Patent Document

CROSS-REFERENCE TO RELATED APPLICATIONS 
     This is the first application filed for the present invention. 
     MICROFICHE APPENDIX 
     Not Applicable. 
     TECHNICAL FIELD 
     The present application relates in general to nuclear medicine and, in particular, to a rubidium generator for cardiac perfusion imaging and method of making and maintaining same. 
     BACKGROUND OF THE INVENTION 
     As is well known in the art,  82 Rb is used as a positron emission tomography (PET) tracer for measurement of myocardial perfusion (blood flow) in a non-invasive manner. 
     Recent improvements in PET technology have introduced 3-dimensional positron emission tomography (3D PET). Although 3D PET technology may permit more efficient diagnosis and prognosis in patients with suspected coronary artery disease, the sensitivity of 3D PET requires very accurate control of the delivery of  82 R activity to a patient being assessed. 
     As is well understood in the art,  82 Rb for myocardial perfusion imaging is produced using a strontium-rubidium ( 82 Sr/ 82 Rb) generator which is eluted using a sterile saline solution (0.9% Sodium Chloride Injection) to produce an  82 Rb eluate ([ 82 Rb] Rubidium Chloride Injection) that is injected into the patient during the PET imaging. Due to the above-noted sensitivity of 3D PET it is desirable to deliver the  82 Rb elution to the patient as far away from the patient&#39;s heart as can be practically achieved. This is best accomplished by using a small vein in the patient&#39;s hand, for example, as the  82 Rb elution injection site. Doing so, however, requires a low pressure, low flow rate elution and precision flow control. 
     There therefore exists a need for an  82 Rb generator that enables low pressure elution and facilitates precision flow control of patient elution injections. 
     SUMMARY OF THE INVENTION 
     It is therefore an object of the invention to provide a rubidium generator column that enables low pressure elution and facilitates precision flow control of patient elutions. 
     The invention therefore provides a method of preparing an  82 Sr/ 82 Rb generator column for low pressure elution, comprising: filling the generator column with an ion exchange material that tightly binds  82 Sr but not  82 Rb, and compacting the ion exchange material to a density that permits fluid solutions to be pumped through the generator column at a rate of at least 5 ml/min at a fluid pressure of 1.5 pounds per square inch (10 kPa); conditioning the ion exchange material; and loading the generator column with a solution of  82 Sr. 
     The invention further provides an  82 Sr/ 82 Rb generator column, comprising: a fluid impervious cylindrical container having a cover for closing the container in a fluid tight seal, and further having an inlet for connection of a conduit for delivering a fluid into the container and an outlet for connection of a conduit for conducting the fluid from the container; and an ion exchange material filling the container, the ion exchange material being compacted within the container to a density that permits the ion exchange material to be eluted at a rate of at least 5 ml/min at a fluid pressure of 1.5 pounds per square inch (10 kPa). 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       Further features and advantages of the present invention will become apparent from the following detailed description, taken in combination with the appended drawings, in which: 
         FIG. 1  is a schematic diagram illustrating the packing of a generator column in accordance with the invention; 
         FIG. 2  is a schematic diagram of the generator column shown in  FIG. 1  suspended in a shielding body and being loaded with  82 Sr; 
         FIG. 3  is a schematic diagram of the generator column shown in  FIG. 1  configured for calibration and patient elutions; 
         FIG. 4  is a flowchart illustrating the method in accordance with the invention for making the generator columns shown in  FIGS. 1-3 ; and 
         FIG. 5  is a flowchart illustrating principle steps in the use of the generator column shown in  FIG. 3 . 
     
    
    
     It will be noted that throughout the appended drawings, like features are identified by like reference numerals. 
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
     The present invention provides an  82 Sr/ 82 Rb generator column for use in positron emission tomography cardiac perfusion imaging. In accordance with the invention, the generator column is filled with an ion exchange material that tightly binds  82 Sr but not  82 Rb. The ion exchange material is compacted to a density that permits fluid solutions to be pumped through the generator column at a rate of at least 5 ml/min at a fluid pressure of 1.5 pounds per square inch (10 kPa). After the generator column is packed with the ion exchange material, it is conditioned with a source of excess sodium cations and loaded with a solution of  82 Sr. The generator column in accordance with the invention enables low pressure injections using a peristaltic pump and facilitates precision flow control of patient elutions. Advantageously, the generator column in accordance with the invention can also be reloaded with  82 Sr a plurality of times. This has distinct advantages. First, residue  82 Sr remaining in the column from a previous load is not wasted. Second, the expense of building and conditioning the generator column is distributed over a plurality of  82 Sr loads, so the overall cost of using,  82 Rb for cardiac perfusion imaging is reduced. 
       FIG. 1  illustrates the packing of an  82 Rb generator column  10  using a method in accordance with the invention. As is known in the art, the generator column  10  is constructed from stainless steel hardware components that are commercially available. In the embodiment shown in  FIG. 1 , a pair of SWAGELOK® reducing adaptors with nuts and ferrules  12 ,  14  are connected to opposite ends of a stainless tubing  16  that is packed with an ion exchange material  18 . In one embodiment of the invention, the ion exchange material  18  is an α-hydrous tin dioxide (Sno 2 .xH 2 O, where x equals 1-2) wetted with a NH 4 OH/NH 4 Cl buffer (pH 10). 
     A 25 micron filter  24  closes a bottom of the cylinder  16  at an outlet end thereof. Likewise, a 25 micron filter  22  closes an inlet end of the cylinder  16  after the cylinder  16  is packed with the ion exchange material  18 . A feature of the invention is that, unlike prior art generator columns in which the ion exchange material is tightly packed so that high pressure elution is required, the ion exchange material  18  is packed only to a density that permits fluid solutions to be pumped through the generator column at a rate of at least: 5 ml/min at a fluid pressure of 1.5 pounds per square, inch (10 kPa). As shown in  FIG. 1 , a simple and practical way of accomplishing, the required packing of the ion exchange material  18  is to repeatedly strike a side of the generator column  10  with an instrument  26 , such as a laboratory wrench, with a force that exerts about 0.1 Joule. Experience has shown that between 50 and 100 strikes are required to achieve the required density of the ion exchange material  18 . 
     After packing of the generator column  10  is complete, a funnel  20  that was used to introduce the ion exchange material  18  into the cylinder  16  is removed and the ion exchange material is leveled with the top of the cylinder  16 . The ion exchange material packed into the generator column  10  has a density of not more than 3 g/cm 3  in the packed state. The filter  22  is then placed on top of cylinder  16  and the SWAGELOK adapter, nut and ferrule  12  is secured to the top of the cylinder in a manner well known in the art. As will be understood by those skilled in the art, the generator column  10  in accordance with the invention is constructed under sterile conditions using sterile components and may be pressure tested for leaks after assembly. 
       FIG. 2  is a cross-sectional view of the generator column  10  suspended in a shielding body  40 . The shielding body  40  is made from a dense shielding material  42 , such as lead, tungsten or depleted uranium optionally encased in a stainless steel shell  44 . The shielding body  42  includes a shielding lid  50  having apertures through which extend an inlet line  34  and outlet line  36 . The inlet line  34  is connected to an inlet end  30  of the generator column  10 . The outlet line  36  is connected to an outlet end  32  of the generator column  10 . The inlet and outlet lines are connected to external tubing lines  60 ,  62  using Luer fittings  56  and  58 . The shielding lid  50  is likewise constructed of a shielding material  52  such as lead, tungsten or depleted uranium encased in a stainless steel shell  54 . 
     After the generator column  10  is packed with ion exchange material  18 , as explained above with reference to  FIG. 1 , the generator column  10  must be loaded with  82 Sr before patient elutions can begin. As schematically illustrated in  FIG. 2 , in one embodiment a syringe pump  80  is used to deliver  82 Sr from a supply  70  through an inlet tube  60  to the generator column  10 . The  82 Sr is bound by the ion exchange material  18  in the generator column  10 . Waste fluid is evacuated through the outlet tube  36  and outlet line  62  to a shielded waste container  90 , in a manner known in the art. 
       FIG. 3  is a schematic diagram of the generator column  10  configured for daily use as an  82 Rb source for cardiac perfusion imaging. A source of sterile saline solution  100  is connected to a saline supply tube  104 . The sterile saline solution  100  is pumped through the saline supply tube  104  by a pump  102 . In one embodiment of the invention, the pump  102  is a peristaltic pump. In accordance with an alternate embodiment, the pump  102  is the syringe pump  80  shown in  FIG. 2 . 
     As understood by those skilled in the art, the pump  102  is controlled by a control algorithm that regulates a flow rate and volume of the sterile saline solution  100  pumped through the generator column  10  via the inlet tube  104  to provide an  82 Rb eluate via an outlet tube  106  connected to a controlled valve  108 . The valve  108  directs the eluate through a delivery line  112  for a calibration elution or a patient elution  110 , or to a shielded waste container  90 . As is further understood by those skilled in the art, control of the system shown in  FIG. 3  is complex and not all of the fluid paths and control mechanisms are depicted because elution control is not a subject of this invention. 
       FIG. 4  is a flowchart illustrating principle steps in constructing the generator column  10  in accordance with the invention. The process begins by preparing the ion exchange material and packing the generator column as explained above with reference to  FIG. 1  (step  200 ). The generator column is then conditioned by saturating the ion exchange material  18  with sodium cations. In one embodiment, this is accomplished by passing 120 ml of 2M NaCl through the column at a flow rate of 0.5 ml/minute followed by waiting for a period of 12 hours. 500 ml of sterile saline solution is then passed through the column at a flow rate of 10 ml/minute. A nondestructive pH test is performed (step  202 ) by testing a pH of the initial sterile saline solution passed through the column. This nondestructive pH test prolongs the life of the generator column  10 . 
     If it is determined (step  204 ) that the pH of the generator column  10  is not alkaline, the generator column  10  is defective and it is disposed of (step  224 ). If the saline solution is determined in step  204  to be alkaline, the generator column is loaded with  82 Sr (step  206 ) in a manner well known in the art using the equipment briefly described above with reference to  FIG. 3 . After the  82 Sr is loaded into the generator column  10 , the generator column  10  is flushed with 1.0 L of sterile saline solution to clear traces of tin: dioxide and any radionuclide impurities. The generator column is then eluted with sterile saline solution and the eluate is tested for trace metals; sterility; radionuclide purity; pyrogens; and pH (step  208 ). If all of those tests are passed (step  210 ) the generator column  10  is ready for use (step  212 ). If any one of the tests fails,  82 Sr is optionally recovered from the generator column  10  (step  222 ) and the generator column  10  is disposed of (step  224 ). 
     During generator use, daily testing is performed for the purpose of patient safety and quality control, as will be described in detail with reference to  FIG. 5 . As long as all daily tests are passed, the generator column can continue to be used for patient elutions. As understood by those skilled in the art, one of the daily tests is a measure of  82 Rb yield. If it is determined in step  214  that one of the daily tests failed, it is further determined whether a reload of the generator column  10  is permitted (step  216 ). Reloading is permitted if the daily test failed due insufficient  82 Rb yield only. If the daily test failed for some other reason the generators column  10  cannot be further used, and the  82 Sr is optionally recovered (step  222 ) before the generator column is disposed of (step  224 ), as described above. If an  82 Sr reload is permitted, it is determined in step  218  whether the number of  82 Sr reloads of the generator column  10  has exceeded a predetermined reload limit. A generator column in accordance with the invention can, be loaded with  82 Sr at least three times before any significant  82 Sr breakthrough occurs. If it determined in step  218  that the reload limit has been reached, certain jurisdictions require that the generator column be flushed and the eluate tested for: trace metals; sterility; radionuclide purity; pyrogens; and pH. If it is determined in step  218  that the reload limit, has not been reached, the process branches back to step  206  and the generator column is reloaded with  82 Sr and steps  208 - 218  are repeated. 
       FIG. 5  is a flowchart illustrating principle steps involved in the daily use of the generator column  10  in accordance with the invention. Prior to each day&#39;s use of the generator column  10 , the generator column  10  is flushed with 50 ml of sterile saline solution (step  300 ) in order, to remove any strontium breakthrough from the generator column  10  into the waste vessel  90 . The operator then waits for a predetermined period of time (step  302 ) before performing a calibration elution (step  304 ). As is well understood by those skilled in the art, under stable conditions the generator column maintains a  82 Sr/ 82 Rb equilibrium which is achieved after about 10 minutes. Consequently, the predetermined wait before a calibration elution is performed is at least 10 minutes. After the required wait, the generator column is eluted with about 15 ml of sterile saline solution at a constant flow rate of about 15 ml/minute. The calibration eluate is tested (step  306 ) for  82 Rb yield and  82 Sr breakthrough. In step  308  it is determined whether the yield is above a predetermined radioactivity limit. As is understood by those skilled in the art, the half life of  82 Rb is very short (i.e. 76 seconds). Consequently, in one embodiment the  82 Rb yield is measured using a positron counter during the elution, in a manner well known in, the art. 
     In step  310 , it is determined whether the  82 Sr,  85 Sr breakthrough is less than a predetermined breakthrough limit. As is also understood by those skilled in the art, all jurisdictions define a threshold for permissible levels of  82 Sr,  85 Sr breakthrough. As is further understood by those skilled in the art, the strontium breakthrough is readily determined by testing the radioactivity of the elution after about 26 minutes has elapsed, at which time the amount of residual  82 Rb is insignificant and does not distort the test results. 
     Before daily use begins, a cumulative volume of all fluids flushed and eluted through the generator column  10  is computed. Since the generator column  10  in accordance with the invention is repeatedly reloaded with  82 Sr, each generator column is identified by a unique identifier, in one embodiment a serial number. If the user of a generator column  10  does not have the facility to reload the generator column  10 , the user must return the generator column  10  to the manufacturer, along with a cumulative total of fluid flushed and eluted through the column during that use. Likewise, when a reloaded column is supplied to a user, a cumulative volume of fluid used to flush and elute the column during all prior reload(s) and use(s) is provided to the user. Control software used to control a volume of fluid used during generator column  10  flushes and elutions accepts the cumulative volume and stores it. The control software then recomputes the cumulative volume after each subsequent flush or elution of the generator column  10 . That computed cumulative volume is compared (step  312 ) to a predefined volume limit. In accordance with one embodiment of the invention, empirical data has shown that 10 to 30 litres of sterile saline solution  100  can be pumped through the generator column  10  before significant  82 Sr breakthrough is experienced, so the volume limit may be set between 10 and 30 litres. 
     If each of the tests  308 - 312  is successfully passed, patient elutions (step  314 ) may be performed in a manner well known in the art. After each elution, it is necessary to wait a predetermined period of time, about 5 to 10 minutes, (step  316 ) to permit  82 Rb to regenerate. After each elution, the cumulative volume is recomputed by adding to the cumulative volume a volume of fluid pumped through the generator column  10  during the patient elution. Then it, is determined whether the control system date has, changed, i.e. a new day has begun (step  318 ). If not, the cumulative volume is compared to the predetermined volume limit. If the volume limit has been exceeded, the generator column is disposed of (step  324 ). 
     If it is determined in step  318  that the control system date has changed, the generator column  10  must be flushed and re-tested per steps  300 - 312 , as described above. If those tests determine that the  82 Rb yield is less than a predetermined limit (step  308 ) then it is determined in step  320  whether the reload limit has been exceeded and if not the generator column  10  is returned for reload and pre-use testing (step  322 ). Otherwise, the generator column is disposed of (step  324 ). It should be noted that if any of tests  308 - 312  fail, the generator column  10  may be returned to the manufacturer who determines whether the generator column  10  can be reloaded (step  320 ) and disposes of the generator column  10  (step  324 ) if it cannot be reloaded. 
     The generator column  10  in accordance with the invention reduces the expense of cardiac perfusion imaging while ensuring compatibility with 3D PET imaging systems by enabling low pressure, low flow rate elutions that can be precisely flow controlled. Research has conclusively established that the generator column  10  in accordance with the invention remains sterile and pyrogen-free for a period of at least six months when used in accordance with the procedures and limits described above. 
     Although the invention has been explained with reference to 3D PET imaging systems, it should be understood that the generator column  10  is equally compatible with 2D PET imaging systems and provides the same advantages of low cost, precise flow control, low pressure and low flow elution and a long service life. 
     The embodiment(s) of the invention described above is(are) intended to be exemplary only. The scope of the invention is therefore intended to be limited solely by the scope of the appended claims.

Technology Category: 1