Differences Between Imaging Modalities For The Detection And Measurement Of Deposited Radioactivity

A number of steps need to be implemented when using two- and three-dimensional imaging to measure lung deposition. Protocols should be in place to define the edge of the lung and the regions of interest, the measurement of tissue attenuation correction factors that are applied to the scanner data, and the calculation and expression of the deposition results. If possible, the correlation of dose and distribution data with clinical outcome measurements obtained at the time of imaging should be undertaken. There is still no consensus regarding the methods and protocols that should be used for these, but there is general agreement that the steps outlined are necessary to obtain meaningful deposition data.

Planar (2D) Scintigraphy

Planar (or projection) imaging using a gamma scintillation camera is the conventional technique for imaging the lung, providing two-dimensional analogue/digital information on the inhaled radiotracer. It is widely used to measure the dose and distribution of inhaled drugs. Each pixel (picture element) does not provide information on depth but represents the sum of the radioactivity along the axis perpendicular to the face of the camera. The collective images provide a good sense of total dose, but they are limited in offering information about dose deposited within the lung.

When measuring deposition, anterior and posterior images are obtained (Fig. 14) and the determination of radioactivity deposited is made by calculating

Figure 14 Planar anterior and posterior images obtained following inhalation of two different-size pMDI aerosols, with the outline of the lung drawn from the anterior and posterior perfusion scans. The difference in geometry and distribution of deposited radioactivity between the anterior and posterior images reflects the proximity of that area of the lung to the gamma camera face.

Figure 14 Planar anterior and posterior images obtained following inhalation of two different-size pMDI aerosols, with the outline of the lung drawn from the anterior and posterior perfusion scans. The difference in geometry and distribution of deposited radioactivity between the anterior and posterior images reflects the proximity of that area of the lung to the gamma camera face.

the geometric mean count rate of these two images. The result can then be expressed as a percentage of the total counts detected, or alternatively can be converted, using, as discussed earlier, tissue attenuation factors specific for the individual being imaged, to a deposited dose of radioactivity (mCi) or microgram quantities of drug. This value can be used to calculate inhaler deposition efficiency as a percentage of the emitted or inhaled dose of radioactivity or drug from the delivery system.

For example, when using a perfusion scan to outline the lung and to correct for tissue attenuation of radioactivity, the total lung dose deposited (TLDd) is calculated as follows:

where

Na = anterior cpm for the lung following radioaerosol inhalation

Np = posterior cpm for the lung following radioaerosol inhalation

TAFq = tissue attenuation factor using perfusion method, cpm/mCi

The dose deposited in the lung (L) as a percentage of the emitted dose or metered dose is calculated as follows:

where ED is the emitted dose or dose available at the mouth, in mCi, and MD is the metered dose from the inhaler, in mCi.

Similar calculations can be done for the different regions of interest in the lung or for the oropharynx and gut. The radioactivity deposited in specified regions of the lung is typically expressed as a percentage of the total lung dose of radioactivity or as a ratio of one region to another, such as the central to peripheral airways. To account for all the activity administered, mouthpieces, actuators, filters, etc. need to be imaged and/or measured in the dose calibrator. In the preceding calculations, the %ED will always be greater than the %MD, but the absolute values calculated for the dose in micrograms will be the same. There is merit in expressing the deposited dose in absolute terms. However, it is essential to measure the emitted dose also in micrograms, particularly when testing subjects with the same inhaler on different days, each day with varying amounts of loaded radioactivity, or when comparing different inhalers in the same subject. As shown in Fig. 15, while the deposition percentages for the lung were vastly different, the absolute amounts of drug delivered were not, a function of different nominal doses.

Single-Photon-Emission Computed Tomography (SPECT)

SPECT imaging is more complex than planar imaging, in that rather than obtaining single anterior and posterior cumulative two-dimensional images of the thorax, the gamma camera rotates through a full 360° obtaining multiple images from different angles [121]. Subsequent manipulation of the data using computers permits tomographic images to be constructed. This approach has potential advantages in that it improves the accuracy of assessing the pattern of deposition within the lungs. However, it has the associated disadvantages of longer acquisition times and requiring relatively high doses to be administered to

Figure 15 Deposition images obtained on two separate days for a 4-kg nonventilated neonate following inhalation of a pMDI radioaerosol, 99mTcO4" salbutamol and a 99mTc-sulfide colloid plus salbutamol nebulizer solution. The lung deposition, expressed as percentages of the emitted dose, showed a twofold difference between the inhalers, favoring the pMDI. However, a similar lung dose of drug was received from both inhalers when the percentages were converted to absolute doses of salbutamol by using the nominal dose for each delivery system. (From Ref. 73.)

Figure 15 Deposition images obtained on two separate days for a 4-kg nonventilated neonate following inhalation of a pMDI radioaerosol, 99mTcO4" salbutamol and a 99mTc-sulfide colloid plus salbutamol nebulizer solution. The lung deposition, expressed as percentages of the emitted dose, showed a twofold difference between the inhalers, favoring the pMDI. However, a similar lung dose of drug was received from both inhalers when the percentages were converted to absolute doses of salbutamol by using the nominal dose for each delivery system. (From Ref. 73.)

improve the counting efficiency per slice. Newer, dual- and triple-headed cameras are now available with reduced acquisition times, and they have become the "work horse" camera in many nuclear medicine departments. The per-pixel resolution (8-10 mm) is similar to or better than that of the gamma camera (10-14 mm). To interpret the scans and obtain accurate data, a CT scan or MRI is required to correct for attenuation and define the edge of the lung [122]. Protocols must be in place to coregister the data from the two machines or, alternatively, density factors are calculated for defined regions and applied to the SPECT emission data on a global basis. Calculation of deposited dose is then made from these data.

Positron-Emission Tomography (PET)

PET imaging provides a series of transaxial slices through the lungs, comparable to a CT scan. The transaxial information is used to reconstruct, postimaging, the lung activity for the other two planes, enabling coronal and sagittal images of the lungs to be viewed. PET resolution is approximately 4-6 mm/slice, enabling up to 120 slices per plane to be obtained. Because of the nature of the emissions and the use of coincidence counting, scatter is minimal and location of the pixels or voxels (volume unit) containing the radioactivity is precise. The ability of PET to examine and quantitate regional or local deposition from the coronal, sagittal, or transaxial views has clear advantages over 2D planar imaging (Fig. 16 [10]).

Correction for the natural decay of the PET isotope used is incorporated into the software protocols; correction for tissue attenuation of the radioactivity is made directly using PET and following each procedure by acquiring a transmission (density) scan with an external source of radioactivity. The advantages are that the geometry is constant, because the patient remains in the same position under the scanner as for the original investigation, and that the corrections are applied to each voxel in each slice of each plane. Applying attenuation correction to deposition data from the emission scans allows absolute amounts of radioactivity to be measured per cubic millimeter of lung tissue, giving the actual topographic distribution of drug throughout the lung. The transmission image also defines the lung borders for each slice, providing landmarks from which to delineate regions of interest in the emission scan (Fig. 17). When the lungs are imaged over time, the kinetics of the drug can be described for the whole lung as well as for specific regions. As with SPECT, multiple regions of interest or shells (Fig. 13), concentric about the hilus, can be defined and the deposition data per region of interest, reconstructed in all three planes. Both volume and dose information are obtained from the PET images. The information for deposited dose is obtained by summing the voxel data from the emission scan for designated regions (slices/shells) and applying the appropriate calibration factors; absolute volumes are obtained by summing

Figure 16 Projection view from a PET scan for one subject with cystic fibrosis. Rotation of the projection view, shown on the right, indicates that the location of aerosol deposited in both the right lung and left lung is posterior and basal, with some impaction of aerosol in the anterior of the left lung. This information is not apparent in the "head-on" view shown on the left. (From Ref. 10.)

Figure 16 Projection view from a PET scan for one subject with cystic fibrosis. Rotation of the projection view, shown on the right, indicates that the location of aerosol deposited in both the right lung and left lung is posterior and basal, with some impaction of aerosol in the anterior of the left lung. This information is not apparent in the "head-on" view shown on the left. (From Ref. 10.)

Figure 17 PET transmission scans for several slices of lung in the three planes showing the difference in geometry of the lung. During the reconstruction of the data, the tissue attenuation factors obtained from the transmission scan are applied to the absolute counts from the emission scan on a voxel-by-voxel basis. In the slice-by-slice analysis of the images, the emission scan of each slice is superimposed on its own transmission slice, allowing a more accurate location of the lung edge for the drawing of the shell regions, a distinct advantage over 2D imaging.

Figure 17 PET transmission scans for several slices of lung in the three planes showing the difference in geometry of the lung. During the reconstruction of the data, the tissue attenuation factors obtained from the transmission scan are applied to the absolute counts from the emission scan on a voxel-by-voxel basis. In the slice-by-slice analysis of the images, the emission scan of each slice is superimposed on its own transmission slice, allowing a more accurate location of the lung edge for the drawing of the shell regions, a distinct advantage over 2D imaging.

the number of voxels in the particular regions and applying volume factors. Data can be expressed in a number of ways, including the dose per unit lung volume.

PET techniques offer the important advantage in that the drug under study can be firmly labeled with the appropriate positron emitting isotope, usually nC or 18F. Thus, deposition reflects the pharmaceutical itself, without interference from free isotope. Fluticasone dipropionate, triamcinolone acetonide, and zanamivir have all been labeled and their dose and distribution in the respiratory tract and/or the nasal cavity assessed with PET [48,50,123].

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