Rubidium generator for cardiac perfusion imaging and method of making and maintaining same

An 82Sr/82Rb generator column is made using 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. An ion exchange material fills 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). The generator column can be repeatedly recharged with 82Sr. The generator column is compatible with either three-dimensional or two-dimensional positron emission tomography systems.

CROSS-REFERENCE TO RELATED APPLICATIONS

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,82Rb 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 of82R activity to a patient being assessed.

As is well understood in the art,82Rb for myocardial perfusion imaging is produced using a strontium-rubidium (82Sr/82Rb) generator which is eluted using a sterile saline solution (0.9% Sodium Chloride Injection) to produce an82Rb eluate ([82Rb] 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 the82Rb elution to the patient as far away from the patient's heart as can be practically achieved. This is best accomplished by using a small vein in the patient's hand, for example, as the82Rb elution injection site. Doing so, however, requires a low pressure, low flow rate elution and precision flow control.

There therefore exists a need for an82Rb 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 an82Sr/82Rb generator column for low pressure elution, comprising: filling the generator column with an ion exchange material that tightly binds82Sr but not82Rb, 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 of82Sr.

The invention further provides an82Sr/82Rb 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).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

The present invention provides an82Sr/82Rb 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 binds82Sr but not82Rb. 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 of82Sr. 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 with82Sr a plurality of times. This has distinct advantages. First, residue82Sr 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 of82Sr loads, so the overall cost of using,82Rb for cardiac perfusion imaging is reduced.

FIG. 1illustrates the packing of an82Rb generator column10using a method in accordance with the invention. As is known in the art, the generator column10is constructed from stainless steel hardware components that are commercially available. In the embodiment shown inFIG. 1, a pair of SWAGELOK® reducing adaptors with nuts and ferrules12,14are connected to opposite ends of a stainless tubing16that is packed with an ion exchange material18. In one embodiment of the invention, the ion exchange material18is an α-hydrous tin dioxide (Sno2.xH2O, where x equals 1-2) wetted with a NH4OH/NH4Cl buffer (pH 10).

A 25 micron filter24closes a bottom of the cylinder16at an outlet end thereof. Likewise, a 25 micron filter22closes an inlet end of the cylinder16after the cylinder16is packed with the ion exchange material18. 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 material18is 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 inFIG. 1, a simple and practical way of accomplishing, the required packing of the ion exchange material18is to repeatedly strike a side of the generator column10with an instrument26, 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 material18.

After packing of the generator column10is complete, a funnel20that was used to introduce the ion exchange material18into the cylinder16is removed and the ion exchange material is leveled with the top of the cylinder16. The ion exchange material packed into the generator column10has a density of not more than 3 g/cm3in the packed state. The filter22is then placed on top of cylinder16and the SWAGELOK adapter, nut and ferrule12is 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 column10in accordance with the invention is constructed under sterile conditions using sterile components and may be pressure tested for leaks after assembly.

FIG. 2is a cross-sectional view of the generator column10suspended in a shielding body40. The shielding body40is made from a dense shielding material42, such as lead, tungsten or depleted uranium optionally encased in a stainless steel shell44. The shielding body42includes a shielding lid50having apertures through which extend an inlet line34and outlet line36. The inlet line34is connected to an inlet end30of the generator column10. The outlet line36is connected to an outlet end32of the generator column10. The inlet and outlet lines are connected to external tubing lines60,62using Luer fittings56and58. The shielding lid50is likewise constructed of a shielding material52such as lead, tungsten or depleted uranium encased in a stainless steel shell54.

After the generator column10is packed with ion exchange material18, as explained above with reference toFIG. 1, the generator column10must be loaded with82Sr before patient elutions can begin. As schematically illustrated inFIG. 2, in one embodiment a syringe pump80is used to deliver82Sr from a supply70through an inlet tube60to the generator column10. The82Sr is bound by the ion exchange material18in the generator column10. Waste fluid is evacuated through the outlet tube36and outlet line62to a shielded waste container90, in a manner known in the art.

FIG. 3is a schematic diagram of the generator column10configured for daily use as an82Rb source for cardiac perfusion imaging. A source of sterile saline solution100is connected to a saline supply tube104. The sterile saline solution100is pumped through the saline supply tube104by a pump102. In one embodiment of the invention, the pump102is a peristaltic pump. In accordance with an alternate embodiment, the pump102is the syringe pump80shown inFIG. 2.

As understood by those skilled in the art, the pump102is controlled by a control algorithm that regulates a flow rate and volume of the sterile saline solution100pumped through the generator column10via the inlet tube104to provide an82Rb eluate via an outlet tube106connected to a controlled valve108. The valve108directs the eluate through a delivery line112for a calibration elution or a patient elution110, or to a shielded waste container90. As is further understood by those skilled in the art, control of the system shown inFIG. 3is complex and not all of the fluid paths and control mechanisms are depicted because elution control is not a subject of this invention.

FIG. 4is a flowchart illustrating principle steps in constructing the generator column10in accordance with the invention. The process begins by preparing the ion exchange material and packing the generator column as explained above with reference toFIG. 1(step200). The generator column is then conditioned by saturating the ion exchange material18with 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 (step202) by testing a pH of the initial sterile saline solution passed through the column. This nondestructive pH test prolongs the life of the generator column10.

If it is determined (step204) that the pH of the generator column10is not alkaline, the generator column10is defective and it is disposed of (step224). If the saline solution is determined in step204to be alkaline, the generator column is loaded with82Sr (step206) in a manner well known in the art using the equipment briefly described above with reference toFIG. 3. After the82Sr is loaded into the generator column10, the generator column10is 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 (step208). If all of those tests are passed (step210) the generator column10is ready for use (step212). If any one of the tests fails,82Sr is optionally recovered from the generator column10(step222) and the generator column10is disposed of (step224).

During generator use, daily testing is performed for the purpose of patient safety and quality control, as will be described in detail with reference toFIG. 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 of82Rb yield. If it is determined in step214that one of the daily tests failed, it is further determined whether a reload of the generator column10is permitted (step216). Reloading is permitted if the daily test failed due insufficient82Rb yield only. If the daily test failed for some other reason the generators column10cannot be further used, and the82Sr is optionally recovered (step222) before the generator column is disposed of (step224), as described above. If an82Sr reload is permitted, it is determined in step218whether the number of82Sr reloads of the generator column10has exceeded a predetermined reload limit. A generator column in accordance with the invention can, be loaded with82Sr at least three times before any significant82Sr breakthrough occurs. If it determined in step218that 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 step218that the reload limit, has not been reached, the process branches back to step206and the generator column is reloaded with82Sr and steps208-218are repeated.

FIG. 5is a flowchart illustrating principle steps involved in the daily use of the generator column10in accordance with the invention. Prior to each day's use of the generator column10, the generator column10is flushed with 50 ml of sterile saline solution (step300) in order, to remove any strontium breakthrough from the generator column10into the waste vessel90. The operator then waits for a predetermined period of time (step302) before performing a calibration elution (step304). As is well understood by those skilled in the art, under stable conditions the generator column maintains a82Sr/82Rb 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 (step306) for82Rb yield and82Sr breakthrough. In step308it is determined whether the yield is above a predetermined radioactivity limit. As is understood by those skilled in the art, the half life of82Rb is very short (i.e. 76 seconds). Consequently, in one embodiment the82Rb yield is measured using a positron counter during the elution, in a manner well known in, the art.

In step310, it is determined whether the82Sr,85Sr 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 of82Sr,85Sr 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 residual82Rb 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 column10is computed. Since the generator column10in accordance with the invention is repeatedly reloaded with82Sr, each generator column is identified by a unique identifier, in one embodiment a serial number. If the user of a generator column10does not have the facility to reload the generator column10, the user must return the generator column10to 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 column10flushes 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 column10. That computed cumulative volume is compared (step312) 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 solution100can be pumped through the generator column10before significant82Sr breakthrough is experienced, so the volume limit may be set between 10 and 30 litres.

If each of the tests308-312is successfully passed, patient elutions (step314) 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, (step316) to permit82Rb to regenerate. After each elution, the cumulative volume is recomputed by adding to the cumulative volume a volume of fluid pumped through the generator column10during the patient elution. Then it, is determined whether the control system date has, changed, i.e. a new day has begun (step318). 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 (step324).

If it is determined in step318that the control system date has changed, the generator column10must be flushed and re-tested per steps300-312, as described above. If those tests determine that the82Rb yield is less than a predetermined limit (step308) then it is determined in step320whether the reload limit has been exceeded and if not the generator column10is returned for reload and pre-use testing (step322). Otherwise, the generator column is disposed of (step324). It should be noted that if any of tests308-312fail, the generator column10may be returned to the manufacturer who determines whether the generator column10can be reloaded (step320) and disposes of the generator column10(step324) if it cannot be reloaded.

The generator column10in 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 column10in 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 column10is 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.