NW/. Med. Biol. Vol. 17, No. 8, pp. 763-768, Inr. J. Rodiat. Appl. Instrum. Parr B Printed in Great Britain. All rights reserved
1990 Copyright
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0883-2897/90 53.00 + 0.00 1990 Pergamon Press plc
Use of the 82Sr/82RbGenerator in Clinical PET Studies* GOPAL B. SAHA,? RAYMUNDO T. GO, WILLIAM J. MACINTYRE, THOMAS H. MARWICK, ANNETTE BEACHLER, JANET L. KING and DONALD R. NEUMANN Department of Nuclear Medicine, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195-5074, U.S.A. (Received
4 April 1990)
The use of the 8’Sr/82Rbgenerator in clinical positron emission tomography (PET) studies of myocardial perfusion has been described. An infusion pump is used to deliver the short-lived **Rb from the generator to the patient. Various characteristics of the generator and the infusion system are described. The 8ZRb yield was 69.8 k 13.3% and the **Sr breakthrough was always less than the limit of 0.02pCi/mCi **Rb. The yield of 82Rb increased with the flow rate and the potency of the generator. Patients with coronary artery disease were studied for myocardial perfusion abnormalities by the **Rb PET technique and images of excellent diagnostic quality were obtained.
Introduction Myocardial imaging with 20’T1at rest and following exercise using single photon emission computer tomography (SPECT) is a simple non-invasive test
for assessing coronary artery disease (CAD) (Williams et al., 1980; Go et a/., 1985; Mahmarian et al., 1988). Because of the poor image resolution due to attenuation and scatter of the low energy photon of **‘Tl, investigators have been searching for better radionuclides and/or better techniques to replace *‘IT1 SPECT. For the past several years, positron emission tomography (PET) using **Rb for myocardial perfusion imaging has been evaluated for accurate assessment of CAD (Budinger et al., 1983; Gould et al., 1986; Wilson et al., 1987). This **Rb PET procedure is considered as an alternative to 20’T1SPECT in institutions where PET scanners are available. ‘*Rb (t,,z = 75 s) decays by positron emission resulting in production of 511 keV annihilation radiations. It is a potassium analog and like *“Tl, localizes in the myocardium as an indicator of myocardial perfusion. **Rb is available from the 82Sr/*‘Sr generator and because of its short half-life requires direct administration to the patient by an infusion system (Yano et al., 1977, 1979; Neirinckx et al., 1982). *This study was presented in part at the Sixth Inrernational Symposium on Radiopharmacology held in Sydney, Australia, 24-26 August 1989. tAuthor for correspondence.
Positron cameras detect 511 keV annihilation radiations with higher sensitivity and exhibit better resolution because of the reduced scatter from the 51 I keV photons and by utilizing a transmission attenuation correction in PET. Both stress and resting images can be obtained with the 82Rb PET technique. The 82Sr/82Rb generator is available from Squibb Diagnostics, Inc. under the brand name Cardiogen82. Since *‘Rb has a very short half-life, its elution and infusion into patients is carried out by an automated infusion system. A report was made by Gennaro et al. (1984) in which the authors described the *2Sr/82Rb system and an infusion system designed by them that delivers 82Rb into the patient. The infusion system described here is devised by CTI-Siemens and is now commercially available. In this report, we will describe the operation of the **Sr/**Rb generator in conjunction with the infusion pump in delivering 82Rb for myocardial perfusion studies of patients by the PET technique.
Materials and Methods The “Sr / “Rb generator The 82Sr/82Rb generator is made of a hydrous tin oxide (SnO,) column on which 100-l 50 mCi 82Sr is adsorbed. 82Rb is eluted with 0.9% NaCl solution. *?jr is produced with 82Srin the cyclotron at up to five times the concentration of 82Srbut detection of either isotope in the generator eluate is very rare.
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The infusion pump
The infusion system that is used in our laboratories is a device made by CTI-Siemens and a schematic of it is illustrated in Fig. 1. It consists of a saline syringe pump connected to the shielded **Sr/**Rb generator which is mounted on a mobile cart. Also included in the system are several valves to control the flow of saline, a positron detector and other associated electronics. The positron probe is a plastic scintillator detector with a photomultiplier tube to radioassay the 82Rb activity eluted from the generator. The detector counts primarily /l particles with a much lower efficiency for annihilation radiations. Different electronic controls in the infusion system select the total volume (mL), dose (mCi), dose rate threshold (mCi/s) for patient, patient volume (mL) and flow rate (mL/min). The infusion stops by whichever limit is reached first: patient dose, patient volume or total elution volume. It is furnished with a divergence valve that directs the initial low level activity to a shielded waste bottle. Once the 82Rb activity reaches the preselected activity level for patient injection, the valve then directs the 82Rb eluate to the patient line. After the completion of the infusion, a complete report is printed out listing all settings, measured infusion volumes and activities, activity profile (mCi/s) as presented to the patient and the detector, and integrated activity in the patient at the end of infusion. The infusion system can be operated in either automatic or manual mode, the latter being used for purging only. For patient infusion, it was always operated in the automatic mode. For all our patient studies, the patient dose, the dose rate threshold, patient volume, and flow rates were preset at maximum values of 60 mCi, 1 mCi/s, 50 mL and 50 mL/min, respectively.
Before the first patient is started, the infusion system has to be calibrated daily by setting an appropriate 4-digit calibration factor. This calibration is verified by comparing the measured activity of 82Rb (time corrected at the end of infusion) with the printed infused activity of **Rb at the end of infusion. A discrepancy of 10% or more requires adjustment of the calibration factor. The yield of **Rb is calculated by dividing the measured activity by the theoretical activity present on that day. The **Sr breakthrough is determined by allowing the eluate to decay for 1 h and measuring the 511 keV photons from 82Rb plus 514 keV photons from *?Sr in the dose calibrator. Then from the ratio of *?G/**Sr provided by the supplier, a correction is made to determine the activity of **Sr. The latter is then expressed in pCi/mCi 82Rb as **Srbreakthrough, which has a limit of 0.02 pCi/mCi. Clinical studies
The 82Sr/82Rb generator is supplied regularly once a month by Squibb Diagnostics, Inc. The nominal activity of 82Sr in the generator is 110 mCi. The PET camera is a POSICAM scanner from the Positron Corporation Houston. The sensitivity of the camera is 225 K cps/~Ci/cm~ and the radial resolution is 5.8 mm at a radius of 1Ocm. Reconstruction of PET images is made by the Positron Data Acquisition System (PDAS) computer after collecting the data in profile mode with on-line microprocessors. Patients with coronary artery disease (CAD) confirmed by coronary arteriography were studied for myocardial perfusion abnormalities by the PET technique using the 82Rb radiotracer. After daily calibration of the infusion system, the iv. patient line
Fig. 1. A schematic diagram of the infusion system used for the 82Sr/82Rbgenerator.
Fig. 2. 82Rb PET myocardial images in transverse or short axes obtained at rest (right) and after dipyl -idamole infusion and handgrip exercise (left). (A) Norma1 myocardial image: the activity distribution is un iform in both the stress and rest image. (B) Myocardial ischemia: stress image shows a segmental defec:t involving the inferior wall (arrow) which shows filling in of the activity on the rest image (arrow). CC) bvlyocardial infarct: the stress and rest images both show a segmental defect involving the lateral wall (arrows).
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The 82Sr/s2Rb generator
was secured into the arm of the patient, while the patient lay supine on the camera table with the heart in the field of view as localized by x-ray fluoroscopy and the laser beam. Since these studies were carried out prior to clinical approval of the generator by the U.S. Food and Drug Administration, informed consent was obtained from each patient. Initially, a transmission scan was obtained with a 12cm wide hollow Plexiglass ring filled with 4-6 mCi “Ga for attenuation correction. Each patient was monitored for vital signs (ECG, blood pressure, temperature, etc.) throughout the study. For rest images, 4@-60 mCi 82Rb was infused into the patient through the infusion line and data were collected after a minimum 45 s waiting period for a total collection time of 7 min. For stress images, myocardial stress was induced by administering i.v. dipyridamole and isometric handgrip exercise (Gould et al., 1986). 4 min after the completion of dipyridamole administration, 4&60 mCi **Rb was infused and data were collected for 4 min. Reconstructed color images were displayed in long and short cardiac axes for interpretation.
Results and Discussion The yield of “‘Rb was 69.8 + 13.3% (range 39-95%). The lower yield was experienced primarily with our first two generators. The later generators always gave higher yields. The ‘*Sr breakthrough never exceeded the limit of 0.02 pCi/mCi s*Rb for any generator. Normally, the patient dose was 60mCi, particularly during the first weeks after receipt of the generator. In the later period of the generator life, the administered activity was less than 60mCi because the preset volume limit of 50 mL was reached before the patient dose limit due to the low activity of the generator. A IO-min wait was sufficient to allow maximum growth of S2Rb for repeat elution. Since the positron detector measures the activity before it is delivered to the patient, the calibration factor of the infusion system takes into account such factors as the length and size (i.e. total dead volume) of the tubing connected from the detector to the patient and, the flow rate. The calibration factor required adjustment at least once a week. The yield of “Rb decreased with the increase in dead volume due to a greater loss of the activity by decay. The “Rb yield increased with higher flow rate due to less activity being lost by decay. As the ‘*Sr activity decreased resulting in the lower concentration of “*Rb in the eluate, a larger volume of saline was required to reach the preselected dose limit. The resting and stress images of three categories of patients (normal, ischemia and infarct) are shown in Fig. 2. In Fig. 2(A), uniform uptake of ‘*Rb is seen and no perfusion defect is present in either resting or stress images. In Fig. 2(B), the perfusion defect ^_ observed in the stress image is filled in with the “‘Rb
activity in the resting image indicating ischemia of the myocardium. The perfusion defect in Fig. 2(C) is present in both resting and stress images indicating myocardial scar due to remote infarction. In our experience, approximately 6-7 patients can be studied in an 8 h shift per day if the ring transmission scanning is used for attenuation correction. If the geometric attenuation correction or a constant @Ge source is used for attenuation correction, the number of patient studies per day can be increased. The estimated absorbed dose per mCi B2Rb has been reported to be 13 mrad for heart, 19 mrad for kidneys and 6.9 mrad for lungs, and the major contribution to the dose comes from ‘*Rb and not from 82Sr (Brihaye et al., 1987). These doses are within acceptable limits. In summary, the ‘*Sr/**Rb generator in conjunction with an automated infusion system is a very convenient source of short-lived ‘*Rb radionuclide for myocardial perfusion imaging by the PET technique. Repeat studies can be performed on the same patient within a short time on the same day, because of the short half-life and constant supply of 82Rb. These advantages should make the PET technique more cost effective than *“Tl SPECT. The generator is a self-contained unit easily operated by a technologist without supervision. With its commercial availability, various quantitative and dynamic studies by the PET technique can now become feasible without the need for an on-site cyclotron. Acknowledgements-The authors thank Mrs Donna Fisher and Mrs Cathy Boyle for their excellent typing of the manuscript and the Squibb Diagnostics, Inc. for supplying the Cardiogen-82 generator.
References Brihaye, C.; Guillaume,
M.; O’Brien Jr, H. A. et al.
Preparation and evaluation of a hydrous tin(IV) oxide 82Sr/82Rb medical generator system for continuous elution. Appl. Radial. Zsot. 38: 213-217; 1987. Budinger. T. F.; Yano, Y.; Moyer, B. er al. Myocardial extraction of s*Rb vs. flow determined by positron emission tomography. Circularion 68: 11I-181; 1983. Gennaro, G. P.; Neirinckx, R. D.; Bergner. B. ef al. A radionuclide generator and infusion system for pharmaceutical quality s2Rb. In: F. F. Knapp Jr and T. A. Butler, editors Radionuclide Generator. Am. Chem. Sot. Symp. Ser. 241; 1984: 135-150. Go, R. T.; MacIntyre, W. J.; Houser, T. S. et al. Clinical evaluation of 360” data sampling techniques for transaxial SPECT 20’thallium myocardial perfusion imaging. J. Nucl. Med. 26: 695-706; 1985. Gould, K. L.; Goldstein, R. A.; Mullani, N. A. et al. Noninvasive assessment of coronary stenoses by myocardial perfusion imaging during pharmacologic coronary vasodilation. VIII. Clinical feasibility of positron cardiac imaging without a cyclotron using generator-produced s2Rb. J. Am. CON. Cardiol. 7: 775-789, 1986. Mahmarian, J. J.; Roberts, R.; Boyce, T. M. et al. Improved detection of coronary artery disease by optimized quantitative analysis of “‘thallium single photon emission tomography during exercise. J. Nucl. Med. 29: 755-756, 1988.
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uptake and extraction after transient ischemia: PET characteristics. J. Comp. Ass&. Tomogr. 11: 6s-66; 1987. Yano, Y.; Chu, P.; Budinger, T. F. et al. 82Rb Generators for imanina studies. J. NW/. Med. 18: 46-50: 1977. Yano, Y.;%finger, T. F.; Chiang, G. etaI. Evaluation and application of alumina-based s*Rb generators charged with high levels of s2Sr/*?3r. J. Nucl. Med. 20: 961-966; 1979.