Data Analysis

When imaging a subject after inhalation of a radiolabeled formulation, it is the radioactivity that is detected and measured; absolute amounts of deposited drug are inferred from the counts of radioactivity in the lung and other regions, based on the assumption that there is a 1:1 relationship between the two components. This relationship holds true for direct-labeled PET products or for those formulations where a firm bond can be demonstrated between the drug and radioactivity for the time taken to acquire all the images.

Determination of Deposited Dose

A number of investigators have addressed the issue of how to determine the absolute dose of radioactivity deposited in the lung and measured by either 2D or 3D imaging. Radioactivity counted over the lung field (counts/time) can be converted to megabequerels (MBq) or microcuries (mCi) detected in the lung by applying various calibration factors. These factors are measured using several techniques that utilize either external phantoms containing calibrated sources of radioactivity or the injection of a known amount of radioactivity and external detection [102-107]. The main source of reduction in the level of radioactivity detected is the chest wall, and this decrease can be as high as 50%, depending upon the subject [107]. The sensitivity of the imaging detector/collimator affects the detection of radioactivity and should be factored into the measurements [108,109]. Tissue attenuation factors vary between individuals with normal lungs and between those with diseased lungs [110-112], with greater variability in the latter group. Hence, these factors need to be determined for each individual studied to accurately calculate the deposited lung dose.

It should be recognized that the deposited dose is a fraction of the dose inhaled and that the inhaled dose is, in turn, a fraction of the nominal, or label claim, dose of the inhaler. Estimates of inhaled doses correlate with the fine particle dose, calculated from the fine particle fraction (% particles < 4.7 mm or <5.8 mm in diameter) of the aerosol and the emitted ex-actuator or ex-device dose from the aerosol inhaler. The latter are measured in terms of radioactivity and drug prior to delivering the aerosol for deposition measurements. Drug deposition in the lung will further be reduced due to losses occurring in the inhaler device and in the oropharynx. This is particularly true for spacers attached to pMDIs, where upwards of 60% of the metered dose remains in the spacer. Fig. 7 illustrates the losses on the actuator mouthpiece and in the spacer, showing how the emitted dose of radioactivity is calculated. When possible, the device should be assayed for radioactivity postinhalation, either using a dose calibrator to measure the absolute amount of radioactivity or imaging the inhaler using the gamma camera and applying the appropriate calibration factors to obtain an absolute dose of radioactivity in the device. If possible, the inhaler can then be assayed for drug. These measurements will allow an estimation of the dose of tracer and drug delivered to the mouth.

Defining Lung Borders and Regions of Interest

Defining the edge of the lung is critical to determining both total and regional deposited doses. Several methods used for delineating the outer lung boundary are described in the literature. The options are:

• A transmission scan with an external source of radioactivity

• Inhalation of a radioactive gas, i.e., 133xenon (133Xe) or 81mkrypton (81mKr)

• Inhalation of an extrafine aerosol (< 1 mm MMAD) of Technegas, 99mtechnetium (99mTc) sulfide colloid or albumin

• Measuring lung perfusion using an injection of 99mTcmacroaggregated albumin

Fig. 8 illustrates examples of images for all of these procedures, acquired using planar imaging and, with the exception of the transmission scan, obtainable with SPECT imaging. The assessment of ventilation, which usually tracks the edge of the lung, has traditionally been measured with radioactive gases, but the inhalation of extrafine aerosols has been shown to give comparable information both in normals and in patients with airways disease [34,113,114]. While perfusion scanning is considered the "gold" standard [104], all these methods provide an acceptable outline of the lung.

Tissue Attenuation of Radioactivity

Using planar imaging, expressing the dose deposited in the lung in absolute terms requires the measurement of global lung tissue attenuation factors

Figure 8 Schematic illustrating losses of radioactivity and drug in a pMDI + spacer delivery system. The emitted dose calculated when a spacer is used is reduced compared to when the spacer is not used, reflecting the loss of drug in the spacer. The radioactivity deposited in the oropharynx and stomach, shown in the 2D image, is from the coarse aerosol not collected by the spacer but inhaled.

Figure 8 Schematic illustrating losses of radioactivity and drug in a pMDI + spacer delivery system. The emitted dose calculated when a spacer is used is reduced compared to when the spacer is not used, reflecting the loss of drug in the spacer. The radioactivity deposited in the oropharynx and stomach, shown in the 2D image, is from the coarse aerosol not collected by the spacer but inhaled.

(TAF) to correct for the reduction of activity due to chest wall absorption. These can be determined from a perfusion scan or a transmission scan or by measuring the thickness of the chest with calipers and calculating the factor from derived equations. The perfusion scan uses a known internal source of injected radioactivity, namely, 99mTc-microaggregated albumin (MAA) particles. Anterior and posterior images of the lung (Fig. 9) are obtained, the lung edge defined, followed by the calculation of the geometric mean count for the delineated lung. This last step is done to correct the acquired counts for the distance factor, i.e., the decrease in sensitivity of detection of activity emanating from the anterior lung when acquiring a posterior image. An error in the calculation of deposited dose of approximately 15% will be introduced if only the posterior image is acquired (M Dolovich, laboratory data). As the actual dose of injected radioactivity is known, a simple calculation can be made relating counts per minute per microcurie (or megabequeral) of activity in the whole lung as follows:

Tissue attenuation factor (cpm/^Ci) from the perfusion scan (Q):

\A injected J

Figure 9 Methods for outlining the whole lung used in planar or 2D imaging. The area defined by the transmission scan appears to be approximately 10% smaller than with the other techniques. Scatter of low-energy gamma rays into the chest wall area is the most likely explanation for the larger lung seen with inhalation of xenon-133 gas. (From Ref. 114a.)

Figure 9 Methods for outlining the whole lung used in planar or 2D imaging. The area defined by the transmission scan appears to be approximately 10% smaller than with the other techniques. Scatter of low-energy gamma rays into the chest wall area is the most likely explanation for the larger lung seen with inhalation of xenon-133 gas. (From Ref. 114a.)

where

Na = anterior perfusion cpm = sum of right and left lung cpm Np = posterior perfusion cpm = sum of right and left lung cpm

Coping with Asthma

Coping with Asthma

If you suffer with asthma, you will no doubt be familiar with the uncomfortable sensations as your bronchial tubes begin to narrow and your muscles around them start to tighten. A sticky mucus known as phlegm begins to produce and increase within your bronchial tubes and you begin to wheeze, cough and struggle to breathe.

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