity is then carried through the right atrium to the lungs and back to the left ventricle LV The LV blood pool is visible in the next frame F6 followed by dispersion in the body and myocardial uptake and clearing of the blood pool F7 10 Once much of the activity has been removed from the blood pool the retained activity is left visible i
75. ckground that would be detected by the PET scanner The operator entered a desired activity dose and elution time which the system used to estimate an elution flow rate for the peristaltic pump The activity vs volume curve recorded during the daily calibration run Figure 1 5 was integrated to determine the volume that needs to be eluted from the generator in order to achieve the requested activity dose The flow rate was determined by factoring this volume by the requested elution time Feedback from the positron counter was used to stop the elution when the activity was reached These elutions are referred to as constant time elutions 16 Rb Elution System Control Ran Klein University of Ottawa The Rb infuser was based on an industrial PC running MS DOS coupled to a LCD touch screen The software ensured that the daily protocol discussed below is followed and generated a recording of each elution In addition some rudimentary error detection was included The system contained all the necessary components in a single cart but had to be calibrated manually at a single flow rate same flow rate as the elutions that would follow by monitoring an external dose calibrator during the calibration run The system was used in a routine clinical setting over 3 years however it proved difficult to upgrade to include new functionality In 18 Epstein et al 2004 simulated a feedback controlled system that varied the ratio of flow bet
76. containing a high concentration of the tracer radiate strongly contrasting with the surroundings A scanner that measures the radiation from the patient can reconstruct tomographic images through the region of interest The concentration of activity is dependent on the interaction of the tracer within the body and is therefore indicative of a corresponding biochemical and physiological processes within the body in contrast to anatomical images produced by modalities such as conventional x ray computed tomography CT and magnetic resonance imaging MRI 1 1 Positron Emission Tomography Positron Emission Tomography PET is the leading nuclear imaging modality in terms of precision and ability to make quantitative measurements The radioactive label is an isotope that decays by positron emission In the nucleus a proton is converted into a neutron Rb Elution System Control Ran Klein University of Ottawa and excess positive charge is ejected in the form of a positron positively charged electron The positron travels a few mm through the surrounding medium and eventually interacts with an electron resulting in a mutual annihilation The combined mass of the electron and positron is converted into two equal energy 511keV collinear photons These high energy photons travel through the body and can be detected by dense scintillating crystals coupled to photomultiplier tubes A typical PET scanner consists of planar rings of detectors
77. corrective algorithm will attempt to further increase the duty cycle beyond Imax up to duty cycle H 1 If Tmax is set too low the activity rate may increase while the correction algorithm increases the duty cycle Otherwise further correction will not result in an increased activity rate The following algorithm is used to adjust Tmax e Keep all the data past the minimum flow ratio avoid confusion with early part of elution e Keep all the data where predicted flow ratio was one keep only the saturated region at the end of the elution 94 Rb Elution System Control Ran Klein University of Ottawa e If the remaining data set is empty do not change Imax as there is no relevant data A Tmax 0 e Otherwise keep only the data relating to rise of activity up to the maximum point o If the remaining data contains more than one data point use the slope of a linear fit of the error vs correction Ss Factor for the change in correction during this time interval Ac using 31 A Thnax z yr Ss 1 Hmax JAG 31 o Otherwise decrease the saturation point slightly A Imax 10 52 o 6 Sx Ps oO 0 0 20 40 60 80 100 5 gt gt x pPeeedoewae eS HB 2 9 2 2 oe ee ow ew oO we wemew we wm eww ewe ew wm ew www ew ew ww ew ew ew ew ewe 0 l 3 0 20 40 60 80 100 3 c x10 O 5p i ee QEV TO 5 gt O MG 20 40 60 2 ro
78. ctive and non harmful Figure 1 3 When a patient is at rest approximately 50 of the Rb is taken up from arterial blood into myocardial tissues over the course of a single blood cycle through the tissue Observation of Rb uptake enables the assessment of myocardial perfusion In 1989 the United States Food and Drug Administration FDA approved the use of rubidium 82 chloride RbCI from a Sr Rb generator system developed by Squibb Diagnostics for clinical use 12 13 The relatively short half life of Rb 76 seconds is both an advantage and a disadvantage The fast decay means a short exposure time for the patient which thus minimizes the health risks involved with radiation exposure In addition repeated scans can be carried out after only 10 minutes as almost no radiation remains from the previous dose Rb Elution System Control Ran Klein University of Ottawa On the other hand the fast decay shortens the maximum scan time and thus reduces the quality of the scans An added difficulty is that the Rb must be produced on site and directly infused into the patient 14 Rb is the product of Sr decay In this context Sr is referred to as the parent isotope while Rb is referred to as the daughter isotope For this application it implies that a batch of Sr can be used to continuously generate Rb activity As Rb decays into stable 8 Kr the decay process ends as is demonstrated by Figure 1 3 Sr Ty 25 5d
79. culated based on the activity counter readings blue and dose calibrator readings red The ratio of integral activity over the elution time black lines is used to assess the accuracy in predicting activity rate at the patient outlet based on activity counter readings The high RMS error of the PCC PWM control at 70 relative activity is partly a result of the initial overshoot which is not discarded as with lower relative activity elutions The initial activity portion cannot be removed as the generator activity will be insufficient to achieve the requested activity without it The source of this overshoot is an initial rise in activity at high flow rates that is too fast for the system to respond to The magnitude of the peak varies significantly based on whether the rise of activity is sampled early enough to afford the prediction algorithm time to respond In most cases the rise is not sampled early enough leading to an overshoot in activity rate of approximately 100 over approximately 2 s as is shown in the lower right figure in Table 5 4 Over a 30 s elution a 100 initial overshoot over 2 s would result in a 26 RMS error even if no additional error is experienced over the remaining 28 s of the elution However the integrator component of the corrective mechanism attempts to correct for this overshoot by reducing the activity rate over the remainder of the elution resulting in an even higher RMS error To make matters worse the activity
80. cy introduces substantial fluctuations in activity These fluctuations are greatly reduced with the cycling frequency increased to 5 Hz while the response remains manageable At 15 Hz cycling frequency the response is a very steep slope throughout the entire dynamic range meaning that small errors in duty cycle II will result in very large errors in the valve flow ratio r Activity curves at various valve cycling frequencies Valve flow ratio 50 1 2 15 Hz 1 E 5 Hz gt 2 Hz 08 O lt x 8 0 6 N wT E 0 4 O Z 0 2 0 i li l 0 20 40 60 80 100 120 Time s Figure 4 5 Elutions at valve flow ratio 50 produced by cycling the generator valve at 2 5 and 15 Hz and corresponding II from Figure 4 4 The activity vs time measurements with valve cycling frequency set to 2 Hz reveal that the low cycling frequency introduces measurable fluctuations in activity With all the above issues considered it was determined that a cycling frequency of 5 Hz provided a balance between smooth activity vs time curves and a manageable valve flow ratio response curve Over the flow ratio range of 0 30 the slope is mildest making it the most favourable working range while the 30 100 range should be avoided due to the sharp response slope however this is not always possible if one wants to elute high relative activities 78 Rb Elution System Control Ran Klein University of Ottawa Modeling of Valve
81. d Valve How Ratio r Figure 5 11 Valve response correction curve used to determine the PWM duty cycle DC required to achieve a desired valve flow ratio The measured curve shown in heavy line is followed more closely by the manually estimated fit dotted line than by the automatically tuned fit dashed line The discrepancy between the self tuned valve response and the measured response is partially due to the self tuning algorithm adjusting the valve response parameters to decrease the overall activity rate errors These errors are not caused solely by modeling of the valve response but also through imperfect system modeling prediction of activity concentration and possibly other unknown factors The self tuned valve response by its nature will try to correct for these error sources A potential limitation in the design of the self tuning algorithm is that the error analysis does not take into account that errors in the valve response also contribute to activity concentration prediction errors Even if the system model and prediction algorithm were perfect errors in the valve response model would lead to erroneous prediction of the effective volume through the generator leading to a false activity concentration prediction Cm As a result activity concentration errors may accumulate as the elution progresses It is 115 Rb Elution System Control Ran Klein University of Ottawa the role of the corrective algorithm to c
82. d enough flexibility to continue development of the control system at a later stage and with no significant change to the existing infrastructure Both the Hardware Interface and Physical_Sequence models allowed for modification as necessary while maintaining the software design The development of the constant activity control is described in the following chapter 70 Rb Elution System Control Ran Klein University of Ottawa Chapter 4 Elution Profile Control The primary motivation for developing the second generation Rb elution system RbES was to introduce the tracer to the patient at a fixed rate of activity measured in MBaq s over a prescribed time period When plotting the activity rate over time in this context referred to as an elution profile a rectangular curve is desired As with any control system the goal is to achieve output behaviour as close as possible to a desired profile In the case of a constant output one can compute a set point detector count rate that corresponds to an ideal output One must then attempt to minimize the deviation between this set point and actual output Typically output error is kept to a minimum by including feedback mechanisms which the control algorithm manipulates to control the actuators A generator bypass line was already included in the first generation Rb elution system to permit flushing of activity to the patient outlet at the end of an elution The valve in place was a t
83. data time has elapsed Breakthrough Data from dose Reading calibrator for Else Exit convolution comparison Wait for Wait for decay Enough time has elapsed or user has aborted Exit Breakthrough to read measurement Reading breakthrough from dose calibrator Exit Dummy State Physical_Sequ indicating that ence sequence was termination gracefully function completed The Output is implemented using an identical switch case statement determining the operations during the current state However there are additional functions that are carried out regardless of the current state One such task is error detection which is carried out through a series of tests on the input data Another common task is data logging implemented by Data Log function which is enabled once actual elution from the generator is started Finally the real time system diagram is updated by rewriting the current measurements and calculations to the GUI fields 3 6 Error Detection A variety of error detection mechanisms have been included in the software to handle hardware malfunctions as well as software errors Error trapping is included in all phases of the program and leads to immediate termination of an elution with an error message which guides the operator towards resolution of the error Table 3 4 lists the errors that the system may detect and their corresponding internal error flag At the beginning of the application the 64 Rb Elution Sys
84. e Figure 3 9 Aperture response of the dose calibrator as a function of distance along the saline line from the vial as assumed initially a and corrected for aperture response with an estimated Gaussian edge b The chamber aperture sensitivity is estimated as a Gaussian of the line distance as shown in 8 Since the line cross section is uniform and the flow rate f ml s is constant distance is proportional to time t s for any given elution A single constant a 1 ml was used to describe the sensitivity response of the chamber over distance The response does not need to be normalized as at distance zero it represents a sensitivity of 1 while it decreases to an asymptote of zero as the distance from the chamber increases This is an accurate description of the assumed aperture sensitivity response a t eA where t gt 0 8 The parameter a was determined empirically from calibration runs at flow rates ranging from 5 to 25 ml min Parameter a was set to 0 7 1 ml which corresponds to a 50 drop in sensitivity over 1 17 ml line volume This volume translates to several centimetres from the dose calibrator s point of maximum sensitivity As can be seen from 8 the aperture correction becomes closer to a step response in time as the flow rate increases 49 Rb Elution System Control Ran Klein University of Ottawa which explains why this effect is more noticeable at low flow rates An example of constant flo
85. e prototype system Pump driver the prototype system communicated with the pump through a polling algorithm included in the physical sequence model The communication protocol with the pump dictates a delay of 300 500 ms between the query and answer by the pump This was handled in the prototype system through a delay loop until the query and answer was completed Since the physical_sequence is refreshed at 1 Hz this delay added significant overhead 30 50 To reduce this overhead a communication driver was written The driver runs as a separate task and is triggered by an interrupt event whenever data are received on the port The data are read tested for errors and updated directly in the real time model before a new query is sent to the pump If a reply from the pump is not received within 500 ms the query is repeated Thus the overhead was substantially reduced leaving more system resources available The new implementation was not transferred to the clinical trial but software crashes were not experienced during 6 months of use on the development system Once the new software is subjected to routine clinical use experience should reinforce confidence in the robustness of the new software 105 Rb Elution System Control Ran Klein University of Ottawa 5 4 Calibration Characterization Over the life span of five generators 284 days 189 calibration runs were conducted at 15 ml min flow rate Figure 5 2 The cal
86. e and make modification and copies The investment in the design of the code although protected by copyright contains intellectual information that is the property of the developer However in practice it is difficult to prove the theft of intellectual property One means of protecting intellectual property in the form of software is to compile it into machine code Although reverse engineering could potentially be used to decode the software the inherent difficulty is enough to deter most This reason in itself is sufficient to justify compiling of the software prior to providing the system to a third party however it was decided to defer this problem to a later stage if wider interest in the RbES is expressed 3 3 Flow Hardware Layout Justification At the heart of the Rb elution system are the saline lines that transport the activity from the generator to the patient The layout of the saline lines sensors and actuators is crucial to implementing a physical system that is easy to control During flow of a radioactive volume through the lines both a transport delay and a radioactive decay take place Therefore the activity at the output is delayed and reduced in relation to the activity at the input If the line volume V and flow rate f are known and fixed one can compute the delay time T and the radioactive decay D as shown below T 7 3 Dae 4 39 Rb Elution System Control Ran Klein University of Ottawa Flow
87. e maximizing the range of relative activities that can be eluted in order to maximize the useful life span of the generator In addition the range of elution durations should be maximized to enable experimenting with the optimal elution profile for accurate perfusion measurements In general the goal is to increase the flexibility of elutions while improving the precision of the elution system with the threshold comparison approach serving both as a starting point and a benchmark to which changes can be compared 72 Rb Elution System Control Ran Klein University of Ottawa 4 1 Threshold Comparison Algorithm with Auto tuning Hysteresis Correction HC TC Initial analysis of the threshold comparison algorithm revealed that elutions ran longer than requested indicating a reduced effective activity rate The prolonged elution time was assumed to be a direct result of the hysteresis of the valve Hysteresis refers to a system behaving differently depending on the direction of change of an input parameter 36 usually due to delayed response In this case the valve opening and closing latencies differ The hysteresis was accommodated by factoring the set point p using a hysteresis factor H The hysteresis correction factor H describes the on off switching characteristic of the generator valve and is expected to change over time with material fatigue tubing wear or other factors Therefore parameter H needs to be tuned continuously T
88. e not expected to change significantly Monitoring of the calibration constant can be used to detect problems in the system Once the daily protocol has been completed successfully patient elutions are enabled until the end of the day Refer to Figure 2 1 for a flow chart of the daily protocol Three patient elution modes are of interest Constant Flow elutions allow the user to specify the flow rate and duration of the elution This elution is identical to early elutions as described by Yano 29 Constant Time elutions allow the user to specify the desired activity and time for the elution The flow rate is automatically calculated based on the activity vs volume curve measured during calibration This mode offers the same functionality as the first generation system 30 Constant Activity elutions allow the user to enter the desired activity and duration of the elution The system automatically estimates a flow rate and controls flow through the generator or a bypass line by a threshold comparison algorithm to achieve fluctuations around the desired set point 18 Rb Elution System Control Ran Klein University of Ottawa Daily Flush gt 10 min wait Calibration gt 10 min wait gt Patient Elution Runs gt 10 min wait Figure 2 1 Daily protocol flow chart At the start of each day a flush and calibration run must performed prior to patient elution runs At midnight the calibration and flush exp
89. e referred to as ionic pumps If a potassium analogue is injected to a patient the tracer will be taken up by the heart muscle cells while the activity level in the blood reduces over time Several minutes later the PET image shows retained activity in the heart contrasting with the low activity of the blood as demonstrated in tomographic images in Figure 1 2 Figure 1 2 Sample Rb uptake images used to measure perfusion in the myocardium A normal heart is shown on the left depicting the elliptic shape characteristic of a long axis cross section The image on the right reveals A reduced blood flow to the septal wall and apex a PN of the left ventricle shown by a relatively e lower concentration of activity along the upper right region of the partial ellipse Although FDG scans for detection of tumours are by far the most popular application of PET today potential applications are only limited by the available tracers As research into the field progresses PET promises powerful new tools both for research and clinical diagnostics Rb Elution System Control Ran Klein University of Ottawa 1 2 Sr Rb Generator a Cost effective Tracer Source The half life of the radioactive isotope dictates how much time can pass between production and scanning After six half lives we tend to treat the tracer as completely decayed as only 1 6 of the original activity remains As a result the proximity of the scanning facil
90. ecaeees 53 Pigptire 3212 Various SCLeenShOtss2oc 420 sistas oohiicevattie seh ose cists Wace E E bation EET TE 54 Figure 3 13 Sequence data and control flow and structure diagram of Software sesseesesseereeeecneeeeenees 56 Figure 3 14 The Hardware Interface model ee ccesceseesecsseeeceseeeeeeceaeeeeaecseesecsevscceaeeeceaecaeeaecaeeeaeeeeeaeeates 57 Figure 3 15 Flow Chart for all elution types ccccceecsessesesceseceeecesecesecenecsaecaeecaeeeaecaeeeaeeeaeseneeneeenseenaeenseenaes 59 Figure 3 16 Inputs to the Physical Sequence M file S Function block cee seeeseereeeeceeeeecneeeeceseeeeeneeeees 62 Figure 3 17 Calibration results with and without the dose calibrator peak removal algorithm 0 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 Cy cles 22 secc scchccsccecsedeceesdacecdisdesbeucedacddeceusscsucdecntsvececassscecdoesadedeessasesevecvesseehensvaesceetes 76 Figure 4 4 Valve response curves at Vyaive 2 5 15 and 100 HZ ce ceceesecesecseecseeeseeeseeeeeeeseseeneeneenseenaes 77 Figure 4 5 Elutions at valve flow ratio 50 produced by cycling the generator val
91. ed The second chapter introduces the second generation Rb elution system RbES built as part of this thesis work following an overview of the literature with regards to similar systems This overview clarifies the work to date and the incremental contribution of the RbES The main topic in this chapter is a description of the RbES prototype which served as a starting point for this project Final notes discuss the performance of the prototype system and issues that needed to be addressed in order to complete its development The subsequent chapters discuss the contributions of this thesis Initially the system requirements are identified chapter 3 as well as guidelines for the development process A discussion of the system model follows in order to justify the layout of the elution hardware that is inherited from the RbES prototype system Rb Elution System Control Ran Klein University of Ottawa This chapter continues by describing the incremental development of the RbES Some hardware modifications for improvement of the usability and safety of the system are discussed but the main focus is on the new software This includes all aspects of the software with exception of the activity rate control system which is left for chapter 4 Special attention is given to the physical sequence that constitutes a complete elution sequence The fourth chapter focuses on the single topic of improving the precision of constant activity
92. ed from 39 959 MBq to 1084 MBq and the calibration constant changed from 3 679 10 to 3 724 10 which is substantially closer to the average calibration constant 3 777 10 69 Rb Elution System Control Ran Klein University of Ottawa Integral Activity at Patient Outlet Vial No Peak Removal 2500 s Detector Convolved 2000 ala Calibrator Delayed 1500 ae lt 1000 D 500 0 0 20 40 60 80 100 120 140 160 180 Time s Integral Activity at Patient Outlet Vial With Peak Removal 2000 q i a Detector Convolved 4500 L a Calibrator Delayed i s 1000 lt 2 500 0 20 40 60 60 100 120 140 160 180 Time s Figure 3 17 Calibration results with and without the dose calibrator peak removal algorithm 3 8 Summary The Rb elution system RbES was based on experience with the first generation system and took into account decisions made when developing the prototype of the second generation system The requirements were identified and served as a guideline throughout the development process These requirements focused primarily on safety and reduced exposure to both the operator of the system and to the patient The complete framework handled all aspects of the daily protocol physical sequence error detection and user interface All requirements were met with the exception of improved constant activity control The design of the system ensure
93. ed light operation to prevent Photoreceptor Coded light C5 Reduced waste overflow signal from reflected light LED intensity No liquid contact Submerged sensor head The ELS 1100 requires 10 28 VDC operating power and returns an open collector capable of drawing up to 40mA In the case of TTL digital logic as is used on the DAQ board a straight connection to a digital input line without the use of a pull up resistor is adequate 12 VDC were supplied directly from the PC power supply which also powers the solenoid valve buffer board The sensor casing is screw threaded so that it can be screwed into the lid and adjusted for height Since no additional hardware was necessary only the purchase cost of the sensor was incurred If the level switch is tripped the current elution continues to completion but a new run is not permitted A warning message is displayed at the end of the run If a new run is attempted without emptying the waste container an error is produced and the elution does not proceed until the waste container is emptied and the elution is restarted 35 Rb Elution System Control Ran Klein University of Ottawa Isolation Transformer To meet Canadian Standards Association requirements the equipment had to pass electrical safety tests These include current leakage to ground tests and surge tests This is especially true since the stainless steel cart and the saline to the patients are both conductors To me
94. egions Further effort on manually improving the fit proved to be difficult It was expected that an algorithm could be developed to optimize the fit based on the actual valve flow ratio range used Although great care was taken to estimate the effective flow ratio data in Figure 4 6 it is inevitable that manual measurements have some error In addition the valve response may change over time due to material fatigue wear and other unknown factors An automated model parameter tuning process using measures from many elutions would be used to estimate the model parameters However before this could be achieved a control algorithm based on this valve response model was developed PWM Valve Life Span Cycling of the valve between states may accelerate the wearing of the mechanical mechanism thus potentially shortening its life span The valve model chosen for the RbES 80 Rb Elution System Control Ran Klein University of Ottawa Asco 37312830 does not have any reliability information published by the vendor However since elutions are short 30 s and the time between elutions is at least ten minutes over heating is not a significant risk A routine work day includes as many as twelve elutions translating to 1800 cycles if the valve is cycled at 5 Hz Since a typical valve reliability measure is at the very least 10 valve cycles a life span of several years can be expected in the worst case Asco is a reputable actuator manufactu
95. el is based on comparison to an external dose calibrator Both calibration results and elution tests confirm that the system model is sufficiently accurate for predicting the activity delivered to the patient based on the on board positron counter readings This result is important not only to patient safety but also to system precision The RbES has matured to the point where it can be routinely used in clinical studies This is reflected both by meeting of the design requirements behaviour verification and system characterization The testing includes not only functionality of the system under ordinary conditions but also in abnormal situations The system is sufficiently automated that no user intervention other than monitoring is required during an elution process Constant activity elutions are implemented by controlling saline flow through the generator or its bypass line using an on off solenoid valve using two methods which are compared in chapter 5 The first method hysteresis corrected threshold comparison HC TC modifies the previously published threshold comparison method 18 by correcting for valve hysteresis The second method cycles the solenoid valve and modulates the pulse width PWM in order to simulate a variable flow valve A predictive corrective control PCC algorithm determines the desired flow ratio through the valve which a valve response model translates to a corresponding pulse width The measured results
96. elapsed time green blocks These readings are processed to control the actuators such as valves magenta blocks pump and GUI Internal variables light blue blocks are used for control of the Hardware_Interface by the Physical_Sequence block In addition to the Hardware_Interface models the model consists of the Software_Interface model and the Valve_Control model The Valve_Control block controls the valves through real time control to achieve constant activity elutions and is discussed in depth in Chapter 4 Elution Profile Control The Software_Interface block is a wrapper of the Physical_Sequence block and collects the input data to a structured array Data transfer to Matlab workspace Pressure gt Average Analog Input mV to ps National Instruments Pressure Average ie PCI 6035E auto RunTime gt Pressure gt OverflowSens Digital Input National Instruments gt Counts PCI 6035E auto Patient Valve Vaveopen p gt VaveOpen ia L PatientValve PredictionRatio gt PredictionRatio Counter Input Generator Valve 7 National Instruments Counter Sum ValveCorrection gt ValveCorrection PCI 6035E auto GeneratorValve Counts gt ae ValveControl Software_Interface ExpectedActivity BAMA f L o ExpectedActivity ra a Counter Reset Timing ntrol_ Valves Trigger Timing for Signal Tracing
97. eliability of the system and to uncover any overlooked bugs and requirements Two identical RbES were built one of which was put into clinical use at the UOHI Cardiac PET Centre in January 2004 after passing the test cases having obtained CSA certification and being approved by the Medical Devices Institutional Review Committee This system implemented all the design requirements except for the improved constant activity control algorithm discussed in the previous chapter PCC PWM The system was capable of all of the previously published elution capabilities including constant flow constant time and constant activity using the hysteresis corrected threshold comparison algorithm HC TC While the clinical system was being used routinely development of the control system continued on the second system The RbES replaced the previous elution system 30 which was only capable of conducting constant time elutions As the technologists adopted the new system for routine use their feedback was used to resolve issues and bugs as they were exposed In addition bug reports were used to assess the robustness of the system The data collected during 103 Rb Elution System Control Ran Klein University of Ottawa clinical use were used to characterize some aspects of the RbES The data included in this report relate to clinical trials over a nine month period from March 2004 to December 2004 During this time the generator was reloaded five
98. em capable of providing a constant and controlled rate of Rb activity over elution times in the range of 15 to 60 seconds for clinical PET scans in humans In addition the system had to be capable of reproducing elution profiles that were tested and understood in the literature the constant flow and constant time elutions Functional Requirements Functional requirements relate to the functionality and features that the system must provide in order to justify its existence e The system must identify faults during run time and provide meaningful messages to the operator e Once an elution from the generator is started the system must be fully automated so as to minimize exposure to the operator 28 Rb Elution System Control Ran Klein University of Ottawa e The system must at all times display the status to the operator in a fashion that is readable from at least three meters from the device e The system must be capable of producing constant flow constant time and constant activity elutions as well as respective tests with respect to an external standard e A record must be kept of all completed elutions for analysis and filing e The system must ensure compliance with the daily protocol described in the previous chapter A flush followed by a calibration run and successful breakthrough measurement must be completed in order to enable patient elutions for the remainder of the day The system should delay at leas
99. ency 100 KHZ Vyatve is the valve cycling frequency and II is the duty cycle of the valve s actuating signal Dyigh Veik Vyatve H 16 NLow 7 Verk Vyatve 1 ID 17 75 Rb Elution System Control Ran Klein University of Ottawa Valve Response Measurements In order to accurately control the effective flow ratio the valve response had to be measured for various cycling frequencies It is desirable that the cycling be fast enough to produce undetectable fluctuations in the activity leading to smooth activity curves In addition the valve flow ratio response to duty cycle should be controllable throughout the entire range 0 100 valve flow ratio To test the transient response a frequency of 100 Hz was used while 2 5 and 15Hz frequencies were used to measure the response in the valve cycling range sn pein nini eer ee oo Pee ee Se 4 E E EE E N 099 es oe E eos a Tenaga 0 9885 H 0 988 T ee 0 9675 fj il paesa 0 987 g 10 i eae ee eeeieeece beet eceee ete 0 9865 gt ae e 0 986 S 8a dd ee ET PEEN E E E 0 985 x HE ft XN Peres 0 98 el H L i oe aa SORES too aean 0 95 A i i i oe ee S E d eee tees aie eee E ie Pra ere o 20 40 60 80 100 120 Figure 4 3 Activity vs time curves as measured with the generator valve cycling at 15Hz at various generator valve duty cycles The rise time
100. ent Mathworks Matlab 6 5 1 Matlab 6 5 1 Environment and Release 13 Simulink 5 0 Emulator Real Time Workshop 5 0 Real Time Windows Target 2 2 C Compiler Watcom C Compiler Watcom C Compiler 11 0c Minimum PC requirements As with any computer controlled real time application it is a combination of software and hardware that determine the overall performance Although the application does not initially indicate the need for much processing power further inspection reveals some issues of concern Matlab versions 6 and above are implemented in Java and therefore are executed by a real time interpreter Java Virtual Machine This interpreter translates Java code into machine code and therefore entails a processing overhead Similarly Matlab is an interpreted language as well and therefore adds an even larger overhead of its own 38 Rb Elution System Control Ran Klein University of Ottawa Although the option of later compiling the application into machine code exists initial development was in Matlab It was determined that the existing PC refer to Table 2 1 will remain unchanged for the time being as processing power did not seem to be an issue with the prototype system Intellectual Property Another consideration when choosing a software development package is protection of the invested work With an exposed interpreter language such as Matlab it is quite simple for any person to view the software cod
101. ent of a predictive corrective control algorithm that attempts to predict the activity concentration at the merger of the generator and bypass lines The predicted activity concentration is used to control the ratio of saline that flows through the generator versus to the bypass line The prediction algorithm uses an activity concentration vs volume curve measured during a daily calibration run and the history of the elution to accommodate fast changes in activity concentration A corrective feedback algorithm consisting of a modified PID loop corrects the valve control signal to drive errors in the measured activity rate to zero The flow ratio of saline through the generator is actuated using a solenoid two way pinch valve cycling at a constant frequency 5Hz with a controlled duty cycle As the duty cycle is increased a higher ratio of saline is routed through the generator thus increasing the activity rate at the merger of the two lines The valve flow ratio response to duty cycle is highly non linear and was modeled using a combination sigmoid and linear function For the valve response model to remain accurate over time a self tuning algorithm was developed This algorithm continuously adjusts the model parameters by small increments through analysis of the activity rate error as a function of the flow ratio collected 96 Rb Elution System Control Ran Klein University of Ottawa during each elution It is expected that ov
102. er many elutions the model parameters will be adjusted so as to reduce the error in the eluted activity profiles With this implementation of the RbES completed performance can be compared to the prototype system which employed a simplistic but reliable control system The ultimate decision is whether any of the control modes hysteresis corrected threshold comparison HC TC and predictive corrective control of PWM valve PCC PWM are sufficient for both clinical and experimental quantitative perfusion measurements using Rb in PET The characteristics of both approaches should be compared to determine the advantages of disadvantages of each approach 97 Rb Elution System Control Ran Klein University of Ottawa Chapter 5 Testing and Characterization Due to the clinical application of this system it was important to conduct a thorough testing of the system in order to uncover any possible errors or unaddressed requirements of the system These tests included both hardware and software aspects Hardware safety considerations mainly concerned electrical safety mechanical robustness and failure to a safe mode Although an elution is permitted to fail it must do so gracefully without threat to the well being of the patient or the operators The test scenarios were designed to confirm that the system behaves in a predictable manner not only in routine situations but also when anomalies such as hardware failure and unexpected meas
103. et these requirements an isolation transformer through which all the electronic components in the cart are powered was added Uninterruptible Power Supply As the cart must be moved around the PET imaging room and time constraints can be tight the system needed to remain powered while unplugged This problem was easily resolved by connecting the PC pump and touch screen display to an uninterruptible power supply UPS The system is plugged into a wall socket at all times and only needs several minutes of battery power while being moved An off the shelf UPS rated for 800 V A was purchased Belkin F6C800 UNV This allows approximately 10 minutes of disconnected time with the all the components powered but no elution in process High Density Plastic Lid Although the generator and waste container are shielded by lead the saline lines are a source of radiation during elutions To minimize exposure the personnel and patients a high density 4 inch plastic lid was added to cover all the lines on the top of the cart This cover absorbs most of the positrons but only a small fraction the gamma radiation which is also of concern Distance is the most effective shielding for gamma radiation 31 which is the reason for automation of elutions The lid was hinged to allow access when maintaining the system and replacing the patient line Software packages Selection of a proper software environment is a crucial decision and should be addressed
104. experience a significant dead time after detection of an event If the activity in the FOV is too high many counts could be lost resulting in a saturation of the measurements or even a reduction in the number of detected counts The technologists who administer the tracer and operate the scanner try to maximize the activity while avoiding saturation of the detectors To facilitate this optimization we would like to spread the activity evenly throughout the elution time which is ideally a rectangular elution profile 18 28 The short coming of Rb is that constant flow elutions as shown in Figure 1 5 are not rectangular and therefore not ideally suited for quantitative perfusion measurement 13 Rb Elution System Control Ran Klein University of Ottawa 1 5 Quantitative Perfusion Measurements Using Rb Two alternative tracers for quantitative cardiac perfusion measurement in PET have been discussed N ammonia which is widely accepted and Rb as a potential substitute The disadvantage of N ammonia is that it must be produced using an on site cyclotron and chemistry lab Since it is introduced to the patient using a syringe pump a rectangular activity vs time profile is created during injection Rb which can easily be obtained using a Sr Rb generator is cheaper to produce than ammonia but has a characteristic activity vs volume profile that is not optimized for PET in general and quantitative perfusion measuremen
105. f the generator at 15ml min Ensures flushing of air bubbles in the saline and Sr breakthrough from the generator Calibration Run flushing of the generator at 15 ml min over 60 seconds into the dose calibrator The integral activity recorded from the dose calibrator is used to calibrate the activity counter and verify that the calibration constant is within tolerance from previous records If the dose calibrator sensitivity is sufficiently high breakthrough measurements are conducted after 20 minutes from completion of the elution If the dose calibrator is not sufficiently sensitive to measure breakthrough the activity can be entered manually after measurement in a more sensitive device In addition the pump flow rate ml revolution can be calibrated by manually entering the actual eluted volume Patient Elutions Over the remainder of the day elutions to the patients can be carried out in three modes 43 Rb Elution System Control Ran Klein University of Ottawa a Constant Activity a prescribed dose is eluted over a prescribed time at a constant activity rate b Constant Time The generator is flushed at a constant rate to achieve a prescribed dose within a prescribed time c Constant Flow The generator is flushed at a prescribed flow rate until a prescribed dose is reached The Rb infusion system software must ensure that the protocol is followed i e that each run is enabled only after
106. g to 70 relative activity over 30 s Intermediate flow rates are obtained by linear interpolation between these limits The flow rate is computed prior to starting of the elution using 28 and is maintained until all the activity has been eluted and flushed from the lines Areq corresponds to the desired activity while Treg is the requested duration The relative activity is computed using Areq factored by the calibration activity Aca while the time ratio 60 Tpeq converts the measure into relative activity rate 90 Rb Elution System Control Ran Klein University of Ottawa 25 5 Arey 60 1 4 0 2 Acu T Req f 1 667 28 Automatic Parameter Tuning Accurate prediction of activity concentration depends on accurate modeling of the system and accurate valve flow ratio The prediction algorithm makes the assumption that the valve response is accurately modeled and that the desired flow ratio is always achieved Since we have confidence in the modeling of the system we must focus on fulfilling this assumption through good modeling of the valve response The valve response model parameters that were estimated manually to achieve a good fit Figure 4 6 do not necessarily ensure the best elution performance in practice In addition the valve response may change over time For these reasons one would like a self tuning algorithm that adjusts the model parameters in order to decrease the error in elution profiles These pa
107. gral Derivative PWM Pulse Width Modulation QA Quality Assurance Rb Rubidium Sr Strontium UPS Uninterruptible Power Supply UOHI University of Ottawa Heart Institute Rb Elution System Control Ran Klein University of Ottawa List of Variables a d Agorbs Agosrs Ags Sr Acal ABreakthrou gh A t Ap t AReq p Ag Ac t Ac Cc v M Cy Npa t NLow NHigh Dro OT AAT DOAN p r0 XO rt uO Inin Imax s t corr Tro TReq Elution Tierm Vyalve Veik Ac Dose calibrator aperture response Activity of delivered Rb Sr Sr MBq Activity eluted during calibration run MBq Activity measured at dose calibrator for breakthrough calculation MBq Measured activity at point P at time t MBq Activity at point P at time t MBq Requested activity MBq Desired activity rate at point P MBq s Desired activity rate at activity counter also referred to as the set point MBq s Measured activity rate at activity counter MBq s Activity rate error at activity counter MBq s Activity concentration vs eluted volume curve measured at calibration MBq ml Measured activity concentration just prior to the merger MBq ml Predicted activity concentration just prior to the merger MBq ml Measured raw count rate at the activity counter detector cps Counts for low high output of the square wave generator Decay during transport between points P and Q unitless Fl
108. h this question is not addressed fully within the scope of this work some indication can be seen from preliminary results of ongoing studies using the RbES Of the patients that underwent Rb perfusion scans at the UOHI Cardiac PET Center 14 subjects participated in a comparative study of Rb and N ammonia perfusion measurement These normal volunteers have low risk of cardiac disease and were scanned 124 Rb Elution System Control Ran Klein University of Ottawa using both tracers and under similar conditions of rest and dipyridamole induced stress of the heart Dipyridamole increases myocardial blood flow through dilation of the coronary arteries The study is planned to continue with additional normal volunteers as well as subjects with coronary artery disease CAD As the tracer is introduced to the patient through an injection into the hand it passes through the right ventricle of the heart the lungs and to the left ventricle of the heart Dynamic imaging of the left ventricle blood cavity allows measurement of the blood activity before significant tracer uptake is experienced in the myocardium If the blood activity curves in the LV cavity using both tracers have a similar shape it can be concluded that the tracers were introduced at a similar rate and that the subsequent perfusion measurement is conducted under similar conditions for both tracers The subjects were scanned on two occasions less than two weeks
109. hat this is the case the system has not been used over a long period needed to reach a firm conclusion Several alternatives to the self tuning algorithm may be considered in the future l Abandoning the PCC PWM algorithm in favour of the simpler but less precise threshold comparison algorithm 2 Removal of the self tuning algorithm leaving maintenance of the model parameters at the hands of the operators 3 Continued research into development of an improved model and tuning algorithm 4 Seeking of a variable flow ratio valve that better meets the requirements for this problem Namely the valve must be fast robust accurate and simple to integrate with the system 127 Rb Elution System Control Ran Klein University of Ottawa Of these options a decision for future steps must be made based on various considerations and how they are weighed If precision is a crucial factor reverting to the threshold comparison controller is unacceptable as the comparison of the two approaches clearly indicates that the PCC PWM has more desirable characteristics Whether or not precision is crucial remains to be determined as the comparative perfusion study continues Replacing the self tuning algorithm with free parameters that can be set by the operator is an unlikely option as this would entail thorough understanding of the system by the technologists A poor selection of model parameters could result in undesirable activity profi
110. he Update stage updates the state of the state machine and initializes the next step routines that are carried out a single time at the beginning of a state while the Output state maintains the actuator states and GUI during the state The Update stage is composed of a large switch case statement for each of the sequence states and condition statements for transition to subsequent states If the transition condition is met for the current state an initialization of the next state is executed and the function return value is set to the next state code The states and their termination conditions are listed in Table 3 3 Table 3 3 Physical_Sequence states and their termination conditions As long as a termination condition is not met the state is maintained unchanged State Name State Termination Condition Next State Description Wait for Wait until pump Pump is running after less than 2 restart tries Flush Bypass Pump Start driver is loaded to Waste and pump starts Else Error is set Termination follows Flush Bypass Bypass route Enough time has Prime Patient Line Option Prime to Waste from pump to elapsed to prime lines Patient Line patient Else Flush run Slow Drip stopcock is Bypass to flushed to the Patient waste Else Cumulative Time Waiting Prime Patient Patient line Enough time has Flush run Cumulative Line from patient elapsed to prime Time Waiting cock stop
111. he auto tuning algorithm adjusts H depending on the difference between the actual and requested elution time T and Treg respectively as is shown in 15 The time variation is factored with H Elution and an adaptation constant yy With yy chosen small enough 0 01 in our case the system is ensured to not change significantly due to outliers but evolve slowly over time Factoring of H is not crucial in this case where H 1 but is intended to ensure incremental changes AH that are orders of magnitude less than H To further reduce the influence of outliers changes to H that are larger than a tolerance interval 5 are rejected with a proper warning to the user AH 74 H Psion Treg 15 Parameter H was manually set to 1 and over the course of 20 random 30 s elutions ranging from 10 70 relative activity H evolved to a value of 1 09 Parameter H showed little change over the next 30 elutions however it was noticed to vary slightly with repeated runs at extreme relative elutions lt 20 or gt 60 relative activity Variation of H at extreme relative activities is likely due to other limitations in the system insufficient activity in the generator varying activity concentrations from the generator and others making it difficult to achieve the requested elution the hysteresis mechanism attempts to compensate for these limitations Although this hysteresis factor resulted in smaller accuracy error numbers the t test p val
112. hich spans most of the elution time is always driven to achieve zero error With the mean error rule the L parameter is a product of two concurrent processes driving the average lower range error to zero and adjusting the upper valve saturation point Imax It is expected that maintaining the mean error rule as the only adaptation rule for parameter L will yield better self tuning characteristics however this was not tested within the scope of this work Analysis of Tuned Valve Response Comparing the valve response curves produced with manually estimated parameters and self tuned parameters Figure 5 11 reveals some interesting issues The response graph generated with self tuned parameters dashed line follows the measured response less closely than the manual estimate dotted line The region of operation of the valve is 114 Rb Elution System Control Ran Klein University of Ottawa 0 25 lt r lt 1 0 which corresponds to very small changes in the duty cycle 0 97 lt IT lt 0 9975 The response in this range caused very large changes in flow ratio due to very fine duty cycle changes an unfavourable response Valve Response Correction Curve PWM 0 998 Dc Nn 0 996 0 994 0 992 s Measured 0 99 a Manual Estimate Converged Estimate 0 988 0 986 0 984 0 982 0 98 0 25 0 3 0 35 04 045 0 5 0 55 0 6 0 65 0 7 0 75 08 085 09 0 95 1 Desire
113. iation in Error v s Valve Flow Ratio Variation in Error v s Valve Flow Ratio 40 20 m k pe tA a ky x ape ee g ir go 4h eS g itr Fu ee S m 2 ee S a Leper E g lt ae 204 20 ATI 0 F o a Aia 9 a oe AL 0 00013404 40 AL 2 4034e 005 40 AL 1 0082e 005 E k AG 0 72043 AG 0 56796 AG 0 10833 60 60 60 0 3 035 04 045 05 055 06 0 3 0 32 0 34 0 36 0 38 0 4 0 42 0 3 0 32 0 34 036 0 38 04 Desired Flow Ratio Desired Flow Ratio Desired Flow Ratio Instantaneous Activity Rate at Patient Outlet Instantaneous Activity Rate at Patient Outlet Instantaneous Activity Rate at Patient Outlet 1 5 1 5 1 5 T RMS 34 285 g 16 1288 T 14 6962 g 1 a4 k gt gt 20s 205 205 0 0 0 Oo 20 40 60 80 ie 20 40 60 o 20 40 60 Time s Time s Time s Figure 5 6 Illustration of the effect of accelerated self tuning of the valve response model over three successive elutions at 30 over 30 s The top graph represents the measured error vs the valve duty cycle while the bottom portion compares the eluted activity rate to the requested activity rate As the linear slope and sigmoid scaling parameters are adjusted the RMS error decreases The same process can be demonstrated over a different set of data in which 30 relative activity 30 s elutions were repeated 87 times The evolution of parameters and the resulting RMS error and elution time error is shown in Figure 5 7 As the valve response is self tuned the RMS erro
114. ibration constant appears unchanged with a standard deviation of 2 16 Closer inspection revealed a small but significant correlation between the eluted activity and the calibration constant K p 0 0044 1 0 0585 as is demonstrated by Figure 5 3 A linear fit revealed a small slope 2 59 10 MBq ml cps MBq 95 confidence interval 1 09 10 4 09 10 in the relation between calibration constant MBq ml cps and generator activity MBq Over the life span of a generator the calibration activity can change by as much as 2500 MBq This results in 1 7 change in the calibration constant over the life of a generator which is considered a negligible effect These results show that the calibration process is both reproducible and is relatively constant throughout the entire range of useful activities z x10 Variation in calibration constant over time oO 4 UK Pete 3x Sepak ie ro ne mE Hak AE et ae aa Helical lay sit elka ul RE IHR a yet eS es oD O ey 3 S SE 20 7 cS 2m 1 5 0 0 50 100 150 200 250 300 Activity over time 4000 Generator reloaded 1000 Activity MBq N wo 150 200 250 300 Date days Figure 5 2 Calibration constant over the course of a generator life top and the Rb activity from the generator during calibration over the same time period bottom 106 Rb Elution System Control Ran Klein University of Ottawa x10 Correlation of activity and calibration c
115. imately the system will be used without tracking of the parameters and if the elution profiles worsen it is unlikely that the technologists will be capable of readjusting the parameters Ultimately clinical trials will shed light on the long term performance and reliability of the self tuning algorithm 5 6 Elution Tests With the system tuned in both the HC TC and PCC PWM control modes comparisons were performed to determine a preferred method In a typical clinical application elutions are 30 s long and the activity is matched to the physical size of the patient Typical relative activities range from 10 for a small patient and a hot generator to 70 for a large patient and a cold generator 116 Rb Elution System Control Ran Klein University of Ottawa The control algorithms were compared through ten sets of 30 s elutions of 10 30 50 and 70 relative activity Both HC TC control and PCC PWM were assessed for comparison For each run the elution time error was defined as the difference between the actual elution time required to reach the requested activity and the requested time 32 In addition the RMS error relative to the requested activity rate was calculated as an indication of the accuracy of the algorithm in maintaining a constant activity rate 33 The time error is an indication of the average activity rate throughout the elution while the RMS error is a measure of deviation of the activity profile from the ideal
116. inere e eie ee a n EEEE EE E E a pare aaie E Sie 28 Non Functional Requirements cccsccesccssesssesscesseeseceseceseceeeceaeceaecaaecsaecaeeeseeseeseeeeeeseeeseeeseenaecnsecneeeneeenes 29 Other Requirements v cs5 lt 255 pics ts paeepeccact bop dgsacageas ewes pte de cacibed badene postesh a daetben S 30 3 2 Initial Design Considerations vices ccccccseceseess cctcessegentes ca ch ecudeted tides sed cs E E E E REE a a 32 Safety rra ceed va EEE E E REE E sede hen tee sete ace bs Beate eee ota Tate ee Ea We edh oan Tee 32 Process Monitoring ie serenon n eves E E se E E E cde cessation svisa aeaedvaidage RE 33 Hardware Modifications i233 s ccctien eats eliein eras elisa einen Minis nai tesa 34 Software packages ve c 2c scse cceieks vescescncceesishees cvsecsad ie ao Ea ae EE Ea SE Keo E S R SEEE EEEE S e EEEE EEEa 36 3 3 Flow Hardware Layout Justification ccccccccseesseeceeseeeseeeeeseeesecesecaeceeecseecaeeeseeeceseeeseeesereneeeeeeesenaees 39 Pump Speed Variation rnnsinniinii irene e iis ie Eee EE SEE E EE E E A i 40 Bypass Ratio Control isinne uein essee e E aos E EE e EE Te EE eSEE Ee EEEE e E Ea Seisa 41 3 4 Design of Physical Processes neon r A E EE E E ER E eek E OA 43 R n s quence innne een e EEE A E OEA E et OEE EE E EAA EE 44 Calibration eroro ron E EE E EE E RER ERLE EI EEEN AEE ERE ER ER 45 Breakthrough Activity Measurement reion aniei n E E E EEEE E O 50 IU Ot ests ie ena E O E E EERE E N EEEN E E oT 52 35
117. iological distribution of specific molecules within the body in a non invasive manner nuclear medicine imaging has become a leading diagnostic tool A compound labelled with a radioactive isotope is introduced to the patient usually by injection and its location in the body is later imaged using a scanner sensitive to the emitted radiation The compounds referred to as radiolabelled tracers are designed to interact within the patient so that they collect in a region of interest by participating in a biochemical process of interest Over time the radioactive label in the tracer decays resulting in emission of radiation Given a closed system containing radioactive material an exponential decrease of activity is observed as time progresses The rate of decay is a characteristic property of the radioactive isotope and is measured as a statistical average of the time that passes until half the original activity remains This measure is referred to as one half life T1 2 and can vary from split seconds to countless years depending on the isotope In molecular imaging one would like to use an isotope that lasts long enough to perform the measurement but short enough to minimize exposure to the patient A short half life also carries the benefit of reducing the time between repeated scans of the same subject Typical imaging applications use isotopes with a half life ranging from several seconds to several hours When imaging the patient objects
118. ion The elution is terminated once the requested dose is reached regardless of how much time has elapsed 5 The activity delivered to the patient should not exceed the dose set by Health Canada guidelines 2200 MBq This issue is handled in part by safety issue 4 but is also ensured by the limited activity in the generator 2000MBq and the use of an autonomous pump that is programmed with a finite elution volume The worst case scenario is thus the 32 Rb Elution System Control Ran Klein University of Ottawa possibility where the elution system software does not respond the valves do not fail to a safe mode the autonomous pump continues running indefinitely and a hot generator is being used In assessing the worst case scenario we have concluded that no more than the total generator activity could be eluted In such a case it is expected that the technologist monitoring the elution system would notice that the PC no longer responds and would take action by resetting the system 6 The amount of Sr breakthrough activity must be strictly limited to the Health Canada guidelines This issue is addressed by daily breakthrough tests as part of the daily protocol ensured by the system These safety concerns are of utmost importance and were addressed at all levels of the development and testing Process Monitoring Monitoring of the flow of activity to the patient is critical as a safety feature as well as a means of prec
119. ire A minimum of 10 minutes must pass between elutions At midnight 2 2 Hardware Description The second generation elution system focused on improving usability automation and precision The primary goal was implementation of a constant activity elution mode Since the first generation elution system has been proven as a reliable design it served as a basis for the second generation infuser The hardware remained almost unchanged while the software was completely rewritten using Matlab Simulink os ea u TF ge LO Figure 2 2 Hardware component diagram of the RbES prototype 18 was not altered The system is based around a PC which interfaces with the various sensors and actuators Based on the mode of operation and measured data the real time software controls the pumps and valves These in turn affect the flow of saline through the generator or its bypass line to the patient dose calibrator or waste container The system acquires data from a pressure sensor activity counter pump and the dose calibrator which is used to monitor the process and control the elution Figure 2 2 shows the overall design of the second generation Rb infuser Rb Elution System Control Ran Klein University of Ottawa Computer The PC was modified to allow interfacing with other system components An additional RS232 serial port was added through a PCI board The data acquisition card was installed on a second PC
120. ision control The delivered activity is dependent on the activity leaving the generator and on the flow rate to the patient outlet The flow rate is set by the software and controlled by the autonomous peristaltic pump However pressure in the lines must remain within pump manufacturer specifications to ensure that the flow rate is accurate If the pressure is above 30 PSI 207 kPa backwash of fluid through the rotor head can result leading to an effective flow rate that is lower than expected The pressure sensor is used to sense high pressure in the saline lines due to blockage This mechanism also prevents bursting of the lines as pressure increases The pressure sensor is located downstream of the pump head and before the generator valve This position allows monitoring the pressure in the lines regardless of the state of the valves Since the lines are filled with liquid the pressure is equal in all parts of the line If pressure above 20 PSI 138 kPa is measured for 3 seconds the elution is stopped and an appropriate message is displayed to the user Activity measurements are vital for monitoring the delivery to the patient The accumulated activity is used to stop the elution when the requested dose is reached In addition the activity counter can be used as feedback to the controller to achieve constant 33 Rb Elution System Control Ran Klein University of Ottawa activity elutions The activity counter measures the activi
121. ition steps can be missed necessitating a feedback mechanism Early experimentation in our lab 18 20 was conducted with a variable pinch valve with a one sided pincher and position feedback The problems mentioned above did surface leading us to conclude that a variable valve at least of this type was not suitable for our application As a result other alternatives were sought On Off Pinch Valve The use of a solenoid on off valve overcomes the complications involved with the variable pinch valve In addition the solenoid mechanism is far simpler leading to a lower price simpler implementation faster response and increased reliability These benefits come at the expense of precision as the solenoid can only achieve two positions fully open and fully closed Figure 3 4 Flow control DES a a through the generator using a variable pinch F F valve on the generator J line One must place a pinch valve on the generator line with the spring set to stop flow This is intended to achieve a fail safe state where the generator flow is blocked if no power is supplied to the solenoid When the valve is open saline flows through both the generator and the bypass line at rates that are dependent on the relative resistance in each path Figure 3 4 When the valve is open it is hoped that the majority of the flow will be through the generator line This assumption however is unrealistic since the compressed tin oxide co
122. ity to the tracer production facility is limited If the tracer is sufficiently long lived it can be transported between facilities however if the tracer half life is less than several hours the tracer must be produced on site Many of the PET isotopes are created using a cyclotron This highly specialized and expensive piece of equipment accelerates protons for bombardment of a specific target The nuclear interactions during the bombardment can form desired isotopes In many cases these isotopes are then passed on for synthesizing the tracer molecule through a series of chemical processes Due to the complexity and expenses involved in operation of a cyclotron much research has focused on finding simpler and more cost effective alternatives for PET tracer production This would be especially useful in regions of low population density common in a country like Canada where the cost of a cyclotron cannot be supported Rubidium 82 Rb has been identified as a suitable tracer for perfusion measurements and can be readily produced using a Sr Rb generator described below As a 1 column element in the periodic table Rubidium is a reactive cation which is physiologically similar to potasstum K 11 Potassium and rubidium exhibits avid uptake in certain tissues in the human body such as the myocardium When Rb decays by positron emission it is transformed into stable Krypton Kr which is a noble element and is therefore non rea
123. l Ran Klein University of Ottawa These considerations served as guidelines throughout the control system development process The intermediate development steps are discussed in order to clarify the difficulties involved with this control problem and to justify decisions PID Control Conventional approaches typically use proportional integral differential PID controllers driven by feedback measurements to drive the actuators so as to minimize the output error The dynamics of the controller are intended to compensate for the dynamics of the mechanical system plant in order to achieve a more favourable overall system response PID controllers are well established and serve as a default approach in many applications Three scalars P I and D in 21 must be tuned to optimize the control signal C to the plant response In theoretical models controller optimization can be achieved through state space modeling and optimal control calculation techniques In practical situations where modeling of the plant is either too difficult or too time consuming the controller may be tuned through trial and error GaP R t f E e de p 0 Bropo iional 0 Proportiona Differential Tnitegral The three parameters of a PID controller correspond to factors of the error its integral and its proportional differential to produce a control signal to the actuator Figure 4 7 The output error is the difference between the desired plant output
124. le pincher allowing flow through one tube while blocking flow through a second These valves are manufactured by Angar Scientific and were chosen for their proven reliability Buffers To supply the required current to the flow control valves the need for buffers arose The control signals were fed directly from the data acquisition board digital I O and amplified using solid state relays Crydom The buffer mounting board also manufactured by Crydom was modified by exchanging the pull up resistors with pull down resistors This modification was conducted as a safety precaution to ensure that the valves fail to a safe 21 Rb Elution System Control Ran Klein University of Ottawa position flow through the bypass to the waste container should control lines become inactive Activity Counter Some of the positrons emitted during decay are absorbed in a fluorescent optical fibre scintillator and converted into photons A photon detector Hamamatsu H7155 coupled to the optical fibre is used to count these photons For each recorded event a 30ns TTL pulse is sent through a coax cable to the DAQ on board general purpose counter timer GPCTR The photon counting head is a single package containing a high voltage power supply and a high speed photon counting circuit 5 VDC powers the photon counting head and a coax TTL cable supplies one output pulse for each photon counting up to 1 5 million counts per second It is i
125. lerators Spectrometers Detectors and Associated Equipment Vol 504 No 1 3 pp 129 138 2003 4 K Mah C B Caldwell Y C Ung C E Danjoux J M Balogh S N Ganguli L E Ehrlich R Tirona The impact of FDG PET on target and critical organs in CT based treatment planning of patients with poorly defined non small cell lung carcinoma a prospective study Int J of Radiation Oncology Biology Physics Vol 52 No 2 pp 339 350 2002 5 R S Beanlands Positron emission tomography in cardiovascular disease Can J Cardiology Vol 12 No 10 pp 875 883 1996 6 M R Costanzo S Augustine R Bourge el al Selection and treatment of candidates for heart transplants Circulation Vol 92 pp 3593 612 1995 7 H Schelbert R Bonow E Geltman J Maddahi M Schwaiger Position statement Clinical use of cardiac positron emission tomography Position paper of the Cardiovascular Council of the Society of nuclear Medicine J Nucl Med Vol 34 pp 1385 8 1993 8 K Baete J Nuyts W Van Paesschen P Suetens P Dupont Anatomical based FDG PET reconstruction for the detection of hypo metabolic regions in epilepsy IEEE Trans on Med Imag Vol 23 No 4 pp 510 519 2004 133 Rb Elution System Control Ran Klein University of Ottawa 9 10 11 12 13 14 15 16 17 18 J S Lee D S Loo S K Kim S K Lee J K Chung
126. les In order to improve precision while maintaining complete automatic tuning of the system it is most likely that further research is required First and foremost this research would need to better assess the automatic tuning performance of the current implementation Part of this assessment should be selection of the learning parameters yr yc and yr to improve the learning rate while maintaining a reasonable immunity to abnormal elution results Further experience with the existing system will indicate if additional development is required and would also serve as a benchmark to which other improvements could be compared Other models and tuning techniques could also be considered Further research could look at a model that better describes the valve response than the sigmoid linear model does Alternatively a simpler model that can be tuned with fewer parameters even if less characteristic of the true response can be sought Since the desired flow ratios typically fall within the 25 100 range there is no need to model the entire dynamic range of the valve A final possibility is searching for or developing a valve that can accurately control the valve flow ratio directly If this were the case modeling and tuning of the valve response could possibly be avoided or simplified Such a valve would require a fast response time enabling to fully open and close within a fraction of a second In addition the valve would have to be sufficient
127. lumn of the generator resists the flow of saline A more advanced solution is necessary Double Sided On Off Pinch Valve Flow ratio control was achieved using a single two sided solenoid actuated pinch valve on the bypass line and generator line Figure 3 5 The valve allows flow through one line at a time This is equivalent to having an on off pinch valves on each line operating 42 Rb Elution System Control Ran Klein University of Ottawa opposite to one another The valve is spring loaded to ensure failure to the bypass open generator closed position This valve is referred to as the generator valve and is the liquid flow control equivalent of a selector or demultiplexer Figure 3 5 Flow control through the using a double pinch valve on the bypass line and generator line generator sided 3 4 Design of Physical Processes Prior to the daily clinical use of the system certain maintenance measures must be carried out as dictated by the daily protocol These include flushing of all the lines in order to remove Sr breakthrough and air bubbles that could accumulate during hours of standby In addition the Sr breakthrough must be measured and a complete system test must follow The daily protocol was designed to include the following elutions with a minimum of 10 min period between runs for the generator to recharge 1 Flush Run flushing of all the lines in the system as well as a 50 ml flush o
128. ly a sufficiently large reserve is present in the waste container to complete the elution 67 Rb Elution System Control Ran Klein University of Ottawa Software Errors As a final measure error mechanisms are included to test the software itself If an invalid physical sequence stage or a run type is set then an error code is set If the real time sequence stops prematurely before the exit stage of the physical sequence this is an indication that an error has been detected by the real time kernel Finally if the pump communication driver does not terminate and clear in time within 1 5 s this too is reported as a software error All these errors are intended for the developer for diagnostic purposes and are indication of errors in the software itself Warnings Warning messages Figure 3 12b are intended as important messages that should be addressed immediately but are not critical to the success of an elution The list below indicates the warnings that may be generated e Total volume eluted through the generator is above 90 the specification volume for clinical use e Calibration constant has varied more than 10 from the evolving average Outlier Highlighting As the system is redundant in design certain measurements can be tested by comparing to expected values One such measurement is the calibration constant for the activity counter which is computed in each daily calibration run The calibration is co
129. ly precise so that fine changes in flow ratio could be generated Finally the valve would have to be simple enough in design so as to ensure a high degree of reliability while making integration into the current system easily achievable 128 Rb Elution System Control Ran Klein University of Ottawa Of these considerations it seems that the most benefit could be gained for the least effort by revaluating the range of readily available flow control valves However if an alternative to the current two way pinch valve is still not feasible it appears that further research and development of the valve response model and its self tuning algorithm is the most promising route for future improvement of the RbES 129 Rb Elution System Control Ran Klein University of Ottawa Chapter 6 Conclusion This thesis describes the development of the Rb Elution System RbES as a complete system to automatically administer precise amounts of Rb activity from a Sr Rb generator for use as a perfusion tracer in PET This work describes the system hardware which for the most part was handed down from previous work 18 20 and the complete development of the software Much of the work focuses on development of a control system that can directly administer a constant rate of activity to the patient despite variation in activity concentration from the Sr Rb generator as a function of time and eluted volume Analysis of the system mod
130. m as many scans as possible between reloading of the generator This issue has only been addressed in the context of of the range of relative activities that can be eluted to patients Chapter 1 However several other factors must also be taken into account 121 Rb Elution System Control Ran Klein University of Ottawa Breakthrough Sr Activity Elution of Sr and Sr isotopes half life of 25 and 65 days respectively to the patient is undesired as Sr tends to accumulate in the bone marrow which is particularly radiation sensitive 15 Of concern to us was premature Sr breakthrough due to the pulsating flow of saline through the generator as the valve is cycled Daily calibration samples are used to test for the breakthrough of Sr activity if significant Sr activity is detected the generator cannot be used on humans The specifications of our generator permit 20 L of saline to be eluted before Sr breakthrough should be experienced We continued to use the generator on the development system past the specifications and experienced first breakthrough after approximately 40 L were eluted through the generator Once breakthrough appeared it was tracked over two months The measured breakthrough activity reached a maximum around the 40 day However if the activity is corrected for Sr decay it becomes clear that the breakthrough Sr to PRb activity ratio continues to increase as shown in Figure 5 15 82Sr 2Rb activity ra
131. maining activity is greater than the designated limit this is an indication of excessive Sr breakthrough and elution to patients should be avoided 1 3 Rb Elution Profiles The generator continuously produces Rb isotopes If saline is not flushed through the generator recharging occurs as the Sr continues to decay and the concentration of Rb in the generator volume increases The total Rb activity stabilizes within approximately 10 minutes as parent daughter equilibrium is reached as a function of Sr and Rb decay rates Figure 1 4 The level of equilibrium is dependent on the amount of Sr activity in the column Activity Figure 1 4 Rb activity during recharging of a generator An asymptotic rise is observed up to the level of Sr activity Time 0 10 min If saline is pumped through the generator the amount of Rb inside the generator decreases to a new asymptote as the effect of the flushing takes its role in the equilibrium The Sr decay is the contributing factor while the Rb decay and the flushing are the reducing factors of the overall amount of Rb of in the column Previous research 17 18 successfully modeled the eluted activity during constant flow rate flushing of the generator using variations of 1 The parameters C1 C2 C3 MBq Ry and R 1 ml are determined by fitting to empirical data The parameter f represents the flow rate ml min of the flush and t is the ti
132. me since the flush start A t C C exp R f C exp R f t 1 The curve has a characteristic peak that is reached as the Rb from the column volume is flushed referred to as the bolus stage As time progresses the activity decays to a lower asymptote as equilibrium with the saline flow is reached 19 This is referred to as the continuous stage The activity vs volume curve is nearly independent of flow rate at the bolus stage 18 and the peak activity is proportional to the amount of Sr attached to the 10 Rb Elution System Control Ran Klein University of Ottawa column The asymptote magnitude relative to the peak activity is dependent on the saline flow rate alone Figure 1 5 demonstrates activity concentration MBq ml curves at various constant flow rates through the generator measured ten days apart 20 The activity was measured on the generator output line using a positron counter while the flow rate was kept constant using a peristaltic pump Harvard Apparatus The later curve April 2 2001 has a lower overall magnitude than that of March 23 2001 due to the decay of the Sr however the general curve shapes are identical The continuous stage asymptote is higher for the low flow rates 10 ml min Although one might expect an initial step to maximum activity the initial rise is a result of Rb diffusion in the saline solution and the spatial response of the activity counter 90 T T
133. mportant to note that although not all the emitted positrons are captured in the fibre and not all the photons in the fibre reach the counting head the resulting TTL count rate is proportional to the activity and can therefore be factored by a calibration constant Pump An off the shelf peristaltic rotary pump head and control board manufactured by Harvard Apparatus were used The control board was mounted in an interface box while the pump head was mounted on the cart top to form an aesthetic installation Communication between the pump and the PC is achieved through RS 232 serial communication Control messages include setting the elution volume and flow rate while feedback includes the pump status Continuous pump status checking ensures both synchronization between the computer and the pump as well as fault detection Pressure Sensor A typical medical pressure sensor is attached to the saline lines immediately down stream from the pump This pressure is continually gauged to detect blockages in the line through an increase in line pressure Blockages are caused primarily by air bubbles that can 22 Rb Elution System Control Ran Klein University of Ottawa block the filters and are normally fixed by replacing the filter However blockages can also occur as a result of crystallization in the lines and pinched lines The sensor is supplied with 5 VDC from the DAQ board and returns a 0 05 V analogue signal which is propor
134. mputed based on the daily run but is then compared to an evolving average to ensure variations less than 10 Similarly the activity eluted during calibration and flush runs is compared with the activities of the previous day These activities are corrected for Sr decay which results in lowered activity as the generator ages Patient elution and test runs are tested for discrepancy with the expected values of eluted activity and eluted time Although eluted activity is monitored as a stopping criteria for all runs variations can occur due to response time overshoot or if the total activity is not reached Variation between the requested time and actual elution time for constant time and constant activity elutions is an indication of the accuracy of the flow rate prediction and control algorithm respectively 68 Rb Elution System Control Ran Klein University of Ottawa If any of the above variations exceed 10 of the requested value the variation statistic is highlighted in red This serves as an indication to the user that the elution did not complete as expected and attention to the system may be necessary 3 7 System Refinement Dose Calibrator Spike Removal Algorithm During experiments with the system spikes of activity were recorded from the dose calibrator as the activity rose above 500 MBq By monitoring the dose calibrator display during several elutions it was confirmed that the spikes arise from the dose calibrat
135. n System Control Ran Klein University of Ottawa activity rate is corrected for the Rb decay during transport delay through the volume of the lines from the activity counter to the patient outlet Vco at a constant flow rate f The threshold comparison algorithm presented by Epstein et al 18 was used as a benchmark for evaluating changes in performance during this research and was therefore maintained as an optional elution mode As expected the threshold comparison control results in fluctuations of activity rate around the desired activity rate as is demonstrated in Figure 4 1 for 50 relative activity elution over 30 s The fluctuations typically had a 2 4 s period depending on the flow rate and activity concentration from the generator The relative amplitude of the fluctuations was approximately 30 40 of the set point Instantaneous Activity Rate at Patient Outlet 6 T T T T T T T T RMS 52 6257 Activity Rate MBq s ro Time s Figure 4 1 Elution of 50 bolus activity within 30 s using a simple threshold comparison algorithm as described in 18 The actual activity rate at the patient outlet blue since the beginning of the elution is compared to the desired result green This chapter details the work performed on the control algorithm with the aim of improving the precision of the control algorithm while maintaining or improving other performance characteristics These characteristics includ
136. n the LV heart muscle P12 17 Relative perfusion non uniformities can be easily visualized from retention images P14 17 however in cases of diabetes and multi vessel disease the entire region can exhibit decreased flow which could lead to false diagnosis that perfusion is normal In order to achieve quantitative measurements one must first know how much activity was introduced to the patient during the injection 20 23 24 25 and its distribution over time The quantitative measurements that are provided by dynamic PET can be used to determine the absolute perfusion This process is equivalent to determining a system response based on a known input function controlled elution profile and a measured output function dynamic PET images The ability to measure perfusion quantitatively implies improved diagnostic ability over other modalities 26 The ideal tracer would be a positron emitting isotope that is freely diffused and completely retained and with a practical half life however none exists N labelled T n 10 min ammonia NH3 has been used as the clinical standard for quantification of myocardial perfusion while Rb has been recognized as a cost effective alternative N ammonia is produced using a cyclotron and is then administered using a syringe pump over a fixed interval e g 30 seconds This procedure results in a rectangular elution profile which is well matched with PET technology 27 The detectors on the scanner
137. nated many of these technologies e The sensor must be completely electrically isolated from the saline to avoid shock hazard e The sensor should not have any mechanically moving parts as the saline can leave crystallization which could interfere with the mechanism e The sensor should be easy to clean to keep the system sterile 34 Rb Elution System Control Ran Klein University of Ottawa e The sensor must be small enough to fit in the lead shielding and permit a large enough amount of volume to accumulate in the waste container before being activated e The sensor must fail in a way that would indicate overflow e The total purchasing and integration cost should be kept low With these considerations the ELS 1100 Gems Sensors Connecticut USA Electro optic Level Switch was chosen from a wide range of possibilities It uses an optical transceiver to determine the existence of a surrounding liquid through a change in light refraction as is shown in Figure 3 1 The choice of an optical level switch was due to its small size simplicity and lack of mechanical moving parts The main disadvantage is the need to keep the lens clean from saline droplets and crystallization However the sensor can easily be cleaned by wiping with a wet paper towel If a droplet does form on the switch it will signal an overflow resulting in a fail safe system LED Prism eN E Figure 3 1 Electro optic level switch Diffract
138. nctions to which the variables could be passed as parameters during the function call This completely removed the need to declare the global variables in the function o Global variable structure individual global variables were unified under several data structures Table 5 3 This enabled declaring only a few global variables as needed rather then calling an entire script file 104 Rb Elution System Control Ran Klein University of Ottawa Table 5 3 List of global structures and their contents Structure Content Description Name parametersINI Parameters loaded from the initialization file parametersCAL Parameters loaded from the calibration file such as generator information daily protocol history and calibration parameters for the system runs Parameters structure defining the current elution run created before the elution begins calS Calibration information calculated prior to the elution run logs Log structure created during the elution containing all records pertaining to the actual sequence of events during the elution GUIS Structure containing all parameters related to the GUI In addition a list handles to all dynamic graphic objects is included Improved graphic object management the software was modified to better manage graphic objects through deletion of unused objects or updating of object parameters rather than overwriting them as was inherited from th
139. nerator decays and the administered activity remains constant Sr Breakthrough As saline is flushed through the generator some Sr detaches from the column and appears in the eluate For this reason the column is made sufficiently long 2cm to bind any loose Sr 16 Over time migration of Sr occurs along the column Sr and Sr breakthrough can result if the generator is used indefinitely In high quantities these compounds may have ill effects on health as Sr is absorbed in bone which surrounds the bone marrow As cells in the bone marrow are continuously dividing to produce red blood cells the marrow is susceptible to genetic mutation due to radiation In severe cases this could lead to increased risk of cancer Although no action can be taken to reduce breakthrough once it has started Sr levels can be monitored in the eluate Since the half lives of both PSr and Sr are much longer than that of Rb a measurement of the activity of a flushed solution after sufficiently long time should yield the quantity of Sr eluted Health Canada guidelines dictate that Sr and 85Sr breakthrough not exceed 20 Bq MBgq and 200 Bq MBg respectively of the eluted Rb activity In order to take breakthrough measurements one should ensure that sufficient time passes for the Rb in the sample to decay below the regulation limits approximately 20 Rb Elution System Control Ran Klein University of Ottawa minutes If after 20 minutes the re
140. ning that could lead to conflicting adjustments based on how the data is treated 0 cece eeeeeceeeeeeeseeeeeeeeees 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 c cccecccesccesecesecesecseeeseceeecaeeeseeeeeeeeeeeeeeeeesrenteeereees 114 Figure 5 11 Valve response correction curve used to determine the PWM duty cycle required to achieve a desired valve flow Tati rin eea eoet Ey EE EROE nA ENAA EEE ENEN eben tees eevee 115 Figure 5 12 Comparison of performance measures of elutions n 10 over 30 s at 10 30 50 and 70 r lative ACtIvity s ceninin ea E EE E RE E A E E e a E i E e ii 118 Figure 5 13 Activity rate at patient outlet calculated based on the activity counter readings and dose Calibrator Treading S serrie Suteces Stes cede eee sha Seca och a teas esd ees ea ER 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 c ceesceesceseceseeeseceeeceeeeeeeeseeseeesreeseees 121 Figure 5 15 Breakthrough ratio progression over tiIMe ccccceeseeceesceesceseceseeeseceeceseeaecnaecseecaeeeaeeeseeeeeenneees 122 Figure 5 16 Normalized activity rate vs time curves measured during calibration runs over the life span OP A CCNETALOR ae hassles tec eehieties fence dese ela REE edi eee ke distin Gene
141. not reached within a given time the elution sequence is aborted and an error 44 Rb Elution System Control Ran Klein University of Ottawa gt 6 Calibration instructing to check for blockage is reported Once the threshold activity is reached the elution follows Elution This state is the actual elution of activity from the generator to the patient Two types of elution states are used depending on the elution run type Wait for Cumulative Activity Elution until the requested dose minus an anticipated overshoot activity is reached or the allowed time expires Wait for Cumulative Time Elution for a given time regardless of the amount of activity eluted At this stage the patient valve is switched to the patient outlet as needed This switch is delayed in time to account for the transport delay from the counter to the patient valve As a result only the volume past the threshold activity is eluted to the patient outlet while the initial rise is sent to the waste container Bypass to Patient Flush The final state flushes saline through the bypass to the patient outlet in order to push the activity in the lines to the patient outlet The volume of the patient line plus an extra volume 2 ml are flushed to ensure that no activity remains in the line The extra flush volume can be modified to simulate more closely the sequence followed during injection of 13 i N ammonia Dose Calibrator Reco
142. nt outlet Tco and its associated delivery decay are also accounted for Finally the flow rate is factored to convert the units as shown in the denominator of 6 Early detection of activity by the dose calibrator has been noted and results from detection of activity in the line prior to reaching the vial as demonstrated in Figure 3 7 This is corrected for by time shifting with the respective decay correction of the dose calibrator readings Ao t to correspond with the expected activity curves at the patient outlet The shift time T _ is solved for by minimizing the mean squared error MSE between the activity curves measured by the dose calibrator and calculated from the activity counter readings The shifted and decay corrected dose calibrator readings are symbolized by A ai t in 6 The calibration constant can be most reliably computed by factoring the integral of the measured doses over the time that activity is contributed to the vial as shown in 6 Using the integral activity accounts for all available data and therefore decreases the effect of noise 47 Rb Elution System Control Ran Klein University of Ottawa caw o Datta A 24 DYN ont Teo BE f ee A complimentary approach can be carried out to compute the activity counts Nae t based on the dose calibrator measurements Aca This requires deconvolution of the dose calibrator measurements with Rb decay function and shift decay correc
143. ntrol Ran Klein University of Ottawa Predictive Corrective Control For accurate prediction two conditions must be satisfied 1 The activity concentration just prior to the merger Cy must be accurately predicted 2 The valve response must be accurately modeled In practice perfect prediction is impossible due to measurement errors and imperfect modeling A corrective mechanism should be integrated to complement the prediction by driving the output error to zero A PID loop or variation of it can be used for this correction While the predictive algorithm accommodates fast changes in the activity concentration eluted from the generator the corrective mechanism serves to refine the valve control to reduce long term errors The corrective mechanism must compensate for all the errors and inaccuracies such as activity concentration prediction errors and imperfect actuation of the generator valve oe Prediction Valve Valve PWM ctivity Rate Algorithm Response Duty Cycle Correction Activity Rate Set Point Correction Scaling Measured Corrective Activity Rate Algorithm Figure 4 11 Block diagram of the predictive corrective control of a PWM valve The corrective mechanism included in the RbES is a modified PID loop with a forgetful proportional component as shown in Figure 4 10 In addition the correction must be scaled to account for non linear sensitivity of the valve in the predicted duty cycle range Figure 4 11
144. ome activity spill over However we believe that most of the overshoot is a result of transport delay between the merge point of the generator and bypass line and the activity counter 2 4 Further Development of the Rb Elution System RbES The primary motivation for developing the RbES is to develop an infusion system capable of eluting a given activity at constant rate over a prescribed time period from a Sr Rb generator independent of generator age so long as sufficient amounts of activity can be provided by the generator The system is required to operate in a clinical setting and therefore must be reliable easy to operate and above all safe The prototype that was developed prior to the work of this thesis was incomplete with the following issues still needing attention e Precise constant activity elutions were not achieved Fluctuations around the set point needed to be significantly reduced through an improved control of flow through the generator e Only a few error detection mechanisms were implemented Of those that were implemented the report to the user was uninformative e There was no means for the operator to manually terminate an elution if a problem was noticed during the elution e A key requirement of this system is to reduce radiation exposure to the technologists by automating the system and allowing monitoring from a distance Although this goal was mostly achieved in the prototype system bre
145. ompensate for errors during the elution and also reduce prediction error but some degree of error is inevitable Since the elution begins with a high activity concentration from the generator as the bolus portion of the activity curve is eluted the valve flow ratio during the beginning of the elution is kept low During the later portion of the elution the valve flow ratio increases if a high relative activity was requested Since more prediction error is expected as the elution progresses the activity rate at higher ranges of valve flow ratios r lt r is associated with more prediction error than the activity rate associated with the lower range of valve flow ratios r lt r For this reason the error measurements associated with the lower valve flow ratio range must be weighted more heavily for adjustment of the model parameters Both the theoretical analysis and experimental analysis point to a stable and converging self tuning model of the valve response over repeated elutions with the same requested profile However some variation in ideal parameter values is expected between requested profiles The amount of variation cannot be estimated with the available data but could be addressed by future research The experience to date is over a relatively short time period and in a well monitored environment Furthermore these results were measured using a single generator In a clinical setting generators will be replaced every 2 months approx
146. on Emission Tomography cccccesccescceseceseesecseecaeeeseeeseeeeseesseenseceaecaecsaecsaecsaeaecaeeeeceeeaeeseeeeas 4 1 2 Sr Rb Generator a Cost effective Tracer SOULCE c ccescsssssssssessesessessessessessessessessessessessesseesesseeseeseene 7 Sr Br akthrougbhn asenn e e E E E E RRE E T E else TEE E E ai 9 13 RD Elution Profilese rans re PR EE AEE CA E ee mn 10 1 4 Constant Activity Elution for Quantitative Perfusion Measurement in the Left Ventricle of the Heart 11 1 5 Quantitative Perfusion Measurements Using PRD c ccccccssessesssssssessescsessessescssssssssssussessesessessesesseeseeens 14 Chapter 2 The Second Generation Rb Infuser a starting PpOint cc ccccccccccscesessssessessesessessesessessssessesseeeese 16 2 1 The Daily Protocol and Elution Types ccccccccssessseesseesceeseesseeecnsecesecaecsaecsaecaeeeaeeeeeeeeesereseeneeeeeenaees 17 2 2 Hardware Description serne ian an cbse sac a E o EEE E E RE E e iien 19 2 3 Prototype Performance nsise raii eaii rii A E cue lives E E R E R O ii 25 2 4 Further Development of the Rb Elution System RDES c cccscsscsseesssssessessessesessessessessessesseesesseeseeses 26 Chapter 3 System Design and Conceptual Understanding 0 ccceccceescsesceeeeesecesecceceeeeaeeeneeseeeeeeeneeneeeeenes 28 SD A L OTR TE secs ies des scapes dts se ctacedes sa toca beacia each od dode ponder cab is dnt ube c cantatas E E wes igher petits 28 Functional Requirements s
147. on for profit self governing organization which tests and certifies equipment in order to ensure compliance with safety standards 98 Rb Elution System Control Ran Klein University of Ottawa Entela Toronto Ontario The test includes electrical leakage proper grounding power isolation and power consumption These tests ensure general safety from electrocution fire hazard and surge protection The measurements obtained for certification are listed in Table 5 1 Table 5 1 Canadian Standards Association CSA field evaluation for electro medical equipment results for two RbES systems Test System 1 System 2 Electrical Rating 1 19A 120V 60Hz 1 19A 120V 60Hz Line to chassis surge 1000V Pass Pass Chassis to ground polarity with lt 1 Pass lt 1 Pass ground open normal Reverse Chassis to ground polarity with lt 1 Pass lt 1 Pass ground closed normal Reverse Although most of the fail safe mechanisms were implemented in software the hardware design also handled some of these aspects Test cases including hardware failure tests are described in Appendix A These are intended to ensure that the patient is not exposed to more than the radiation dose set in health regulation guidelines Hardware malfunction scenarios were tested such as a computer crash power outage disconnected control lines etc The Worst Case Scenario Even after much emphasis on developing a
148. ons 15 60 s however at longer durations 120 and 240 s the HC TC method has difficulty controlling low relative activities At durations of 240 s the PCC PWM method can perform elutions using as low as 36 relative activity elutions while HC TC can only achieve relative activities where activity was at least 69 The measured maximum relative activities were almost identical throughout the entire range of durations The HC TC method was not capable of achieving low activity rates leading to premature elution of the requested activity Pump flow rates were set in the same manner for both control algorithms to avoid bias however it may be that by better adjusting the saline flow rates this short coming of the HC TC method could be overcome Relative HC TC Relative Activity Range Relative COP Relative Activity Range Activity Activity ra LA 140 120 100 80 60 40 20 o 15 30 60 120 240 15 30 60 120 240 Duration s Duration s Figure 5 14 Range of relative activities that can be achieved using the HC TC method left and the PCC PWM method right without significantly influencing the precision The high range indicates that the requested activity is higher than can be provided by the generator while the low range indicates activity that is too low for the control algorithm to generate 5 7 Generator Life Span In order to increase the cost effectiveness of Rb generators one would like to perfor
149. onstant re T EA LOTS get 0 suet gt K 0 00036805 2 5878e 009A r 0 0585 Calibration Constant MBq ml cps N 0 500 1000 1500 2000 2500 3000 3500 Activity MBq Figure 5 3 Correlation of calibration constant to generator activity Calibration Constant vs Flow Rate Calibration elutions are performed with a saline flow rate of 15 ml min but elutions are performed in the range of 5 25ml min Since the calibration constant is a measure of efficiency intrinsic and geometric of the activity counter it is expected that this constant remain valid regardless of elution flow rate To test this assumption five sets of calibration elutions were conducted at flow rates ranging 5 25 ml min at increments of 5 ml min Figure 5 4 The value of the calibration constant did not vary significantly over the range 10 25 ml min however a slight decrease was noted at 5 ml min flow rate This reduction may be due to longer transport times to the dose calibrator than expected due to inaccuracy in the line volumes At this low flow rate significant Rb decay is experienced while at the higher flow rates the delivery time error is 2 to 5 times shorter 107 Rb Elution System Control Ran Klein University of Ottawa a Variation in calibration due to flow rate x 10 x 3 5 i j 2 5 0 5 10 15 20 25 30 Flow Rate ml min Calibration constant MBq ml cps N Figure 5 4 Calculated
150. or itself and not from the RbES or the communication protocol As the activity in the dose calibrator rises it switches scales to avoid saturation This scale transition is not smoothed lasts approximately 5 seconds and is uncontrollable Furthermore the peaks can be in the form of an increase or decrease in measured activity or combination of the two in the form of two consecutive peaks These peaks can vary by many orders of magnitude from the actual measurement It was determined that during calibration runs the spikes have a significant effect on the calibration constant in some but not all cases To accommodate this artefact an algorithm was implemented to remove these spikes A search window of 7 seconds was passed over the entire curve to locate the ratio rp i between the center activity and the average of the two extreme readings If the maximum ratio in the entire series is considered significant by 13 where T is a threshold ratio all the readings in the window are deleted and interpolated from adjacent values The process is repeated until no more significant peaks are found 2 Aea 7 f gt T 13 Aali 3 A 1 3 With T set to 0 1 good results were obtained Almost all peaks were removed while max log r t maxi log the overall curve shape appeared to be unchanged Figure 3 17 demonstrates the same calibration results with and without the peak removal algorithm The corresponding MSE chang
151. ow rate ml min Sigmoid factor for valve response model Sigmoid horizontal factor for valve response model Hysteresis of the generator valve Activity counter intrinsic efficiency cps Bq Activity counter calibration constant 10 cps ml Bq Average activity counter calibration constant 10 cps ml Bq Linear slope of valve response model Constant offset of valve response model Count rate set point counts s Desired measured flow ratio at time t Threshold desire flow ratio at which dIT dr 2 L Valve duty cycle ratio at time t Valve lower and upper bounds of duty cycle Ratio of Sr to Sr isotopes at time t since manufacturer measurements So Measured time shift correction of dose calibrator curve s Transport delay between points P and Q s Requested Elution Time s Measured Elution Time s Time delay of initial error removal mechanism IERM s Volume of lines between points P and Q ml Measured correction to eluted volume ml Hysteresis learning factor Valve response upper limit learning factor Valve response linear slope learning factor Valve response sigmoid scaling learning factor Dose calibrator aperture response time constant 1 ml Decay constant 1 s 0 0091 for Rb Forgetting factor in modified PID controller Valve cycling frequency Hz Counter clock frequency Hz Range of correction during saturation Rb Elution System Control Ran Klein University of Ottawa Introduction Thi
152. own in 22 The proportional component depends on previous errors whose weights gradually decreased over time With set to 0 995 the current error reading E n has a weight of 1 while the previous reading E n 1 has a weight of 0 995 But the weights of earlier readings say E n 100 corresponding to 5 s earlier due to refresh rate of 20 Hz have a significantly reduced weight 0 606 Most of the error correction is based on recent history which strikes a balance between the controller s speed of response to change in error and immunity to noise The model of the forgetful PID controller is shown in Figure 4 10 S n E 0 S n 22 Corrective 7 3 Controller Correction i a tn Ses ay os ea a Se ype eee en Seve a ee ee Figure 4 10 Modified PID correction implementing a forgetful proportional component Predictive Control The critical disadvantage of feedback control is that the controller response is always delayed In this case the delay is relatively long compared to the total elution time This delay combined with the varying activity concentration from the generator makes a simple feedback controller inadequate 39 40 To avoid delayed response one would like to predict the activity concentration at point M Figure 3 3 where the bypass and generator flows 85 Rb Elution System Control Ran Klein University of Ottawa merge One option is measuring the activity in the generator line just prior
153. positron counter exist on two levels The first ensures hardware functionality by verifying that some counts background activity are always being detected Background activity is unavoidable and should result in some counts If the counter value is unchanged over 5 consecutive seconds an error is reported At a higher level the software ensures that a threshold activity is reached within a given time window This tests that sufficient activity is eluted from the generator as expected Dose Calibrator Communication Errors Although the dose calibrator is tested prior to every calibration or test run for proper settings it is also tested for communication errors during the elution This is intended to ensure that it is not unplugged or turned off during the calibration or test resulting in false readings Maintenance This test includes testing of the waste container overflow switch If the waste container is found to be full in the first 5 seconds of the elution the elution is aborted with a proper message This is to avoid overflow of the waste leading to a spill inside the cart and onto the printer PC UPS or power cords on the lower shelf If overflow is detected during the elution but after the first 5 seconds a warning message is displayed at the end of the elution and the next elution will not start until the waste container has been emptied However the elution continuous without interruption to avoid aborting an elution needless
154. pproach to radiodosimetry Appl Radiat Isot Vol 38 No 3 pp 233 239 1987 N J Epstein A Benelfassi R S Beanlands R A deKemp A 82Rb infusion system for quantitative perfusion imaging in 3D PET App Radiat Isot Vol 60 pp 921 7 2004 134 Rb Elution System Control Ran Klein University of Ottawa 19 20 21 22 23 24 25 26 21 28 G P Gennaro B C Bergner P S Haney R H Kramer M D Loberg Radioanalysis of Rb Generator Eluates Appl Radiat and Isot Vol 38 No 3 pp 219 225 1987 N J Epsein Modeling and simulation of a rubidium 82 infusion system Internal document at University of Ottawa Heart Institute Cardiac PET Unit August 2001 K L Gould PET perfusion imaging and nuclear cardiology J Nucl Med Vol 32 pp 579 606 1991 L Golanowski R A deKemp R S Beanlands T D Ruddy 2000 Variance and covariance of Rb kinetic parameters computed simulations and dynamic PET studies Proceeding of the 22 annual EMBS International Conference pp 1096 99 2000 W J Lin R R Sciacca R L Chou A F Laine S R Bergmann Quantification of perfusion in human subjects using Rb and wavelet based noise reduction J Nucl Med Vol 42 pp 201 208 2001 K Yoshida N Mullani K L Gould Coronary flow and flow reserve by PET simplified for clinical applications using rubidium 82 or nitrogen
155. r initially increases but then decreases as the parameters G and L converge The elution time error increases in magnitude almost in unison with the RMS error During the entire training session Tmax is unchanged as the desired valve ratio does not reach the region 100 open required for tuning Imax The evolution of parameters G and L can also be viewed on the plot of the parameters Figure 5 8 Parameter L is initially far from its nominal value and adapts slowly Parameter G adapts faster and overshoots its nominal value Once L begins to converge to its nominal value the over correction of G becomes prominent and its correction reverses As both parameters evolve they converge towards their nominal values and remain relatively stable in 17 subsequent runs G 26 5 0 65 L 0 00677 0 00017 111 Rb Elution System Control Ran Klein University of Ottawa Trax 1 0 5 Parameter L and G adaptation 0 1 1 1 L T T T T T T TT o 20 40 60 80 Sr gt S L A N 0 01 l l N Ww 0 005 i 255 ses o 20 40 60 80 100 G M 204 a 10 20 154 Sick o f f f f 0 20 40 60 80 100 o RMS Eror 100 5L 50 0 o i fi fi L fi fi fi o 20 40 60 80 100 0 1 2 3 4 5 6 7 a Time Eror w L x 10 OL 50 1 L 1 1 o 20 40 60 80 100 Sample Figure 5 7 Evolution of parameters G and L Figure 5 8 Evolution of parameters G and L during self tuning through repeated runs of
156. rameters should be adjusted through small increments in order to reduce the effects of problematic elutions on the parameters In addition small adjustments allow convergence to nominal values without exaggerated overshooting On the other hand if the adjustments are too small convergence may be too slow The predictive corrective control of the pulse width modulated valve PCC PWM was designed so that the only free parameters are in the valve response model These parameters listed in Table 4 2 can be tuned based on the activity rate errors measured over the course of a constant activity elution The algorithm for tuning these variables is detailed below 91 Rb Elution System Control Ran Klein University of Ottawa Table 4 2 Parameters used by the prediction algorithm Parameter Manually Converged Affects tuned value value Sigmoid scaling 16 26 5 Sharpening of the knee in the response G Response at low valve flow ratios r lt r Linear slope 0 004 0 0067 Slope of linear range L Response at high valve flow ratios r lt r Valve upper bound 0 997 0 9975 Threshold when valve response is equivalent to Imax full open If too large peaks will occur at beginning and end of elution profile Valve lower bound 0 0 Overall error trend Tin Activity too high elution too short bound needs to be lowered Activity too low elution too long bound needs to be raised
157. rate elutions The use of an on off valve as opposed to a variable flow valve is justified The justification is partially through the ability to simulate variable flow by cycling the valve between its two states at a constant rate and modulating the duty cycle pulse width modulation This leads to modelling of the valve response and developing a control algorithm A combination of varying activity concentrations from the Sr Rb generator long transport delays and short elution times render non model based control systems inadequate This problem is resolved using predictive corrective control a prediction algorithm is developed to compute the activity concentration from the generator based on the volume eluted through it This is made possible by the good reproducibility of the activity concentration vs volume curve from the generator which is measured using a daily calibration run The eluted volume and any transport delays can also be computed with sufficient accuracy making prediction of the valve control possible A corrective mechanism driven by a conventional feedback loop is also included The resulting control algorithm is referred to as a predictive corrective control of a pulse width modulated valve PCC PWM Chapter five attends to two topics testing of the complete RbES as a final product and comparing PCC PWM performance with a simple threshold comparison TC control algorithm included in the prototype system Testing of
158. rding In the case of calibration or test runs additional readings must be recorded from the dose calibrator These reading must be over at least the duration of the elution 2 x elution times in total To ensure that sufficient readings are always taken data logging continues for 360 seconds following the elution stage The calibration procedure is primarily intended to calculate the calibration constant K in 2 for the activity counter This constant gives physical meaning to the events that are counted by the detector Since this number is dependent on many parameters which cannot all be calculated an alternative has been proposed to calibrate the counter to an external 45 Rb Elution System Control Ran Klein University of Ottawa standard 19 20 The use of a dose calibrator as a reference calls for conversion of units and accounting for decay during the calibration process In addition the dose calibrator acts as an integrator as activity accumulates in the vial Transport delay from the activity counter to the dose calibrator Tco and its associated decay must be accounted for as well The calibration constant is an overall measure of the counter s efficiency incorporating geometric and intrinsic factors Figure 3 6 Lead Shielding Optical Fiber Detector Positron Paths Saline Aperture Line Wall Figure 3 6 Schematic diagram of the activity counter illustrating some
159. rectangular form Typical elution profiles using both control modes are demonstrated in Table 5 4 Elution Time Error T piion Treg 32 r 2 if A ES c Te Error RMS 100 33 c Table 5 4 Typical constant activity elution profiles for various relative activities and over 30 s Relative HC TC PCC PWM Activity Instantaneous Activity Rate at Patient Outlet Instantaneous Activity Rate at Patient Outlet z115 r r r g 04 r r r r r g 4 RMS 45 5195 k 03 g 2 63 10 E os Wee D g 2 oat 2 o i l 2a l 40 50 60 70 80 90 100 110 120 40 50 60 70 80 90 100 110 120 Time s Time s Instantaneous Activity Rate at Patient Outlet Instantaneous Activity Rate at Patient Outlet gt 3 a15 T T T T T 3 Fi RMS 12 2317 2l Z 1 3 g 0 30 i gt os z SB 49 3151 2 o 1 f 1 L g o fi 1 1 10 20 30 40 50 60 70 10 20 30 40 50 60 Time s Time s Instantaneous Activity Rate at Patient Outlet Instantaneous Activity Rate at Patient Outlet 6 gt 15 T T T T V k RMS 52 6257 Fi FA 4 1p Q 50 gt 2 gt 05 g 2 2 2 o o S S E E E 10 10 15 20 25 30 35 40 45 50 55 Time s Time s Instantaneous Activity Rate at Patient Outlet Instantaneous Activity Rate at Patient Outlet g 8 r r r r F 6 r r 2 al Q Q 70 o 2 2 2 0 g 0 5 5 Time s 117 Rb
160. relative activity were justified as a reasonable range for clinical applications A newly loaded hot generator should have about 2000 MBq bolus activity first 15 ml eluted and would decay to approximately 785 MBq within 5 weeks At the UOHI Cardiac PET Center a typical dose is 550 MBq while a small dose is 200 MBq A small dose on a hot generator corresponds to 10 activity while a cold generator and a large dose corresponds to approximately 70 generator activity Typical elutions are 30 seconds long and were therefore used in these measurements Instantaneous Activity at Patient Outlet 16 T T T T Activity Rate VBq s Time s Figure 2 5 Elution of 50 bolus activity within 30 s using a simple threshold comparison algorithm as described in 18 The actual activity rate at the patient outlet blue since the beginning of the elution is compared to the desired result green 3 A A Bq are physical units that measure the number of nuclear disintegrations per second In our case we use MBq referring to one million positron emissions per second 25 Rb Elution System Control Ran Klein University of Ottawa Using a threshold comparison approach Epstein et al reported fluctuations around the set activity rate of about 40 as demonstrated in Figure 2 5 These fluctuations were believed to be caused by a delay in the activity measurement due to the real time system refresh rate 50 ms and s
161. rer recognized as meeting the highest quality standards However only long term experience will clarify this reliability issue 4 3 Variable Flow Control Algorithms Even with an ideal actuator in place an appropriate controller must be designed The goal of the controller is to monitor the progress of the process and make proper adjustments to the actuator in order to reduce the output error Development of a controller must take into account the nature of the system being controlled the desired results and the limitations of the design Several key points to be considered during the development of the RbES controller are listed below 1 Typical elution times are short 30 60 seconds leaving little time for conventional feedback controls to stabilize 2 Feedback to the system has a relatively long inherited delay due to the time required for activity to flow from the generator to the activity counter and the need to accumulate counts 3 The feedback delay is not constant due to variation in flow rates 4 The activity concentration in the saline flowing from the generator varies as the elution progresses but the activity concentration vs eluted volume relationship is constant 18 5 Most of the activity from the generator is contained in the initial bolus phase One would like to make use of this activity rather then pass it to the waste to achieve high relative activity elutions 81 Rb Elution System Contro
162. robust system that can identify and handle potential errors there is always the risk of overlooking some erroneous scenarios An additional cause for concern is that there may be situations when errors cannot be detected In order to clarify the level of risk the following worst case scenario was developed The generator has recently been loaded with Sr and morning flush and calibration runs pass successfully with 6800 MBq and 3400 MBq measured activities respectively A large patient is to be imaged so an elution is started with a high dose 1500 MBq over 30 s The elution volume is limited by the maximum elution volume parameter 30 ml which the autonomous pump is set to deliver The elution begins normally the threshold activity is passed and patient valve is opened As the activity concentration from the generator is still relatively low the generator valve is set wide open With the valve fully open all the activity from the generator is routed to the patient At this point the operating system stops responding which prevents the software application from controlling the RbES The 99 Rb Elution System Control Ran Klein University of Ottawa actuators remain in their previous state since the hardware is unaffected the generator valve and patient valves are open and the pump is running Although the technologist should be monitoring the system at this point he she may be distracted by an urgent call of the patien
163. ror while writing elution file Restart the system 40006 Error while loading INI file Restart the system 40007 Error while loading CAL file Restart the system 40008 Error while loading elution file Restart the system 40009 No calibration file found for today Conduct calibration run before proceeding Positron Detector 50001 50002 No counts read by positron detector Check wiring to interface box Threshold activity not reached Check plumping for air bubbles and blockage and ensure that the generator is properly connected 50003 Threshold activity could not be found in calibration curve Recalibration may be necessary Capintec Dose Calibrator 60001 Communication error with Capintec dose calibrator encountered during elution Check connection between computer and calibrator and restart the elution Maintenance 70001 Software 90000 90001 90002 90003 90004 Otherwise Waste container full Empty container and restart elution Unexpected procedure step encountered Contact the developer Unpredicted termination of Physical Sequence Contact the developer Unexpected Run_Type value detected Contact the developer Real time processes not responding on clean up Contact the developer Illegal desired pump state passed Contact the developer Unknown error code reported Contact the developer User Intervention Error Code Meaning Termination of elution and exit issued by operator Emergency stop button pressed No
164. rough the touch screen which will display a keypad and exit button Other buttons and radio buttons must be added only at relevant states and 30 Rb Elution System Control Ran Klein University of Ottawa immediately removed at the end of each state Prior to initiating an elution all the parameters set by the user must be displayed for confirmation The real time graphics display must include a system diagram with updated information about the state of the system This includes the current activity rate reading flow rate valve status and expected accumulated activity at the patient outlet In addition progress bars must be included for each stage of the elution so as to facilitate monitoring of the system An emergency stop button must be enabled throughout the elution and take immediate effect to bring the system to the safe mode At the end of an elution reports must be generated based on the type of elution and its mode of completion If an error is detected a red screen including details of the error and recommendations to resolve the issue must be displayed If the emergency stop button is pressed a yellow screen must contain an appropriate message On successful completion a grey screen must list statistics relevant to the elution In addition a separate window must list a comprehensive display of all statistics in addition to activity curves relating to the activity rate and the integrated activity at the patient outle
165. s work describes the development of a Rubidium 82 Rb infusion system for use in positron emission tomography PET The system is based on a Sr Rb generator which produces Rb activity continuously The system is aimed at administering the activity to patients in a precise and controlled manner Rb is used as a PET tracer for measurement of myocardial perfusion blood flow in a non invasive manner Conventionally Rb perfusion imaging has allowed measurement only of the relative perfusion with healthy regions of the myocardium serving as the standard to which reduced perfusion can be compared However in cases of globally reduced perfusion no healthy standard is available which may lead to misdiagnosis Quantitative perfusion measurements aim to solve this problem It is believed that in order to improve their robustness the Rb activity should be introduced at a constant rate of activity The goal of this project is to develop a system that is capable of eluting Rb at a constant rate of activity from a Sr Rb generator for use in a clinical and experimental setting The first chapter begins by introducing PET and its applications In particular the chapter focuses on perfusion measurements in the left ventricle heart muscle The focus then shifts to perfusion tracers and how they are produced Once the need for Rb is justified the functioning history and application of Sr Rb generators are describ
166. ses as high as 2200 MBq per scan but scans may be repeated as needed Typically two scans rest and stress are conducted at any one session meaning that the guidelines permit routine exposure to 4400 MBq Thus this analysis concludes that this worst case scenario will result in radiation exposure that is within the guidelines and thus of no significant risk to the patient s health 5 2 Test Cases In addition to testing during general use of the system test cases were written to validate the design requirements and test for bugs The cases were written at an early stage of 100 Rb Elution System Control Ran Klein University of Ottawa the development process with the requirements in mind and later updated as the implementation details became finalized No formal test approach was used but in order to ensure thoroughness the tests attempted to exercise as many the software branches as possible including creating simulating errors As stated above the test cases also include a hardware testing aspect in the form of malfunction detection testing and actuator response verification The tests were all carried out manually by the tester Manual testing was necessary because testing included monitoring of the system display and actuators in a way that could not be easily automated In addition due to the real time nature of the system it was undesirable to further consume system resources with automated testing software Finally
167. sessessesseesseeees 6 Figure 1 3 Sr Rb decay Seq ete Sica ctseccasc detec ctanscasvevaasiinyscbossuvesvdss dynasslal wnnsierclbncsodicmitarcenionuxrsiatssess 8 Figure 1 4 Rb activity during recharging of a generator cccsscsssesssessesssessesssesseessessecsessseesecssessesssessesseessess 10 Figure 1 5 Generator activity volume curves with different flow rates and at different times eee 11 Figure 1 6 Dynamic Rb imaging of a canine heart c cccscsssesssessessssssesssessessusssecsesssecsscsscssecsusesecsessseeseeeseess 12 Figure 2 1 Daily protocol flow chart secorir a ode enka tocessaesddsecte E EEA A EE A 19 Figure 2 2 Hardware component diagram of RbES sessssssssreesssrssrsseseesessteressteresteserstsseenesseeresseseeseseesesses 19 Figure 2 3 Photograph of the assembled RbES and its Components cc eeceseeeeeseceeeeeceeeeeceseeeeeaecaeeeeeneeaees 24 Figure 2 4 Photograph of top cover of the RDES cee ceeecseseceseeeesseceeesecseeseesecsevsecsaeeeceaecaeesecaeeeaeeeeeaeeaees 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 c cccceescescessceesceecesecaecaecseecaeeeaeeeeeeeeeeeeseeeneeeneeeeenaeenaes 35 Figure 3 2 Response of transport of activity through a fixed volume line at a fixed flow rate eee 40 Figure 3 3 Flow control through genera
168. sport time from the generator to the merging stopcock Tgm t is calculated by integrating the flow through the generator over Vom using 27 The transport time Tgu t is used to estimate the Rb decay between the generator and merger Dem t in 26 and 27 However the decay from the generator to the activity counter during the calibration run Doc must be backwards corrected since the generator outlet is the point of reference for the Rb decay To clarify the concept one must remember that the activity in the line changes as transport time passes therefore both the time shift and its corresponding decay must be corrected to any given reference point the estimated generator outlet t Dey e 7 where Voy f r e de 27 t t Toy t The volume shift Vv included in 26 improves alignment of the prediction activity Corr curve with the actual elution curve This adjustment is crucial for compensating for delays in pump start response time and any other introduced delays During the beginning of the elution the valve is fully opened which allows reproducing the initial rise of the activity vs volume curve measured during calibration When significant activity but less than the set point activity is measured the activities vs volume curves are aligned through a volume shift to minimize the MSE The optimized volume shift v serves to fine tune the activity Corr prediction in 26 87 Rb Elution System Co
169. stness is of utmost importance to ensure that the center is continuously productive In the United States mobile PET units have been providing services to rural areas Since a cyclotron cannot be mounted on a truck these services have been limited to tracers with sufficiently long half lives to be transported This not only limits the types of diagnosis 14 Rb Elution System Control Ran Klein University of Ottawa that can be obtained but also significantly increases the costs of operation N ammonia is too short lived for transportation therefore excluding perfusion measurements from the services offered Generator produced isotopes such as Rb could serve as an ideal substitute as a perfusion tracer The price and complexity of installing maintaining and running a cyclotron have limited accessibility to PET to only the wealthiest regions With the development of cost effective radionuclide delivery systems such as a constant activity Rb elution system state of the art quantitative perfusion PET scans can be offered to regions of low population density as well as to less wealthy communities 15 Rb Elution System Control Ran Klein University of Ottawa Chapter 2 The Second Generation Rb Infuser a starting point This chapter discusses previous work in the development of systems to infuse Rb tracers at the UOHI and elsewhere Capabilities and limitations of these systems are discussed and the motiva
170. stopping of the elution If the rise is detected early enough to avoid the overshoot as with most cases at low flow rates the total elution time to reach the same activity may be longer thus introducing a variation in elution time error With the current implementation the variation in early rise detection is a fundamental limit Range of Relative Activities as a Function of Elution Duration Although 30 s elutions are the norm there may be reason to believe that longer elutions may permit more accurate measurement of perfusion 18 27 28 Since this issue is being addressed through a current study at the UOHI it was deemed necessary to assess the system characteristics at various elution durations A second set of elutions was aimed at determining the minimum and maximum relative activities that can be eluted from the generator as a function of the elution duration Elutions of 15 30 60 120 and 240 s were used as a test set in which the maximum relative activity was determined empirically The success of each elution was evaluated by testing for no significant drop in activity recorded at the end of the elution due to insufficient activity in 120 Rb Elution System Control Ran Klein University of Ottawa the generator and that both the RMS error and elution time error remained unchanged from the 30 s elutions As the results in Figure 5 14 show the performance between HC TC and PCC PWM is similar for short elution durati
171. t Test Runs For each of the patient elution types constant flow constant time and constant activity a test mode must be offered as well These modes are identical to the patient elution modes but include data logging from the external dose calibrator These data are used to confirm that the actual activity as delivered to the patient outlet is similar to the expected activity These modes can be used to test the system Elution Recording and Reports Data logging for analysis and recording is at 1 Hz regardless of other measures and will include a log from the start of the elution until its termination For all elutions the elapsed time activity counts line pressure and generator valve open time must be logged In the case of calibration runs and elution tests the dose calibrator reading and the serial communication delay must also be logged In addition the elution settings and event times must be recorded 31 Rb Elution System Control Ran Klein University of Ottawa 3 2 Initial Design Considerations Safety A first concern with any system that interacts with humans is safety and even more so when the system is used clinically and interacts directly with the patient s body The design must have multiple robust mechanisms to ensure that in any case of failure the patient is not at risk The following safety requirements were set and tightly followed 1 Under no circumstances may any electric current leak thro
172. t The system continues routing activity to the patient The autonomous pump continues to run until the prescribed volume 30 ml is reached Although the valves remain in an open position the stopped pump prevents further flow of Rb to the patient When the technologist returns to monitor the system she he notices that the user interface is not responding or updating In response the computer is switched off which cuts power to the DAQ and buffer boards and the valves return to their safe positions It is unlikely that the pump will continue eluting past the preset volume 30 ml The pump chosen for this application is reputed for its reliability and accuracy due to the use of a stepping motor to actuate the peristaltic head In terms of reliability the use of a stepping motor indicates that the pump controller must remain operational in order to actuate the pump If the controller locks up the actuator by design will stall thus limiting the deliverable volume to the prescribed dose This is considered the worst case scenario since it results in a maximal dose to the patient The cycling signal is produced by a hardware counter on the DAQ even when the computer stops responding the signal is still generated During this time it is expected that most of the bolus activity will be eluted to the patient resulting in an eluted activity as high as 4000 MBq depending on the generator activity Health regulation guidelines permit activity do
173. t 10 min between runs Non Functional Requirements The non functional requirements are additional constraints on the design that define desirable behaviour or design of the system These requirements do not define the functionality that the system must provide e The system must not pose a health risk to patient operator or any other person under any circumstance e The system must react in a predictable and controlled manner at all times e Any detectable error will result in a controlled termination of the elution with all actuators in a safe mode o Patient valve set to waste o Generator valve set to bypass o Pump stopped e Between each run the application will be completely re initialized so as to prevent the chance of any data being carried over to the next run e The system must be self contained with an interface to an external activity measurement standard for calibration and testing purposes 29 Rb Elution System Control Ran Klein University of Ottawa Other Requirements Performance Since the Rb elution system is designed as a real time application it must meet performance requirements that are suited for the task at hand As with the prototype system the most crucial sensor for the control algorithm is the activity counter as it is the sole sensor participating in the feedback loop In order to measure activity in the line positron counts must be collected over sufficiently long time Howe
174. t in particular To achieve the benefits of both tracers we would like to produce an elution system that can control the flow through the Sr Rb generator to achieve a rectangular activity vs time profile during injection to the patient It is expected that if this is achieved perfusion measurements using both 3N ammonia and constant activity Rb elutions could yield similar results Constant activity Rb however would serve as a cheaper solution to centers that do not have access to an on site cyclotron It follows that once constant activity Rb elutions are achieved a comparison study of perfusion measurements with Rb and N ammonia would precede clinical use Constant activity Rb elutions will serve the immediate need for such a study It is also anticipated that constant activity elutions are vital to achieving a reproducible quantitative perfusion measurements in a clinical setting 25 The Rb elution system must therefore be designed to meet the strict requirements for routine clinical use The goal of using a Rb elution system in routine clinical PET work dictates an emphasis on accuracy robustness minimal maintenance and operational simplicity These criteria are set by the nature of a system that interacts directly with human patients and is operated by technologists that must perform multiple tasks in a timely fashion Since this system is most suitable for centers that do not have access to a cyclotron robu
175. tatus The opening screen displays a timer countdown until the next elution can be started Figure 3 11a This accounts for the minimum 10 min interval required between elutions The countdown can be skipped if desired by pressing the skip button Once the countdown completes the timer is replaced with an appropriate message as shown in Figure 3 11b The screen can then be pressed to initiate the GU Sequence function If errors are detected during the initial testing an appropriate message is displayed and the program is halted as is demonstrated by Figure 3 12a The sequence will not continue until all errors are resolved In the case of a warning to the user a dialogue is displayed and the sequence will continue upon acknowledgement Figure 3 12b 6 32 remaining for generator recharge Touch Window To Continue Tass a b Figure 3 11 Opening message screen with generator recharge countdown timer a and without b The generator information screen is displayed first which gives information as to the state of the generator activity and history Following is a prompt for a user ID code which is useful for avoiding tampering by unauthorized personnel as well as enabling test runs which were commonly used during the development cycle but have no clinical application The user is then prompted to select a run type Figure 3 12c The options presented to the user 53 Rb Elution System Control Ran Klein Uni
176. tawa vary depending on the user ID expiry of the generator time since last flush and time since last calibration These considerations are aimed at ensuring that the generator is not used for clinical applications if it has expired In addition it ensures that the daily protocol is followed including a flush and calibration including a test of breakthrough activity at the start of each day Depending on the chosen run type the user is prompted for additional information such as patient number dose activity elution time flow rate priming of the patient line etc At all stages the input is checked for validity and warnings are presented to the user with detailed explanations Figure 3 12d If a calibration or test run is chosen the Capintec dose calibrator is tested for communication and proper settings Finally a confirmation screen Figure 3 12e is displayed with all the inputs for the user to review After confirmation the real time sequence is initiated with the proper settings set as global variables Post Run Stage Although chronologically the real time sequence follows the post run stage is discussed first due its relative simplicity On termination of the real time sequence one of three possible scenarios exists 1 A successful run has terminated and the elution results must be presented 2 An error has occurred during the real time process and a proper message must be reported to the user 3 The elution was
177. tem Control Ran Klein University of Ottawa error flag is set to zero If at any point the flag changes to a value other than zero the elution will terminate with the error message screen Table 3 4 Detectable errors and their corresponding flags Pressure 10003 High pressure encountered Check generator and waste lines 10004 High pressure encountered Check generator and patient lines 10005 High pressure encountered while pump should be stopped If the problem persists contact the developer Pump communication 20001 Pump communication error Check pump control cable and power and restart the elution 20002 Pump version mismatch detected Contact the developer Pump operation 30001 30002 Pump stalled Check proper line position in pump head and ensure that there are no obstructions Pump should be running and is not Restart the elution If the problem persists contact the developer 30003 Pump should be stopped and is running Restart the elution If the problem persists contact the developer 30004 Pump failed to start Restart the elution If the problem persists contact the developer Computer Resources 40001 Time has stalled during run Contact the developer if problem persists 40002 Error while backing up calibration file Restart the system 40003 Error while writing calibration file Restart the system 40004 Error while writing elution file extension exceeds limit Use a new patient number 40005 Er
178. the prerequisites have been completed successfully All the above elutions are similar in sequence and only vary in parameters therefore a single physical process was implemented Run sequence All elution types follow the same general set of events These events are designed to keep the lines primed at all times and to ensure flushing of all activity in the lines to either the waste container or the patient outlet No activity should remain in the patient line at the end of an elution in order to provide the prescribed dose to the patient and reduce background activity The following sequence is common to most elutions 1 Flush Bypass to Waste The volume in the lines from the pump head to the patient valve Point P is flushed through the bypass to the waste container in order to remove air bubbles and activity that may remain from a previous run 2 Priming of the Patient Line When a new patient line is connected it must be primed prior to elution to the patient This is done by eluting the volume of the line filter and needle with saline through the bypass A slow drip session follows allowing completion of the priming and connection of the line to the patient The dripping state is performed at a low flow rate to avoid squirting of excess saline from the open ended needle 3 Waiting for Threshold Activity The generator flush is commenced while the activity counter readings are monitored If a minimum threshold activity is
179. the region 1 lt r lt 95 then a linear fit is produced and its slope Sy serves as a correcting factor dashed line in Figure 4 13 referred to as the slope rule However if not enough data points are present as in the case of Figure 4 14 the mean error in the lower range EL is used as the correcting factor referred to as the mean error rule This combination of corrections is expressed in 30 In the later case the linear slope is adjusted so that the average error in the lower range 0 lt r lt r is driven to zero This logic is important to include otherwise low relative activity elutions may evolve to a state where the error in the lower range is uniform across all valve flow ration due to adjustment of G but this error may not be zero ALS More than 4 ia points v L S 30 Otherwise Yi L E Valve Upper Bound lax The valve upper bound Imax is defined as the duty cycle at which the valve response saturates in an open position For I gt max the effective flow ratio r is 100 i e complete flow through the generator Adjusting this parameter can only be achieved if relevant error data are measured during the elution The predicted activity concentration from the generator near the end of the elution must be insufficient to achieve the desired activity rate Since the predicted activity rate is less than the set point the valve flow ratio will be set to 100 If the measured activity rate is less than the set point the
180. the system and its features These 15 tests include ensuring the elutions proceed in correct sequence and that the hardware actuators perform correctly During each elution sequence the cases call for visual monitoring of the display and actuators by the tester Final elution results are analyzed to 102 Rb Elution System Control Ran Klein University of Ottawa ensure that the actual elution statistics fall within the tolerance range Finally all record files are scrutinized for correct formatting and data Error Handling Testing As a requirement the system software was designed to detect malfunctions at the earliest possible stage and take action to avoid escalation to the worst case scenario or spoiling of the clinical test In most cases the system copes with malfunctions by immediately stopping the elution in a controlled manner setting the actuators to their safe mode and generating a meaningful message to the operator Each message includes the reason for failure and suggestions to resolve it The 23 error handling tests verify that errors are detected proper action is taken by the system and that the errors are reported in a meaningful manner Of the 25 detectable errors all but 3 errors are tested for proper handling The remaining errors cannot be easily simulated and are unlikely to occur 5 3 Testing in a Routine Clinical Setting Monitoring of the system during routine clinical use was intended to assess the r
181. the system demonstrates that the system is matured for clinical and experimental use Comparison of the two control algorithms indicates that PCC PWM is better for precision elution of Rb activity at a constant rate As a result of the comparison studied in the chapter the system performance is well characterized Rb Elution System Control Ran Klein University of Ottawa The final chapter draws conclusions from this project These conclusions are related to the achievements as well as to the limitations of the design Future work is suggested in order to overcome these limitations or achieve incremental results This work has resulted in the following publications e R Klein A Adler R S Beanlands R A deKemp Precision Control of Eluted Activity from a Sr Rb Generator for Cardiac Positron Emission Tomography Proceedings of the IEEE EMBS 26 Annual International Conference 2004 Vol 1 pp 1393 96 e R Klein N Epstein A Benelfassi R S Beanlands R A deKemp A Rubidium 82 Infusion System for Quantitative Perfusion Imaging with 3D PET Proceedings of the 3 Annual Imaging Network Ontario Symposium pp 98 2004 e R Klein R A deKemp N Epstein RBES Rb82 Elution System Copyright 1016208 Unpublished November 14 2003 Rb Elution System Control Ran Klein University of Ottawa Chapter 1 Introduction to Molecular Imaging and Dynamic PET With the ability to image the phys
182. time process has started stall the pump head Observe that the program halts and that an appropriate error message is reported Fail Repaired RelatedT ests wd a a IE3a c Figure 5 1 Sample test case layout User Interface Testing To reduce the chance of operator error the GUI is simple in design and all inputs are validated An important aspect of this is limiting the user intervention to relevant functionality through a step by step menu The touch screen interface displays only the information relating to the specific step in the menu collecting a single input at any given time Buttons that are not relevant to the specific step are disabled or removed from the screen entirely In addition each operator input is verified to be within a valid and reasonable range If this is not the case the operator is either asked to confirm the entered value or correct it As a final measure the user is asked to confirm all the elution settings prior to starting of the automatic sequence To test the user interface each software branch is executed by at least one of the 11 test cases The tests guide the tester to perform specific actions and to observe certain behaviour of the user interface such as disabling of buttons and appearance of messages In addition the final results screen graphs and printouts must be scrutinized for mismatches and errors Functional Testing This category applies to testing of the overall functionality of
183. times with 3700 MBq of Sr The RbES was flushed and calibrated at the beginning of every work day whether or not scans were scheduled During the trial period 667 patients underwent Rb rest and stress perfusion scans Of those patients 653 were scanned with the usual constant time elutions and 14 were scanned using the HC TC constant activity mode Computer Crash Issue During clinical use a chronic problem of random computer crashes during the real time sequence 2 3 of reported clinical elutions n 925 was observed The crashes were manifested through total lock up of the operating system forcing a reboot the computer This situation made analysis of the problem very difficult Although the source of these crashes was not absolutely determined it was suspected that system resources were mishandled and over consumed To address this possibility the software was altered with the following points of emphasis e Global variables The software that was inherited from the prototype system used over one hundred global variables to communicate data between scripts and functions The declaration of these variables in each function was carried out through the global declare script Since Matlab is an interpreted language the repetitive calling of this script adds significant overhead To reduce this overhead two concepts were enforced throughout the software o Function based design where possible scripts were replaced with fu
184. tio 0 025 82Sr Breakthrough 0 02 0 015 0 01 0 005 Q 5 b gt 9 Figure 5 15 Breakthrough ratio progression over time as measured and corrected for Sr decay We have no data to suggest premature breakthrough due to the cycling valve However testing on additional generators is required to determine whether breakthrough is accelerated or not Sr breakthrough does not appear to be a safety concern as it changes slowly and is tested for on a daily basis as part of the daily protocol 122 Rb Elution System Control Ran Klein University of Ottawa Activity Curves The activity rate vs volume curve collected during the daily calibration run is used to predict the activity concentration from the generator as part of the prediction algorithm A question that arises is whether these curves change over the life time of the generator It is clear that their amplitude decreases as the Sr in the generator decays Figure 5 2 bottom but the shape of the curves had not been investigated Calibration curves over the life of the generator were normalized by their peak activity rate and plotted on the same graph with the colours varying blue to orange in order of date Figure 5 16 This graph reveals that over the life of the generator the bolus volume becomes smaller evident as a narrower peak This may be a result of the Sr migration along the generator column resulting
185. tion This message is intended to guide the operator to the problematic lines Pump Communication and Operation Errors Pump communication is over an RS 232 serial connection with a software implemented polling algorithm every 400 ms Loss of communication to the pump is a critical error and it is therefore important to set the valves to their safe modes so that elution to the patient does not continue if the pump fails to stop The pump software version is also verified on initialization as an additional safety measure As the pump is polled its status is verified to ensure that it correlates with the physical sequence stage Timing windows of 3 seconds have been included to allow sufficient time for communication and response The pump is also capable of reporting stalling of the pump head due to increased mechanical resistance 66 Rb Elution System Control Ran Klein University of Ottawa Computer Resources Errors relating to the computer and software are abundant File access errors are checked and reported throughout the software In addition time stamps are checked during the real time application If time stamps are lost the software can no longer reliably control the real time process This issue has come up at the prototype system where computer resources were over consumed This test is still included mostly as a diagnostic tool for the developers Positron Detector Errors Errors corresponding to the activity
186. tion for the present work is given In 1981 Yano et al 29 described a Rb elution system which could be used clinically to achieve constant flow rate elutions over a prescribed time constant flow elution by controlling a stepping motor coupled to a specially designed syringe pump This system included no feedback mechanism for monitoring data collection or testing Gennaro et al 1987 19 described the use of a positron counter mounted on the generator output to measure the activity vs time curves In addition Gennaro et al developed a method of automatically calibrating the positron counter for efficiency geometric and intrinsic based on an ion chamber dose calibrator The positron counter readings were convolved with the Rb decay function and corrected for time delay to simulate the elution to the dose calibrator The ratio of the dose calibrator reading and the convolution resulted in the calibration constant Gennaro et al was then able to measure the activity vs time curves from the generator The first generation Rb elution system developed at the UOHI was described by Alvarez Diez et al 1999 30 This system included a positron counter used to monitor clinical elutions as well as recording the elution profile the rate of activity delivered during the elution sequence A generator bypass line was added to allow flushing of the lines to the patient at the end of the elution thus ensuring that no activity remains as ba
187. tion for time TcotT as shown in 7 Although this curve can be useful for verification of results it is undesired for calibration calculation as the deconvolution is inherently noisy A t T e r f N eet E 7 7 et Tor co 7 Both calibrator and detector readings are recorded over the course of a one minute flush at 15ml min and an additional two minutes following The detector readings are converted to the calibrator readings and vice versa As a result four curves are obtained as is demonstrated in Figure 3 8 The pairs can be compared to calculate the calibration constant Calculation of the calibration constant based on the area under the calibrator readings and their estimate from the detector improves accuracy through the use of all available data These areas can be calculated by integrating the activity over the interval that activity is being eluted Integral Activity at Patient Outlet Vial T T T N o I Detector Convolved Calibrator Delayed a T Integral Activity MBq a T T li li 0 20 40 60 80 100 120 140 160 180 Ti Instantaneous AUG dt Patient Outlet T T T I I Detector Delayed Calibrator Deconvolved 0 5 Activity Rate MBq s i i 80 100 120 140 160 180 Time s Figure 3 8 Sample calibration run results The top graph demonstrates the recorded and estimated
188. tional to the line pressure Since pressure in liquid is uniform readings can be calibrated using an external pressure gauge connected to the same line The pressure is constantly monitored and can lead to program termination if the pressure rises above a set threshold 25 30 psi for a prolonged period of time Dose Calibrator A Capintec CRC 15 Ramsey New Jersey series dose calibrator is supported as an external device for calibration purposes This dose calibrator is the gold standard throughout the nuclear medicine industry and is a common tool in medical radiation labs The CRC 15 is composed of an ionization chamber which is used to detect ionizing radiation and a console which powers and monitors the chamber as well as provided a user interface Communication between the PC and the dose calibrator is achieved through RS 232 polling by the PC The dose calibrator is utilized in the system for both calibration and testing During calibration the dose calibrator readings are used as a reference to which activity counter readings are compared During test runs the calibrator readings are used to verify the expected results Assembly All the components are assembled in a stainless steel cart shown in Figure 2 3 The generator was placed in the cart and surrounded by lead rings to provide maximum radiation shielding All the saline lines were mounted on a modified top cover for easy access and monitoring Figure 2 4 A high density
189. tor using a bypass line maintains a constant flow rate through all tS TIMES 6s aes E EAE E tte ths Neate athens ates ak et Seane Sa heat ca E ene nat 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 emer ator MNS sree veces Aosnes cath AS E E EEE EEEE ato tt adage water geese tas betes ebedesde 43 Figure 3 6 Schematic of the activity counter relating some of the factors that contribute to its efficiency MEASUIE uest ccs cvsssnrsunenepescuensegouedncpecevensibstvsdescvenaradged ed ansrieededtensesiesbsveruvictyos eaa ar a a E aini 46 Figure 3 7 Dose calibrator chamber measurement diagram ssssesssseeeiesessststsrtsretsrsrsteteststsssiseerrsesesseereee 47 Figure 3 8 Sample calibration run results ssssesesessesesssessesessesesessssesesrentsessesesteresssessesestenesesessesesrenesesseresee 48 Figure 3 9 Aperture response of the dose calibrator as a function of distance along the saline line from aAA A el A A T E E A E E E E E E 49 Figure 3 10 Example of a constant flow test run without top and with bottom a Gaussian aperture COITECHION ofc PAE Wea TE Ut EA bs acee slaves cok TEE N dd las dda doug A ETE 50 Figure 3 11 Opening message SCTCEM sseeeseesseeecesececeecserecesececcesecaseecneeseesasecssaecasenecsesssenaeecesaecatn
190. ty in the volume in its field of view Since the volume is flowing these measurements represent activity delivery rate MBq s Equation 2 relates the measured counts N t and flow rate f ml min to the activity rate at the detector AW MBq s where V is the volume in the FOV and k cps Bq is an efficiency measure of the detector 19 The efficiency and volume are combined into a single constant K which is measured during the calibration process as explained later 4 2 s l _fiml min aleps Q s k cps Bq V ml 60 s min 10 MB ml min gt K 22a Aim min Les ml cps 60 s min Accurate activity counting and accurate flow rate generation are vital to ensure that the measurement of activity rate is accurate Hardware Modifications Waste Overflow Level Switch The waste container is located on the top shelf inside the cart and is contained within lead shielding to minimize exposure to the operator The prototype system did not include a mechanism to avoid overflow If overflow occurs the saline could drip to the lower shelf which contains electronic devices such as the UPS PC and printer Therefore it is desirable to incorporate an overflow prevention mechanism It was decided to include a level switch that could be used to prevent further elutions and generate a warning to the user A wide variety of level switches are available based on various technologies However our requirements elimi
191. ues in Table 4 1 indicates that these are not statistically different partly due to the large standard deviation of elution time errors 73 Rb Elution System Control Ran Klein University of Ottawa Table 4 1 Comparison of elution time accuracy using the threshold comparison algorithm with HC TC and without hysteresis correction Relative activity Flow Rate Time Accuracy p value n 10 ml min Hysteresis correction HC TC 5 0 062 11 67 1 18 33 0 88 25 0 37 Although the hysteresis compensation may slightly improve the elution time precision it does not reduce the activity rate fluctuations To overcome the fluctuations a completely different approach was investigated 4 2 Variable Flow Control To overcome the fluctuations inherent in the simple threshold comparison algorithm the on off valve had to be modified to a variable valve As explained in the previous chapter the use of a variable valve was abandoned following earlier studies due to complexity poor reliability and mostly due to slow response characteristics Instead the solenoid control signal could be modified to simulate a variable valve in two ways Cycling Valve Control An on off valve that periodically cycles between the two states can be used to simulate an analogue valve The valve is set to open and close at a constant frequency but the time that it is open is varied by changing the width of the control p
192. ugh the saline line Saline is essentially water with dissolved salts to ensure pH and salinity similar to that of the blood Due to these solutes saline conducts electricity quite well Even the smallest current directly through the body can cause discomfort or pain It is for this reason that the saline in the system is electrically isolated Throughout the system saline is enclosed in silicon or PVC tubing with plastic connectors 2 Only a limited amount of saline may be infused to the patient and at a limited rate Even in the case of a software crash the flow and quantity must be controlled and limited The off the shelf and reliability proven peristaltic pump is programmed with a desired maximum volume and flow rate and runs autonomously However the computer monitors the pump s status and issues a stop command if the pump does not terminate within the prescribed time limit 3 The pressure in the line must not exceed 20 PSI 138 kPa This is to ensure the accuracy of the effective flow rate and to reduce the risk of line bursting The pump head is rated to 30 PSI 207 kPa In the event that the pressure limit is exceeded for more than 3 seconds the elution is immediately terminated 4 The activity delivered to the patient must not exceed the requested dose as to reduce saturation of the PET scanner sensors and needless exposure to the patient The activity readings from the counter are used to monitor the progress of the elut
193. uires an interpreter at real time adding a significant processing overhead it greatly simplifies development Matlab provides services to compile the M file S function into executable code DLL file providing improved performance and better protection of intellectual property Compilation however requires some customization of the Matlab code and is a fairly involved process It was therefore decided to use the interpreter during the development stage M file S functions The Matlab and Simulink framework dictates a strict yet flexible template for all Simulink blocks implemented through Matlab code The framework describes a complete 60 Rb Elution System Control Ran Klein University of Ottawa state machine through two main stages that are executed each iteration The Update stage checks conditions to change state and is also used to initialize the upcoming state The Output stage conducts the operations associated with the current state such as recalculating outputs and updating a display In addition an initialize stage is called when the object is loaded and a terminate stage is executed just prior to closing the object The RTWT manages the current stage Initialize Update Output or Terminate to the M file S function by passing a stage parameter on each S function call Parameters are passed to the physical sequence through global variables while the real time collected data are passed through the Simulink block inp
194. uitry Implementation of the Variable Flow Control Both approaches are identical in implementation and vary only in PWM frequency While transient state actually implements a variable valve the cycling valve only simulates variable control through time integration Therefore the transient state is advantageous if it can be implemented successfully Implementation of the PWM valve was achieved using one of two general purpose counter timers GPCTR included in the DAQ The GPCTR can be operated in several modes to serve different purposes One such mode is an externally triggered counter as was used for the activity counter Another mode is a continuous rectangular pulse generator The counter is triggered by an internal 100 KHz clock while two registers are set to indicate the number of counts generating a high output and the number of counts generating a low input The output of the counter was routed to the generator valve buffer Crydom solid state relay which generates the current needed to actuate the valve To set the registers the counter must be stopped initialized and restarted using a dynamic link library dll provided by National Instruments A Matlab Simulink driver was written that accepts the cycling frequency as a parameter and the duty cycle as a continuous input and sets the registers whenever the duty cycle is updated The counter register values are computed using 16 and 17 where vex represents the counter clock frequ
195. ulse Pulse Width Modulation PWM can be regarded as varying the average time that that valve is open to the generator path and therefore varying the ratio of flow between the two paths Figure 4 2 In effect setting the pulse width varies the duty cycle of the control signal in the range of 0 100 where 100 corresponds to a full saline flow through the generator and 0 corresponds to full flow through the bypass line Valve Control Signal Time averaged Pulse width modulation signal Figure 4 2 Pulse width modulation control of a solenoid valve to simulate a variable pinch valve Flow through the generator increases as the duty cycle is increased Transient State Control Theoretically by further increasing the frequency of the valve control the valve can be forced to hover in a transient position 37 The valve behaves as a low pass filter of the 74 Rb Elution System Control Ran Klein University of Ottawa control signal and the actual magnetic field generated by the solenoid is less than the full operating field strength Precise tuning of the duty cycle can force the solenoid and spring applied forces to cancel out with the resulting plunger position in a transient state As with the cycling valve varying the duty cycle controls the valve position The exact signal frequency is not critical so long as it is higher than the valve s natural frequency and low enough that it can be generated by the driving circ
196. ure en Ore Cy gt Flow Ratio Readings ValveOpen Zero Order d4 Gy Overflow Sensor State OverflowSens Zero Order d5 Capint isti Te gt pintec Acquisi as physcai guen CapAcqTime Zero Order S Function2 iii 5 5233 Capintec Reading CapActivity Zero Order E oe Heie diki pumpCode Zero Order fe Flow Ratio Set By Prediction PredictionRatio Zero Order d1 PE Flow Ratio Correction ValveCorrection Zero Order gt AA Pediity Fete Eo Error Zero Order Hold11 Figure 3 16 Inputs to the Physical_ Sequence M file S Function block The Physical Sequence The Physical_ Sequence code utilized the Update and the Output stages of the M file S function for separate tasks The Update stage determined the state for the next iteration based on the current state the type of elution run and the accumulated data When a state transition is initiated the next state is initialized by preparing the GUI for the next state computation of variables and sending commands to the actuators The Output stage performs updating operations within the current state This includes updating the actuators and GUI while performing real time data gathering and computations The Update and Output stage tasks overlap only in the sense that the Update stage performs Output tasks only as an initialization of a stage that should occur at a single instance of stage transition In 62 Rb Elution System Control Ran Klein University of Ottawa summary t
197. urements occur Full characterization of the system s capabilities is also important This includes confirmation of the physical model and the activity counter calibration constant The self tuning algorithm was scrutinized to ensure convergence to nominal values as well as stability Finally the constant activity capabilities of the system were characterized The range of relative activities that can be eluted from the system at different durations is of particular interest as it indicates the operating range of the system Characterization of the predictive corrective control of a pulse width modulated cycling valve PCC PWM was analysed by comparison of results to the hysteresis corrected threshold comparison control HC TC The testing and characterization phase allowed determination of whether PCC PWM is a preferred alternative to HC TC as a control method for the Rb elution system In addition these tests help validate the readiness of RbES for routine clinical use 5 1 Safety Testing Safety to operators and patients is the most important requirement of the design As demonstrated in the design process of chapter 3 much emphasis was placed on reducing the chance of both current leakage and radiation exposure To ensure electrical safety a CSA certification was obtained for both the development and clinical system Certification was obtained through testing by a third party Canadian Standards Association a n
198. utes of decay to reach 2x10 of the original activity This is the minimum time that must pass until the breakthrough measurement can be taken The ability to accurately measure the breakthrough depends on the sensitivity of the dose calibrator The Capintec CRC 15R Capintec Inc New Jersey that was used during the development of the Rb Elution System is rated to a sensitivity of 0 002 MBq 35 In order to measure 2x10 of the initial activity the flushed dose during calculation must be at least 0 002 2x10 100 MBq In a clinical setting the generator must be capable of eluting at least 500 MBq to ensure good quality scans If the eluted Rb activity is insufficient to accurately measure breakthrough the automatic measurement is skipped The operator may manually enter the breakthrough activity from a more sensitive instrument Elution Tests The system behaviour must be tested to confirm that the supplied activity is accurate During routine patient elution runs confirmation of the output activity is based at the activity counter which is upstream from the patient outlet If modeling of the system is accurate then the activity at the patient outlet can be precisely determined based on readings from the activity counter The system model was confirmed through testing of elutions As part of the design test runs had to be implemented for all patient elutions These runs execute the exact sequence of the corresponding patient
199. uts These inputs include the various sensor data elapsed run time accumulated generated flush time and other measures of the valve control block The simplicity through which this block can be integrated in the Simulink implementation raises an important question which functionality should be implemented in Simulink and which should be programmed as part of the S function As a general guideline it was decided to leave only the sensors data real time clock and any results of the real time valve control block as inputs to the Physical_ Sequence block for the sake of simplicity All the computational graphical and data collection functionality is implemented through the Physical_ Sequence S function The inputs to the Physical Sequence function were collected and structured by the Software _Interface block within the Hardware_Interface The Physical_Sequence function is called through the use of a function call block within the Simulink model The implementation is shown in Figure 3 16 where the long vertical bar acts as a multiplexer and combines all the inputs into a single array The zero order holds are all run at the same rate which is set by a local parameter Ts 1 s and are intended to convert all inputs to the function s sampling rate 61 Rb Elution System Control Ran Klein University of Ottawa gt fa rf orn tine Time Zero Order phd 10 C4 gt _ gt Activity Counter Readings Counts Zero Tt er Press
200. validate the accuracy of the model of the physical process from the activity counter to the patient outlet This ensures that the physical process during transport of the activity from the activity counter to the patient outlet or dose calibrator is well understood and can be modeled over the entire range of flow rates This means that one can predict the activity profile at the patient outlet accurately based on measurements from the activity counter This result is valid as long as the line pressure remains sufficiently low to avoid backwash through the pump head and a false flow rate 109 Rb Elution System Control Ran Klein University of Ottawa 5 5 Analysis of the Self Tuning Model The control algorithm was designed in such a way that manual adjustment of the system should not be needed To achieve this the system needs to self tune the valve response model parameters to nominal values so as to reduce the activity rate errors over time Although it is desirable that the valve response adapt quickly to changes in the system it is more important that the self tuning algorithm be robust Poor measurements due to malfunctions or errors must not cause the model to diverge significantly from its nominal parameters For example if the saline supply line is pinched during an elution no activity will be drawn from the generator leading to low activity rate measurements but this is not an indication that the valve response has changed In
201. ve at 2 5 and WSDL seeps ioe overs a geen Pitan ss eee AE Seed eat oie eB E a een aco E ds 78 Figure 4 6 Valve response Vvave 5 Hz with the swapped axes allows to determine the duty cycle needed to achieve a desired valve flow ratio oo eeseesscseeesceseeecesecseeecesecseesecsevseceseeeeeaecatesecaevseeeaeeesneeateaes 79 Figure 4 7 Closed loop controlled system using a PID controller 00 0 0 e ce eceeseseceeceeeecesecseeseceseeeaeeeeeaeeaeaes 83 Figure 4 8 Affects of PID controller parameters on system response cscceseceecsceeseeesceeeceeseeeeeeseeeteesseenaes 83 Figure 4 9 Sample simulation results of a PID controlled elution 00 ee eeeeeeeeeeeseeeeeseceeeseceecaeeseeneeeeeaeeaes 84 Figure 4 10 Modified PID correction implementing a forgetful proportional component ceeeee 85 Figure 4 11 Block diagram of the predictive corrective control of a PWM valve cc eeceeeceeeeceeeeeeteeeees 88 Figure 4 12 Simulation of perfect control with erroneous activity concentration prediction due to a slight volume shift s2 ssh sai et Mavis ties dee ed ee Rc ee 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
202. ver one must account for the limited counter capacity 24 bits to avoid counter overflow Assuming a detector efficiency of 1 and a measurement of 30 MBq the counter would overflow in just over half a second To avoid counter overflow readings are taken at 20 Hz Jitter must be avoided in order to ensure that the activity measurements are accurate This frequency provides the base refresh rate of the real time application The real time user interface and the physical sequence state machine could run at a slower refresh rate but not less than 1 Hz A refresh rate of 1 Hz was chosen to reduce processing overhead as much as possible while still maintaining a reasonable refresh rate of the GUI In order to meet these criteria both hardware and software performance and services should be considered An operating system capable of providing real time scheduling services must be chosen The combination of software packages and hardware must ensure that the processes can be executed within a reasonable time and minimal jitter to the real time scheduling User Interface The user interface must be informative allow the operator to control all the features of the elution system but also limit the user input to ensure validity The elution system software may run as an application leaving access to all other features of the operating system so as to enable the system manager to conduct maintenance and collect data The interface must be solely th
203. versity of Ottawa Rb 82 Elution System Rb 82 Elution System 7 8 9 Catbrason 7 8 9 Entered Activity 1000 MBq is Constant Actvay r higher than the last calibration 4 5 6 4 5 6 activity 634 4066 Generator may T Content Time not be able to meet demand Enter a new value or press Enter to continue Constant Flow 4 anyway 1 2 3 1 2 3 del 0 del 0 ENTER Restart E c CO al RD 82 Elution System RI x Current Run Settings Test Activity Elution Results Start Constant Activity Elution Exton Time 42 1 465 Volume Deviation 28 6 X 7 8 9 Actavtty 200 MBq 7 8 9 Ehted Volume 4 963 mi Time 908 Eed Actvty 68 1335 MBq Profile MSE 329 4 5 6 4 5 6 Flow Rate 14 14 mimin Activity Deviation 9 13 1 2 3 1 2 3 Requested Actvity 60 6 MBq del 0 Yes Restan del 0 e f PAn H E m o os o o Rb 82 Elution System Faa LAA PF at tamawa an ESERI a poosena i A en 7 8 9 i 7 8 9 r 1 2 3 ugnies speen Das rae od Whe 9 se M Es gt w del 0 del 0 E a Ak Cy Figure 3 12 Various screenshots of the GUI a Error message b Warning c Data entry d Out of range data e Confirmation f Elution results g Elution graphs h Elution stage and progress 54 Rb Elution System Control Ran Klein University of Ot
204. w test run at 5ml min is included in Figure 3 10 depicting the integral activity with and without aperture correction This improved modeling of the dose calibrator aperture response allows more accurate comparison of the expected activity profile to those measured by the calibrator Integral Activity at Patient Outlet vial No Aperture Correction 15 T T T Detector Convolved Calibrator Delayed 10 Integral Activity MBq a li i li o 50 100 150 200 Integral Activity at Patient Outlet vial With Aperture Correction T T T T Detector Convolved Calibrator Delayed a jo T Integral Activity MBq a i 50 100 150 200 Time s fo Figure 3 10 Example of a constant flow test run without top and with bottom a Gaussian aperture correction a 0 7 The calibration process must be carried out daily as part of the daily protocol This is intended to not only to fine tune the system but also to ensure a complete system test Some variation is expected in the calibration constant as a result of errors and noise If the variation is above 10 from a cumulative average the calibration run does not pass and a warning is generated to the operator The average as is calculated in 9 may gradually adapt to accommodate long term changes in the system while rejecting random errors The average is used as the
205. ween the generator and the bypass line to achieve a constant activity rate constant activity elutions A prototype was constructed based on the same proven design as the first generation system which was intended to add constant activity functionality and improve usability A simple threshold comparison algorithm was used to compare the instantaneous activity rate to a set point Although the simulations used a three way variable pinch valve to control the flow between the generator and its bypass line the prototype used a 2 way solenoid on off pinch valve The system was experimental and used to demonstrate the feasibility of the concept This system was the prototype of the second generation rubidium elution system RbES The RbES had to ensure the same functionality as the first generation system while adding constant activity elution capability improved user interface and additional automation to reduce radiation exposure to the operator and patients The system was based on the hardware design of the first generation system but had an updated computer system user interface and operating system which enabled more advanced developments 2 1 The Daily Protocol and Elution Types The daily protocol was first described during the development of the first generation system and is intended for routine system maintenance system diagnostics and clinical preparation of the system The aim of the protocol is to ensure that the system is in full
206. wo way solenoid pinch valve that could either direct flow through the generator or the bypass line at any given time In addition an activity counter was included in the design to allow data collection and monitoring of the elution of activity With these elements in place the problem was reduced to developing a controller capable of directing saline through the generator or its bypass line by actuating the generator valve in order to achieve a constant rate of activity using feedback from the activity counter The control algorithm presented in the prototype system 18 used a simple threshold comparison which was only intended to demonstrate the feasibility of eluting at a constant activity rate If the measured activity rate was higher than the set point saline flow would be directed through the bypass line If activity rate dropped below the set point flow was directed through the generator The set point was calculated based on the desired activity rate at the patient outlet and was corrected for transport delay as is shown in 14 1 Aggy 42 ai 14 Reg The set point p denotes the number of counts per second to be measured by the activity counter to achieve the desired rate at the patient outlet This rate is converted to raw detector counts using the calibration constant K The rate at the patient outlet is computed based on the requested activity Areg and the requested elution duration Treg The desired 71 Rb Elutio
207. y ready for clinical use 21 Rb Elution System Control Ran Klein University of Ottawa Chapter 3 System Design and Conceptual Understanding Development of the RbES described in this work was started from the research prototype that was already partially functional as described in the previous chapter Although this meant less flexibility in the overall design of the system it provided a starting point that could save much time and effort in the development process The hardware was based on the first generation elution system 30 which had been routinely used over three years in a clinical setting and had proved to be reliable The software on the other hand was in an unfinished state and proved to be unstable The constant activity control algorithm described in 18 was simplistic and left much room for further improvement Therefore it is the software that would undergo the most development with few minor additions revisions to the hardware Before commencing the development the prototype design had to be understood and the project had to be defined 3 1 Requirements The Rb infuser was destined for human use from the start This dictated tight safety requirements that must be considered throughout the design process Safety considerations focused both on the patient and the system operator and included mechanical electrical and radiation exposure risks The main goal of this project was to design and implement a syst
208. y rp Ago ry The dose calibrator is sensitive to the radiation of Rb decay which is a consequence of Sr decay The Sr activity is not measured directly ABreakthrough is the measured breakthrough activity by the dose calibrator after sufficient time has passed for the initial Rb activity Agorn to decay The equation corrects for the dose calibrator sensitivity to the different isotopes their decay sequence and their abundance If the generator is reloaded with Sr the 26 7 Sr ratio s t becomes unknown since there is contribution from both the remaining Sr isotopes on the column and the new amount that is loaded The breakthrough is calculated based on the assumption that all the breakthrough activity measured is contributed by Sr The Sr breakthrough is calculated as a ratio of the calibrator sensitivity This implicitly assumes is that all the activity is resulting from Sr activity and that a corresponding amount of Sr isotopes are also present The bias in this estimate is intended to err on the safe side Ags _S Ags Ags and 82Rb R Ago pp 0 48 Ag pp 12 51 Rb Elution System Control Ran Klein University of Ottawa Health Canada guidelines dictate that breakthrough ratios must be less than 2x10 and 2x10 for Sr and Sr respectively 34 In order to confirm that the breakthrough is less than these ratios the Rb dose must be given enough time to decay below these levels which corresponds to 19 8 min
209. ye Dye Ay Duc f u PO 4 With ideal valve response the actual flow ratio is equal to the predicted flow ratio r t Similarly if the activity concentration just upstream from the merger is successfully predicted then Cy Cm Substituting 23 into 24 reveals that the activity rate at the counter A is the desired activity rate A and perfect control is obtained as shown in 25 Act Tyc Dyc f Cy rO Ac 25 86 Rb Elution System Control Ran Klein University of Ottawa The prediction algorithm estimates Cy based on the activity vs volume curve obtained during the calibration run of the same day C v The predicted activity concentration at the merger Cy is interpolated from Cc v based on the volume that was eluted through the generator since the beginning of the elution as shown in 26 The eluted volume is obtained by integrating the flow ratio r t from the beginning of the elution and multiplying by the saline flow rate f The integrated volume is corrected through a volume shift Vac since the measurements during calibration relate to the counter position rather than that of the merge The activity concentration Cy is estimated as the mean activity concentration over the next sample period S using 26 Dee e Doe During the transport from the generator to the merger significant time can pass if low Cu 6 Cc s rdr Vuc a 26 t 0 flow ratios are used The tran

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