Ventilation–Perfusion Scanning: Stuck in a Rut, Perhaps, but the Road Ahead Is Not So Clear

TO THE EDITOR: The recent editorial by Michael Graham states that the reason ventilation–perfusion (V/Q) SPECT has been slow to be adopted in the United States is due to confusion about the approach to interpretation of the studies; however, he states that the issue has been resolved—that is, follow the European procedure guidelines, eliminate probability categories, and interpret the studies as the presence or absence of pulmonary embolism (1). Some of the data supporting these statements deserve further discussion. However, this letter will focus on one particular aspect, the ventilation agent used for SPECT. To support the thesis that SPECT should be standard, the editorial specifically references one prospective and two retrospective publications supporting the use of SPECT (2–4). The ventilation agents used in the first two were ^81mKr and ^99mTc-Technegas (Cyclomedica Ltd.). Both are excellent ventilation agents; however, neither is available in the United States. The third publication did not use ^99mTc-diethylenetriaminepentaacetic acid (DTPA) as stated in the editorial but rather evaluated ^99mTc-macroaggregated albumin SPECT without a ventilation scan.

¹³³Xe and ^99mTc-DTPA are by far the most commonly used radiopharmaceuticals for ventilation studies in the United States. Most imaging clinics use ^99mTc-DTPA because it produces good image quality, can obtain multiple views that match perfusion projections, and does not have the radiation safety issues of ¹³³Xe. The downside is that in patients with chronic obstructive pulmonary disease, multiple central hot spots caused by turbulent airway flow are often seen, which can result in poor-quality and even nondiagnostic images. This becomes a particular problem with SPECT. ¹³³Xe is used at many institutions because the entire ventilator cycle can be viewed, hot spots are not a problem, and delayed washout is a sensitive indicator of obstructive lung disease, the most common alternative diagnosis to pulmonary embolism. Dr. Graham states that he uses ^99mTc-sulfur colloid aerosol. ^99mTc-sulfur colloid and ^99mTc-pyrophosphate aerosols are used at very few institutions, and published data supporting their clinical use are extremely limited.

Technegas has been available in Australia and Europe for years. Since 1986, there have been approximately 180 scientific publications about this radiopharmaceutical, with overwhelmingly positive sentiment and data on its safety and clinical efficacy. Anyone who has seen images of ^99mTc-Technegas compared with ^99mTc-DTPA aerosol or ¹³³Xe readily appreciates the clear superiority of Technegas. The Australian manufacturer has been trying to obtain Food and Drug Administration (FDA) approval for Technegas in the United States for several years. However, the FDA has made this extremely difficult. Even though most imaging clinics in the United States use ^99mTc-DTPA aerosol, the FDA will not allow a direct comparison between the two. The reason given is that the FDA never approved ^99mTc-DTPA for ventilation studies. We presently use it on an off-label basis. Therefore, the FDA is requiring that Technegas be compared with ¹³³Xe, even though ¹³³Xe is used in a minority of imaging centers. In addition, the FDA has required a large multicenter protocol that must include at least 375 subjects with a final diagnosis positive for pulmonary embolism and 375 that are negative for pulmonary embolism. The protocol is complex, time-consuming, and expensive. As a result, the sponsor is having difficulty finding institutions willing to participate and patient accrual has been poor. Many predict that this study will never be completed and that we will not be able to use Technegas in the United States in the foreseeable future. The FDA is hindering good patient care in the United States and disregarding the extensive experience in Australia and Europe. A simple direct image comparison of Technegas with ¹³³Xe or ^99mTc-DTPA aerosol is all that should be needed. Its safety has already been demonstrated by the experience worldwide.

I agree with Dr. Graham that V/Q SPECT should become the standard—that is, if we had a ventilation agent that would routinely provide good diagnostic SPECT images. Institutions with generally healthy patients who do not have cardiopulmonary disease may get away with using ^99mTc-DTPA aerosol with SPECT in most patients, but for institutions with many cardiopulmonary disease patients, particularly those with chronic obstructive pulmonary disease or asthma, ^99mTc-DTPA aerosol SPECT can be quite problematic.

The FDA should reexamine its complex protocol comparing Technegas and ¹³³Xe with the sponsor and devise a protocol that would simply examine the value of Technegas ventilation images versus ¹³³Xe or ^99mTc-DTPA aerosol images, using a protocol that can be accomplished with a limited number of patients in a reasonably short time. The extensive literature should be part of the approval process.

In summary, I agree that SPECT, particularly SPECT/CT, is the future of V/Q imaging. However, we unfortunately are not there yet, mainly because the FDA has hindered that progress, and this has adversely affected state-of-the-art optimal patient care.

• © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.