Tc-99m is obtained from “milking” a molybdenum-99 (Mo-99) generator (Fig. 12-2). Mo-99 is obtained as a by-product from the fission of uranium. Mo-99 is chemically separated from the other radionuclides in the reactor product. Purified Mo-99 as anionic molybdate solution is loaded on to the generator column, which contains alumina. The alumina, which is positively charged, is able to adsorb Mo-99 ions. The assembly is then autoclaved. Several normal saline washings of the column yield eluate containing Tc-99m. These washings are subjected to several quality control tests to determine eluate volume, radionuclide purity (“moly” breakthrough), radiochemical purity (proper chemical form of technetium as pertechnetate), pyrogenicity, sterility, and/or alumina breakthrough. The half-life of Mo-99 is 66 hours allowing for weekly delivery of the generator to elute Tc-99m.

Figure 12-2 Molybdenum-technetium generator.

The eluted technetium can now be tagged to the appropriate pharmaceutical for use. When radionuclides such as technetium are tagged to specific pharmaceuticals, they are called radiopharmaceuticals. The pharmaceutical portion of the diagnostic radiopharmaceutical is present in very small amounts and will not elicit any pharmacologic response in the patient. The radioactive component is present in even smaller amounts. The technetium-99m radiopharmaceuticals for use in the emergency situation are listed in Box 12-1.

The radiopharmaceuticals are made up from “cold kits” supplied by manufacturers. With the exception of HMPAO (hexamethylpropyleneamine oxime), the kits are generally stable for up to 12 months. These kits provide a very convenient method of preparing radiopharmaceuticals in facilities that may not be close to laboratories. Technetium-99m can assume oxidation states ranging from I to VII based on the number of electrons available for reaction with ligands. The lower the oxidation state the less stable it is and the most likely to react with ligands. The most stable electronic configuration for technetium is the state with the value of VII where it is present as the pertechnetate ion and unlikely to tag to a ligand. Consequently, in order to produce a Tc-99m–labeled radiopharmaceutical, the technetium has to be first reduced to a lower oxidation state. This is most commonly accomplished by the addition of tin. As well, some cold kits contain antioxidants such as ascorbic acid or gentisic acid, which not only retard oxidation of the radiolabeled product, but also improve the stability of the kit. Tin II (stannous) supplies electrons and in the process becomes oxidized to tin V (stannic) ion. The various oxidation states of technetium allow the formation of a variety of different radiopharmaceuticals, which adds to the value of technetium as a nuclear medicine staple.

Reagents in the “kit” vial are generally freeze-dried and packed under vacuum. Alternatively, they may be combined with an inert gas such as nitrogen. This ensures that the tin in stannous form will not get oxidized to stannic form by exposure to the atmosphere. The amount of tin in the reagent vial is critical to the preparation of the radiopharmaceutical. Inadequate amounts of tin allow the oxidation of free pertechnetate, which ultimately degrades the image obtained and could potentially render a study nondiagnostic.

Indium-111

In-111 is produced in a cyclotron from the radioactive parent Cd-112. It has a half-life of 67 hours (2.8 days). The principal photons are 178 keV and 247 keV. The relatively long half-life of In-111 allows sequential imaging (Fig. 12-3).

Figure 12-3 Decay scheme for In-111—electron capture.

Xenon-133

Xe is an inert and relatively insoluble gas produced by the fission of uranium-235. It is used in its radioactive form most commonly for ventilation studies. Xe-133 has a physical half-life of 5.3 days and, in the face of normal pulmonary function, a biological half-life of approximately 30 seconds.

The main disadvantages of Xe-133 are the low photon abundance (36%) and low tissue penetration of the 81 keV gamma ray. The low photon energy generally mandates the initial use of the xenon, that is, before the administration of the technetium lung perfusion agent. Overlying soft tissue, such as breast, can produce artifacts on the xenon images.

Gallium-67 Citrate

While Ga-67 citrate cannot be used for an emergent situation requiring a diagnostic test within a few hours of requisition, it is an important radionuclide for the workup of infection, which constitutes an emergency of sorts.

Gallium-67 is produced in a cyclotron from the parent zinc-68. Gallium-67 decays by electron capture to stable zinc-67 in 3.26 days (Fig. 12-4). The transition energy, which is 0.997 MeV, is dissipated by several electron capture transitions. Several gamma photons are emitted that are used for imaging. The principal ones are 93 keV with 37% abundance, 185 keV with 20% abundance, 300 keV with 17% abundance, and 394 keV with 5% abundance.

Figure 12-4 Decay scheme for gallium-67.

The exact mechanism of uptake of Ga-67 citrate is not precisely known. After intravenous administration of Ga-67, the complex dissociates to become bound to transferrin.

The principal organs that localize gallium are the liver, spleen, and bone marrow. The excretion of gallium is bimodal, initially through the kidneys and later through the GI tract. Persistence of gallium activity in the kidneys beyond 24 hours should be cause for further workup. There is some uptake in the lachrymal and salivary glands and the lactating breast. This is attributed to the high concentration of lactoferrin in these tissues. Both transferrin and lactoferrin are metabolized in the liver, which accounts for the uptake in the liver. Gallium is believed to behave like iron and utilizes the transferrin mechanism and responds to procedures like total body irradiation in a manner similar to iron saturation of transferrin.

IMAGING EQUIPMENT

The components of the detection system/gamma camera (Fig. 12-5) include the following:

Collimator

Scintillation crystal and optical coupling

Array of photomultiplier tubes

Signal processor, which analyzes the X-Y position of the signal

Pulse height analyzer

Computer integrated into the camera

Figure 12-5 Components of a gamma camera.

Gamma rays emitted from the patient enter the NaI crystal after passing through the collimator. The collimator used varies with the situation. Gamma rays are converted into light within the crystal. An array of photomultiplier tubes is coupled to the scintillation crystal. The light from the crystal is converted into an electric signal, which is proportional to the amount of light generated in the crystal. The electric signals from the photomultiplier tubes are processed by the circuitry to generate position signals and the energy signal. The latter is proportional to the energy of the gamma ray emitted by the radionuclide. The pulse height analyzer analyzes and selects only the signals, which fall in the energy range preset for the radionuclide under consideration. The correction of the X and Y position of the signal, as well as the energy discrimination/pulse height analysis, is performed in the memory of the computer, which is integrated into the gamma camera. The information is recorded as an image in the memory of the computer and displayed on a color or black and white monitor. Each study (which could be composed of several images) is stored to be retrieved for review and reporting.

LUNG SCINTIGRAPHY

The most common indication for lung scintigraphy is to determine the likelihood of pulmonary embolism. Less common indications include lung transplantation, preoperative evaluation, and right-to-left shunt evaluation. We devote this section to the discussion of ventilation and perfusion scanning for pulmonary embolism.

Pulmonary Embolism

The incidence of pulmonary embolism (PE) and its detection have increased with the increasing frequency of long-distance travel and consequent loss of mobility. This has been further complicated by the aging of the population and the increasing incidence of underlying illness such as heart disease and peripheral vascular (including venous) disease.

PE is the third most common cause of death in the United States with 650,000 occurring each year. PE seems to present with greater preponderance in hospitalized patients. Given the high prevalence of the condition, its lethality, and the fact that a large number of patients with PE have atypical presentations, it is recommended that every patient with chest pain be worked up for PE.

Venous thrombosis, in contrast to arterial thrombosis, is caused by problems with the plasma clotting system. There is minimal platelet participation in the venous versus the arterial process. Furthermore, thrombus formation in the cardiac chambers is seen most commonly with slow flow conditions similar to venous thrombosis.

There is increasing evidence that an underlying coagulopathy may be responsible for spontaneous deep venous thrombosis (DVT) and PE. Hypercoagulability may be congenital or acquired. Primary or acquired deficiencies in protein C, protein S, or antithrombin III are known to be common causes of DVT and PE.

There are many risk factors for DVT and PE. It is well known that, among these, prolonged immobility, recent surgery, pregnancy, and underlying malignancy initiate DVT.

Radiopharmaceuticals and Techniques

The major function of the lungs is to effect the exchange of CO₂ for O₂ from the blood. This is accomplished by perfusion of the capillaries in the walls of the alveoli where inspired air brings in O₂ and is exchanged for CO₂ in the deoxygenated blood. The CO₂ in the alveoli is then discharged to the outside via expiration. These two aspects of the respiratory anatomy and physiology are assessed in nuclear medicine. Pulmonary perfusion is assessed by the administration intravenously of technetium-99m macroaggregated albumin, whereas the various phases of ventilation are studied using gases or aerosols.

In pregnant women, a perfusion-only lung scan should be considered if the chest x-ray is normal and the patient has no history of smoking or lung disease. Since Tc-99m is excreted in the breast milk, the patient should be encouraged to express and store milk for 2 days until the radionuclide has decayed sufficiently.

Xenon can be used to assess all phases of ventilation. The most commonly used technique involves having the patient breathe xenon through a spirometer. The patient exhales as deeply as possible and then inhales 10 to 20 mCi of Xe-133. The respiration is suspended at the end of the inhalation for 15 seconds, while the first image is obtained. The patient breathes xenon out into a spirometer, which constitutes a closed system. Approximately 2 L of oxygen are used to dilute the expired xenon (Fig. 12-7). The patient rebreathes this mixture for 2 to 3 minutes, at which time another static image is obtained. This constitutes the equilibrium image. After equilibrium has been reached, fresh air is breathed in until the xenon is completely washed out. Images are obtained every 15 seconds for 2 to 3 minutes. For patients with chronic obstructive pulmonary disease (COPD), the washout phase may be delayed up to 5 minutes to image areas of regional airway trapping. This entire process presupposes that the patient is able to cooperate with breathing into a spirometer or a closed system. The initial/single breath reflects the regional ventilatory rate. The equilibrium phase depicts the aerated volume of the lungs, while the washout phase delineates trapping. Xenon is fat soluble and partially soluble in blood, which will cause deposition in the liver, particularly in patients with fatty replacement in the liver.

Figure 12-7 Normal xenon-133 ventilation lung scan. The ventilation is usually performed before the perfusion study. Due to rapid clearance of lung activity of xenon-133, a posterior view study is performed to maximize area of the lung seen. Comparison to perfusion is less than optimal.

Krypton-81m

Kr-81m has also been used for ventilation imaging. The photon emissions of 176 and 192 keV and the short half-life of 13 seconds allow equilibrium imaging of the lungs in multiple projections. However, the short half-life precludes obtaining single-breath and washout images. Kr-81m is obtained from rubidium-81, which has a half-life of 4.6 hours. While krypton generators are available, the cost of the generator can be quite high, due to the short half-life of rubidium-81. The activity administered is 1 to 10 mCi.

Radiolabeled Aerosols

Radiolabeled aerosols are used for studying lung ventilation. Aerosol studies do not allow dynamic imaging. Dynamic imaging, while excellent for assessment of respiratory function, is not required for PE studies.

The most commonly used aerosol is Tc-99m diethylene triamine penta-acetic acid (DTPA) in a volume of 2 mL put into the nebulizer of an aerosol delivery system. The aerosol is prepared by injecting 30 mCi of Tc-99m DTPA into the nebulizer of the delivery system. Side tubing in the system allows oxygen to flow through a flow meter at the rate of 8 to 10 L/min. Generally, only a small amount of activity (1 to 2 mCi) is delivered. The trachea is the critical organ in the aerosol ventilation study. One of the major advantages of this system is that it can be attached to an endotracheal or tracheostomy tube. In patients without airway tubing, the aerosol is inhaled through the mouth while a nose clip is applied. In either circumstance, little or no patient effort or cooperation is required to deliver the aerosol into the airway. The aerosol is usually delivered with the patient in a supine position so that it is distributed evenly. No special venting is required with Tc-99m DTPA as it is with xenon. The second major advantage of using Tc-99m DTPA is that the imaging characteristics are ideal. Therefore, the Tc-99m DTPA study can be performed either before or after the Tc-99m MAA study. If the ventilation study is performed before the perfusion, the amount of activity required is between 1 and 2 mCi. However, if the perfusion study is obtained first, the number of counts accumulated for the ventilation study has to be 3 to 4 times greater than for the perfusion.

In the workup for PE, Tc-99m DTPA aerosol is ideal, since images can be obtained in projections to match the ventilation images. After inhalation, aerosol particles are deposited in the distal airways and not the alveoli. Following inhalation, the Tc DTPA particles dissolve in the fluids within the alveoli and ultimately diffuse across the epithelial barrier into the circulation. As long as the epithelial barrier is intact, the aerosol diffuses relatively slowly into the circulation. The half-time disappearance of the aerosol from the alveoli is about 80 minutes. This is much faster in patients whose epithelial barrier may be deficient, as in COPD or in smokers. The Tc DTPA that has entered into the circulation is cleared via the kidneys. Larger particles are deposited in the central airways, the mouth, and the alimentary tract (from swallowed particles) (Fig. 12-8).

Figure 12-8 Tc-99m DTPA aerosol images. Normal study shows six views, and corresponding six views are obtained for perfusion. Comparable images make interpretation of lung scan much easier than with single posterior view xenon-133 study.

Technegas

Technegas is composed of ultrafine particles of Tc-99m-labeled carbon particles produced by combustion of pertechnetate at 2500° C in a graphite crucible. A technegas generator is portable and produces fine images. The smaller particle size makes this a better agent than Tc DTPA aerosol, particularly in patients with COPD.

Chest X-Ray

It is important to have a chest x-ray for evaluation before performing the ventilation-perfusion (VQ) scan (Fig. 12-9). It is good practice to have one that has been obtained within 24 hours of performing the VQ scan. It would be ideal to have a full-inspiration posteroanterior (PA) and lateral chest x-ray available for interpretation. However, a large percentage of the patients who are at risk for PE in the hospital or the intensive care unit setting may have several other cardiopulmonary pathologic processes that could interfere with the reading of the VQ scan. In these patients, one has to be satisfied with the portable radiograph, which is rarely of the quality of the standard PA and lateral radiographic study.