Pulmonary embolism (PE) has the potential for major morbidity and mortality. Given the protean manifestations of PE, clinicians frequently utilize diagnostic imaging to determine the presence or absence of PE. The two principal modalities utilized are ventilation–perfusion (VQ) imaging and computed tomography angiography (CTA). Both modalities have been well validated for the diagnosis of PE 1,2.
One of the principal advantages of VQ over CTA is a lower radiation dose to the patient: 2.5 versus 15 mSv, respectively 3. The dose for the VQ scan can be broken down into 0.5 mSv for ventilation using xenon-133 (133Xe) and 2.0 mSv for perfusion using technetium-99m (99mTc)-macroaggregated serum albumin. The interpretation of VQ scans in many centers is based on guidelines published by the PIOPED II investigators 4. The identification of PE is based on the detection of defects in the perfusion phase that are unmatched on the ventilation phase. As a result, the identification of a normal perfusion phase excludes PE regardless of the appearance on the ventilation phase 5. Studies with small or nonsegmental perfusion defects do not qualify for an intermediate or high probability scan even if unmatched. A normal ventilation study indicates that any defects identified on perfusion images are unrelated to airspace abnormalities. To obtain the maximum information from the images, the lower-energy photon-emitting ventilation phase should be performed before the higher-energy photon-emitting perfusion phase; hence, all patients undergo dual-phase imaging.
The American College of Radiology Appropriateness Criteria suggest that perfusion-only imaging may be warranted in patients with a rapid deterioration in clinical condition and in patients who are not good candidates for CTA 6. Prior work has demonstrated that there is a similar rate of high-probability scans with perfusion-only imaging and also a higher percentage of intermediate scans but few lower-probability scans 7.
Patients who are younger, without underlying lung disease, and with clear chest radiographs are presumably more likely to have a normal ventilation-phase study; thus, the results of the VQ study may rely largely on the perfusion phase of imaging. The goal of our study was to identify a subset of patients for whom ventilation-phase imaging does not provide additional diagnostic information and may be considered for perfusion-only imaging for the diagnosis of PE in the future.
Materials and methods
The local institutional review board approved this retrospective and Health Insurance Portability and Accountability Act-approved study. Informed consent was waived. Five hundred consecutive VQ scan reports, dated between 2 June 2011 and 11 November 2011, with the indication for possible acute PE were reviewed. Ventilation imaging was performed with 133Xe and perfusion imaging was performed with 99mTc-macroaggregated serum albumin. All patients were required to undergo a chest radiography within 24 h.
Information on ventilation abnormalities, perfusion defects, PIOPED II classification, age, sex, chest radiograph results, and presence of respiratory disease was recorded from the radiology reports. The radiology reports were in standardized language and provided information on the associated chest radiograph, ventilation phase, perfusion phase, and final results. The ventilation and perfusion phases of imaging were evaluated independently for abnormalities and the perfusion defects were categorized as segmental and nonsegmental; they were then compared to see whether the abnormalities matched with those seen in the ventilation phase.
Additional clinical information on age, sex, and any underlying lung disease (asthma, COPD, pulmonary hypertension, obstructive sleep apena, lung transplant, and chronic PE) was recorded from the referring clinician’s notes. Studies were excluded if they were incomplete or repeated.
For this study, perfusion defects were classified as no defects, nonsegmental, small (presence of at least one small defect), moderate (presence of at least one moderate defect), or large (presence of at least two large defects), which correspond with the PIOPED II classification scheme. As per PIOPED II criteria, two moderate defects are equivalent to a single large defect. Ventilation defects were classified as matched or unmatched. Chest radiographs were classified as clear or not clear, which included any pleural or parenchymal opacities regardless of size. Probability for PE was classified as per PIOPED II criteria as normal, high, intermediate, low, or very low. Respiratory disease was recorded as present or absent. Patient demographic data are shown in Table 1.
Patients with moderate or large perfusion defects were analyzed to assess the utility of the ventilation phase on the final PIOPED II classification. Patients with no defects or with nonsegmental or small perfusion defects were not considered further because of the low likelihood of PE.
A subset of studies (13.6%, 68/500) did not characterize the size of the perfusion defect (i.e. a matched perfusion defect in the right lung). These studies were reviewed by a nuclear medicine physician with 40 years of experience in interpreting VQ scans, and the sizes of the perfusion defects were graded. The reader was blinded to the ventilation phase of imaging and to the final PIOPED II classification. The breakdown of perfusion grading in the subset was compared with that of the remaining pool by means of Spearman’s rank correlation.
Chest radiograph results, age, sex, and respiratory disease status were compared with the ventilation status. The nominal variables (chest radiograph results, sex, and respiratory disease status) were analyzed using a likelihood ratio. The numeric variable (age) was analyzed using logistic regression. A stepwise regression model using the above criteria was then performed to assess the collective influence of the individual variables. Subsets of studies that shared various characteristics were compared with the overall pool using the χ2-test. Statistical analysis was carried out using JMP Pro (version 9.0.0; SAS Institute Inc., Cary, North Carolina, USA) and Excel (version 2010; Microsoft Corporation, Redmond, Washington, USA).
Sixty-five studies (13%) had moderate (n=39) or large (n=26) perfusion defects (Table 1). Of these, 46 studies (70.8%) had defects unmatched on ventilation and three (4.6%) had triple-match defects, resulting in 49 reports (75.4%) classified as intermediate (n=28) or high (n=21) probability for PE. There was a statistically significant association between unmatched ventilation and a clear chest radiograph (P=0.03) and an association approaching statistical significance with younger age (P=0.05). A breakdown by age is shown in Fig. 1. There was a moderate association with respiratory disease (P=0.12) and no association with patient sex (P=0.82). A stepwise regression model confirmed the significance of the clear chest radiograph only (P=0.03) on ventilation matching.
The subset of studies with perfusion defects not adequately characterized on the initial report that were subsequently classified showed an almost identical ratio of intermediate and large perfusion defects (11/68, 16.2%) to that of the total group (65/396, 16.4%), with no statistically significant difference (P=1).
Results of the subgroup analysis with the exclusion of patients with abnormal chest radiographs and/or respiratory disease are shown in Table 2. The percentage of studies with unmatched defects increased from 70.8% (46/65) to 76.7% (33/43, P=0.39) if patients with respiratory disease were excluded, to 82.4% (28/34, P=0.14) if abnormal chest radiographs were excluded, and to 95.7% (22/23, P=0.01) if both were excluded.
Our study is an important first step toward identifying patients for whom ventilation-phase imaging may be excluded in the diagnosis of PE.
The subgroup data shown in Table 2 provide the most useful, and potentially actionable, analysis. Excluding studies with abnormal chest radiographs and respiratory disease results in a very high (95.7%) and statistically significant percentage of unmatched defects. If these guidelines had been implemented and the respiratory phase of imaging had been excluded, there would have been a less than 5% discrepancy from the reference reports if the determination of PE had been made solely on the basis of perfusion abnormalities.
The statistical significance of a clear chest radiograph is expected, as abnormal chest radiographs are more likely to be associated with abnormalities on both ventilation and perfusion phases. Our data suggest that patients with chest radiographic abnormalities would benefit from ventilation-phase imaging but that the opposite may also be true, and hence a clear chest radiograph is one factor to be taken into consideration when deciding whether to exclude the ventilation phase. A surprising detail was the high percentage of studies with abnormalities on chest radiographs (29.6%). Before being approved for a VQ scan, all patients are required to have a chest radiograph reviewed by a radiologist to determine whether the patient is a good candidate for a VQ scan. We did not categorize the size of the defect in this study but suspect that many of the abnormalities were small and the radiologist felt confident in the potential diagnostic accuracy of a subsequent VQ scan. In addition, there are some patients who are not able to undergo a CTA because of a contrast allergy or poor renal function, and a VQ scan, even if possibly of less diagnostic certainty, is the best option available.
Although younger age did not reach statistical significance (P=0.05), we suspect that with a larger sample size it may achieve statistical significance. Younger patients are less likely to have respiratory disease or abnormalities on chest radiographs and are thus more likely to have a normal ventilation phase; therefore, any perfusion defects would be unmatched. Similarly, respiratory disease demonstrated an association with unmatched defects, but no statistical significance (P=0.13). This may be more a function of undiagnosed respiratory disease. Anecdotally, there were also a number of scans in which there were signs of obstructive lung disease on the ventilation phase but no corresponding reported clinical history.
Triple-match defects are a unique challenge in this study, as they represent a situation in which a matched perfusion defect in the lower zones would lead to an intermediate probability interpretation. There were only three cases (0.6%) in the study population, but as they corresponded to at least a moderately sized defect they were all included in the analysis of moderate and large perfusion defects. Thus, they represent a larger portion (4.6%) of those with moderate and large defects. By definition, they were excluded from the subgroup analysis that included clear chest radiographs. The decision to analyze the variables in comparison with unmatched defects, rather than with PIOPED II results, was an attempt to compensate for this discrepancy. However, statistical analysis that focused on PIOPED II results demonstrated small percentage differences in several variables but no changes in statistical significance or in the overall conclusions.
An alternative ventilation agent to 133Xe is krypton-81m (81mKr). 81mKr has the advantage of a short half-life (13 s), which allows for multiple views, a high photon energy (190 keV), which allows for simultaneous acquisition of perfusion images, and a low absorbed radiation dose. Unfortunately, 81mKr is expensive because of the short half-life of the rubidium generator and is not widely available 8.
The limitations of the study are those inherent to a retrospective and single-institution study. In addition, although the total number of scans included was large (n=500), the total number of scans that had moderate or large perfusion defects was much smaller (n=65). This reflects an apparent trend toward increased imaging of patients with a lower pretest probability for PE, as the overall rate of high probability scans was 4.2%, which is much lower than the 13% reported in PIOPED I 1 and the 11% reported in PIOPED II 9. It is possible that, by increasing the number of studies with moderate and large perfusion defects, some of the variables that had a strong association (age and respiratory disease) may achieve statistical significance.
Our study shows that there may exist a subset of patients – younger patients with clear chest radiographs and no evidence of respiratory disease – for whom the ventilation phase of imaging can be excluded and the determination of a PE be based solely on perfusion abnormalities. A prospective study designed to assess these variables in particular would be needed before any definitive changes to clinical practice can occur.
Conflicts of interest
Lars J Grimm: author, Medscape, LLC; editor, Medscape, LLC. Ralph Edward Coleman: Stockholder, Radiology Corporation of America; research grant, General Electric Company; research grant, Eli Lilly and Company; research grant, Molecular Insight Pharmaceuticals Inc.; Medical Advisory Board, MedSolutions; Medical Advisory Board, Radiology Corporation of America.
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