radionuclide imaging of acute pulmonary embolism

UPDATE ON NUCLEAR MEDICINE 0033-8389/01 $15.00 + .OO

RADIONUCLIDE IMAGING OF ACUTE PULMONARY EMBOLISM

Daniel F. Worsley, MD, and Abass Alavi, MD

Pulmonary embolism (PE) is a relatively common and potentially fatal disorder for which treatment is highly effective and im- proves patients’ survival. The accurate and prompt diagnosis of acute PE requires an in- terdisciplinary team approach and may be difficult because of nonspecific clinical, laboratory, and radiographic findings.42, 74 The incidence of venous thromboembolism is approximately one in 1000 per year.57 Approxi- mately 10% of patients with PE die within 1 hour of the event.12 In an autopsy series of 4077 patients, deep venous thrombosis (DVT) or PE was present in 24% of cases, and in 14% of cases PE was determined to be the cause of death.56 For those patients who sur- vive beyond the first hour following PE, treatment with heparin or thrombolytic agents is effective therapy3, 7, 12* 24, 25 The overall mortality in patients with PE who are untreated has been reported to be as high as 30%.l2 Mortal- ity from PE is highest among hemodynami- cally unstable patients and can be as high as 589’0.~~ In contrast, the correct diagnosis and appropriate therapy significantly lower mortality to between 2.5% and 8%.3,11 In a meta- analysis of 25 studies including 5523 patients the rate of fatal PE during anticoagulant therapy was 0.4% among patients presenting with DVT and 1.5% among patients presenting with PE.14 Although anticoagulant therapy is effective in treating PE and reducing mortal-

ity, it is not without some risk. The prevalence of major hemorrhagic complications has been reported to be as high as 10% to 15% among patients receiving anticoagulant or thrombolytic therapy.”, 32, 40 In one study investigating drug-related deaths among hospital patients, heparin was responsible for most drug-related deaths in noncritically ill patients.46 The accurate and prompt diagnosis of PE is essential not only to prevent excessive mortality but also to avoid complications related to unnecessary anticoagulant therapy.

CLINICAL DIAGNOSIS OF PULMONARY EMBOLISM

In the clinical evaluation of patients with established PE risk factors, clinical signs and symptoms were similar in men and women.47 The risk of PE does increase with age. Seden- tary lifestyle, prolonged recovery phase following illness, congestive heart failure, malig- nancy, and increased hip fracture rates in the elderly are factors that increase the likelihood of PE.4*19 The clinical findings of patients with suspected PE and no pre-existing cardiac or pulmonary disease were evaluated in a subset of the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study popula- t i ~ n . ~ ~ The most common symptoms of patients with PE and no pre-existing cardiac or

From the Division of Nuclear Medicine, University of British Columbia, Vancouver General Hospital, Vancouver, British Columbia, Canada (DFW); and Division of Nuclear Medicine, Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania (AA)

RADIOLOGIC CLINICS OF NORTH AMERICA

VOLUME 39 - NUMBER 5 * SEPTEMBER 2001 1035

1036 WORSLEY & ALAVI

pulmonary disease were dyspnea, pleuritic chest pain, and The prevalence of these symptoms was not significantly different when compared with patients in whom PE was excluded. Dyspnea, tachypnea, and pleuritic chest pain alone or in combination were present in 97% of patients with PE.& Like the symptoms, the clinical signs associated with acute PE are also nonspecific. The prevalence of tachypnea, tachycardia, and fe- ver was similar among patients with PE when compared with those in whom the disease was excluded. Increased intensity of the pul- monic component of the second heart sound was more commonly heard in patients with PE. This finding, however, was present in only 23% of patients.65 Immobilization (strict bed rest for more than 3 continuous days) and surgery (an incision under regional or general anesthesia) within 3 months were more common in patients with PE compared with those without.ffi The frequency of other risk factors that were recorded during the PIOPED study was approximately the same between the two groups. Neural networks have been developed to aid in the clinical diagnosis of PE. In simplistic terms, neural networks are computer programs that are ca- pable of processing information similar to the way the human brain processes information. A more detailed description of the application of neural networks in radiologic diagnoses can be found el~ewhere.~ A neural network for the clinical diagnosis of PE has been developed using 50 variables that were available from patients enrolled in the PIOPED These variables included information obtained from history, physical examination, chest radiograph, electrocardiograph, and room air arterial blood gas measurements. The likelihood of PE based on clinical findings as predicted by the neural network was similar to that predicted by experienced clini- cians. Neural networks can provide a repro- ducible assessment of the clinical likelihood of PE and may aid in the diagnostic evaluation of patients suspected of having acute PE. The clinical manifestations of PE, however, were quite variable and lack the specificity to diagnose or exclude clinically significant PE reliably.

D Dimer

D dimer is a plasmin-mediated degradation product of circulating cross-linked fibrin. An

elevated D-dimer level is not specific for venous thromboembolism and may occur in any condition in which fibrin has been formed and degraded by plasmin. Arterial thrombosis, disseminated intravascular coagulation, infections, sepsis, recent trauma, and postop- erative states may all cause elevated D-dimer levels. D-dimer levels are commonly mea- sured using either latex agglutination or en- zyme-linked immunosorbent assay (EL1SA)- based methods. The ELISA-based method is more sensitive and can detect D-dimer concentration levels as low as 30 ng/mL. The test is labor intensive, however, and may take over 36 hours to perform; it is not appropriate for emergency use. The latex agglutination method is a more rapid, semi-quantitative test that can detect D-dimer concentration levels in the 200 to 500 ng/mL range. In a consensus statement from the American College of Chest Physicians there was general agreement that an ELISA-based assay that measures D dimer excluded PE in 90% to 95% of patients and that a normal latex agglutination D dimer was unreliable for excluding PE and should not be perf~rmed.~ In a recent evaluation of a rapid, bedside agglutination assay (Simpl- iRED) in emergency room patients, the test had a negative predictive value of only 81%. It was concluded that a negative simpliRED D-dimer assay does not exclude the diagnosis of DVT or PE in patients presenting to the emergency There are currently no methods to standardize D-dimer results from different manufacturers, and high variations in assay results have been In an attempt to overcome the problems of a low specificity, it has been recommended that the test be performed only on outpatients and used to exclude the diagnosis of PE. Despite this, a meta-analysis of 29 D-dimer studies concluded that the clinical use of the D-dimer assay remains unproved.8

Chest Radiographic Findings in Pulmonary Embolism

Chest radiographs are helpful in excluding diseases that clinically mimic PE and are performed in virtually all patients with suspected PE. In the PIOPED study, chest radiographs were obtained within 24 hours of angiography, and among patients with angiographically documented PE, only 12% (45 of 383) of patients had chest radiographs interpreted as normal.75 The positive and negative

RADIONUCLIDE IMAGING OF ACUTE PULMONARY EMBOLISM 1037

predictive values of a normal chest radiograph were 18% and 74%, respectively. In patients with PE and no pre-existing cardiac or pulmonary disease only 16% had chest radiographs interpreted as The most common chest radiographic findings in patients with PE were atelectasis or parenchymal opacities in the affected lung zone.65, 75

Atelectasis or parenchymal opacities, however, were also the most common finding in patients in whom PE was excluded. Pleural effusions within the affected hemithorax occurred in approximately 35% of patients with PE. Most pleural effusions were small, causing only blunting of the costophrenic angles.” Chest radiographic findings alone were nonspecific for PE. Chest radiographs, however, are essential in the evaluation of patients with suspected PE to diagnose conditions that can clinically mimic PE and aid in the interpretation of the ventilation-perfusion (V/Q) lung scans.

VENTILATION-PERFUSION LUNG SCANNING IN PULMONARY EMBOLISM

The V/Q lung scan has been shown to be a safe noninvasive technique to evaluate regional pulmonary perfusion and ventilation. The technique has been widely used in the evaluation of patients with suspected PE.

Radiopharmaceuticals and Techniques in Ventilation-Perfusion Lung Scanning

The agents of choice for perfusion imaging are either Tc 99m-labeled human albumin mi- crospheres (Tc 99m HAM) or macroaggregated albumin (Tc 99m MAA). Tc 99m MAA particles range in size from 10 to 150 p,m; however, over 90% of injected particles mea- sure between 10 and 90 p,m. Tc 99m HAM particles are more uniform in size and range between 35 and 60 p,m. The injection of labeled particles should be performed with the patient in the supine position, which limits the effect of gravity on regional pulmonary arterial blood flow. Following the intravenous administration of Tc 99m MAA, particles are mixed within the heart and then lodge within precapillary arterioles in the lungs. The usual administered activity is between 74 and 148 MBq (2 to 4 mCi). The distribution of particles

within the lungs is proportional to regional pulmonary blood flow at the time of injection. Approximately 200,000 to 500,000 particles are injected during a routine clinical perfusion lung scan. The blockage of pulmonary precapillary arterioles by Tc 99m MAA is transient, and the biologic half-life within the lung ranges between 2 and 6 hours. In pediat- ric patients, patients with right to left shunts, patients with pulmonary hypertension (PHT), and patients who have undergone pneumo- nectomy or single lung transplantation, the number of particles injected should be reduced. A minimum of 60,000 particles is required to obtain an even distribution of activity within the pulmonary arterial circulation and avoid potential false-positive interpreta- t i o n ~ . ~ ~ When performing perfusion scintigraphy, at least six views of the lungs should be obtained: (1) anterior, (2) posterior, (3) right lateral, (4) left lateral, (5) right posterior oblique, and (6) left posterior oblique. Addi- tionally, right and left anterior oblique views may be helpful in selected cases. Animal studies have demonstrated that perfusion imaging detects greater than 95% of emboli that completely occlude pulmonary arterial vessels greater than 2 mm in diameter.z Despite imaging in multiple projections, the perfusion scan may underestimate perfusion abnormalities. A solitary segmental perfusion defect within the medial basal segment of the right lower lobe is completely surrounded by normal lung. Consequently, a perfusion defect in this segment is not detected on planar perfusion imaging.36

Perfusion scintigraphy is sensitive but not specific for diagnosing pulmonary diseases. Virtually all parenchymal lung diseases (including tumors, infections, chronic obstructive pulmonary disease [COPD], and asthma) can cause decreased pulmonary arterial blood flow within the affected lung zone. Conse- quently, shortly after the introduction of perfusion scintigraphy, ventilation imaging was combined with perfusion scintigraphy to im- prove the diagnostic specificity for diagnosing PE. The pathologic basis for combining ventilation and perfusion scintigraphy was that PE characteristically causes abnormal perfusion with preserved ventilation (mis- matched defects) (Fig. 1). Parenchymal lung disease most often causes both ventilation and perfusion abnormalities in the same lung region (matched defects) (Fig. 2). Conditions in which the ventilation abnormality seems larger than the perfusion abnormality (re-


Figure 1. Technetium (Tc)-99m diethylene-triamine-pentaacetic acid (DTPA) aerosol (A) and Tc-99m macroaggregated albumin (MAA) perfusion (B) images demonstrate multiple bilateral segmental and subsegmental perfusion defects in regions that are ventilated normally (V/Q mismatch). The findings indicate a high probability of acute pulmonary embolism. A faint amount of activity is also present within the renal parenchyma, indicating a right- left shunt.

verse mismatch) include airway obstruction, mucous plug, airspace disease, atelectasis, and pneumonia. Patients with metabolic alka- losis, limited pulmonary vascular reserve, or patients treated with inhaled albuterol may also have failure or inhibition of hypoxic pulmonary vasoconstriction, which results in reverse mismatch.

Perfusion imaging can provide an estimate of the pulmonary clot burden and the hemodynamic effect of PE. In addition, perfusion imaging can also identify patients with a patent foramen ovale or undiagnosed atrial sep- tal defect and elevated right heart pressures who are at risk for paradoxical embolization (Fig. 3) . Most patients with acute PE either completely lyse their thrombus or partially recanalize their pulmonary arteries. In the urokinase PE trial, approximately 75% to 80%

of perfusion defects resolved by 3 months, and perfusion defects that did not resolve by 3 months remained largely persistent when followed for 1 year (Fig. 4). The amount of clot resolution observed in the urokinase pulmonary embolism trial (UPET) is likely an underestimate, because ventilation scanning was not performed and many of the unresolved perfusion defects might have been caused by pre-existing chronic obstructive lung disease. Based on these data, the Ameri- can College of Chest Physicians consensus statement recommends performing a follow- up V/Q lung scan at 3 months following the initial diagnosis to evaluate clot resolution and serve as a baseline for future compari- s o n ~ . ~ If patients are unable to return in 3 months, a V / Q scan at discharge may also be useful.


Figure 2. A, Anterior and posterior Tc-99m DTPA aerosol ventilation images demonstrating a marked inhomogeneous distribution of activity within both lungs. There was poor peripheral penetration of activity secondary to turbulent airflow. 6, Tc-99m MAA perfusion images demonstrate matching perfusion defects. There were no pleural-based regions of V/Q mismatch to suggest acute pulmonary embolism (PE). The findings are best explained by chronic obstructive pulmonary disease (COPD).

Considerable experience with ventilation imaging has been with Xe 133. Alternative ventilation imaging techniques, such as Xe 127, Kr Blm, Tc 99m aerosols, technegas, and pertechnegas, have not been as extensively evaluated as Xe 133. Studies comparing the various ventilation agents are limited, however, based on the available data, there likely are no major diagnostic differences between the agents.', 29 With Xe 133, first breath and breath-hold images demonstrate regional lung ventilation. Equilibrium images are obtained while the patient rebreathes the gas for at least 4 minutes. Regions of the lung that appear as defects on the breath-hold image may normalize on the equilibrium image because of collateral air drift. During washout imaging the patient breathes in room air, and regional air-trapping can be detected as focal areas of retained activity. Ventilation images with Xe 133 are usually obtained before per-

fusion imaging. The imaging technique with Xe 127 is similar compared with Xe 133; however, because Xe 127 has a higher energy than Tc 99m, ventilation imaging with this agent may be performed following perfusion imaging. The advantages of performing postper- fusion ventilation studies are that the patient can be positioned in such a way that the lung demonstrating the greatest perfusion abnormality may be imaged optimally. Also, ventilation imaging may be avoided in selected cases when the perfusion lung scan appears normal. Xe 27 does have several disadvantages; namely, it is more costly than Xe 133 and requires medium energy collimation. When performing ventilation imaging with either Xe 133 or Xe 127, initial breath-hold or wash-in images can be obtained only in a single projection, which limits the comparison with perfusion images that are obtained in multiple projections.


Figure 3. A, Tc-99m MAA perfusion images demonstrate a high pulmonary clot burden with multiple segmental defects (same patients as Fig. 1). B, Anterior images of the skull demonstrate activity within the brain parenchyma indicating a right-left shunt that is related to acutely elevated right heart pressure and a patent foramen ovale. C, A follow-up perfusion image 24 hours following thrombolytic therapy demonstrates marked improved perfusion within the right lung and left lower lobe. 0, A posterior image of the abdomen failed to reveal activity within the kidneys, indicating that the right heart pressures have decreased and the previously patent foramen ovale has closed.

Kr 81m is another noble gas used to evaluate regional ventilation. This agent has a very short physical half-life (13 seconds) and only wash-in or breath-hold images can be obtained. The short physical half-life of Kr 81m, however, enables one to obtain images in multiple projections. Kr 81m is produced from a rubidium 81 generator. The parent radionuclide has a physical half-life of 4.7 minutes; therefore, the useful lifetime of the generator is only 1 day. Similar to Xe 127, ventilation imaging with Kr 81m is generally performed following perfusion imaging.

Ventilation imaging with Tc 99m-radiolabeled aerosols can be performed with several radiopharmaceuticals, including Tc 99m pentetate (DTPA), Tc 99m sulfur colloid, Tc 99m pyrophosphate, Tc 99m medronate, and Tc 99m glucoheptonate. The most popular agent is Tc 99m DTPA; however, this agent

has a relatively short resonance time within the lung, especially in smokers, and in these patients Tc 99m-labeled sulfur colloid or pyrophosphate may be beneficial. Tc 99m- labeled radioaerosols are between 0.5 and 3 pm in size and are produced by the appropriate radiopharmaceutical in a commercially available nebulizer. For a routine ventilation study, 1.11 GBq (30 mCi) of Tc 99m DTPA in 3 mL of saline is placed within the nebulizer. Oxygen is then forced through the nebulizer at high pressure to produce aerosolized drop- lets, which are inhaled by the patient through a mask or mouthpiece. The patient generally breathes from the nebulizer for 3 to 5 minutes or until 37 MBq (1 mCi) of activity is depos- ited within the lungs. The distribution of activity within the lungs is proportional to regional ventilation. Multiple image projections can be obtained, which correspond with those


Figure 4. Tc-99m DTPA aerosol (A) and Tc-99m MAA petfusion (B) images demonstrate multiple bilateral segmental and subsegmental regions of V/Q mismatch indicating PE. A follow-up study 3 months later was essentially unchanged, confirming chronic unresolved PE.

obtained during subsequent perfusion imaging. Ventilation studies with Tc 99m- labeled radioaerosols require minimal patient cooperation, and portable studies or studies in patients on respirators can be performed relatively easily. Disadvantages of Tc 99m- labeled radioaerosols relate primarily to central deposition of activity in patients with COPD or airway obstruction and the amount of activity that is wasted within the nebulizer. In general, ventilation is performed before perfusion imaging; however, ventilation imaging with radiolabeled aerosols can be effectively performed following perfusion imaging, and in patients with normal or near normal perfusion study, ventilation imaging can be omitted.6

Because of the problem with central deposition of Tc 99m-labeled radioaerosol in patients with COPD, newer agents have been developed. These include Tc 99m technegas and Tc 99m pertechnegas. Both of these agents are performed by burning Tc 99m per- technetate in a carbon crucible at very high temperatures, which produces an ultrafine radiolabeled aerosol (particle size 0.02 to 0.2 Fm). Pertechnegas is purged with 5% oxygen and 95% argon, compared with technegas, which is purged with 100% argon. This relatively minor difference causes profound changes in the biologic distribution of activ-

ity. When inhaled, both agents distribute ho- mogeneously within the lung proportional to regional lung ventilation, and very little central deposition of activity is seen, even in patients with COPD. Pertechnegas readily penetrates the alveolar epithelial membrane, and the biologic half-life in the lungs is quite short, measuring approximately 6 to 10 minutes. On the other hand, there is very little transalveolar or mucociliary clearance of technegas, and the effective half-life is approximately equal to the physical half-life. Both agents require minimal patient cooperation, and only 2 to 3 breaths are required to obtain sufficient counts in the lungs to perform ventilation imaging. In general, ventilation imaging with both technegas and pertechnegas is performed before perfusion imaging and multiple projections that correspond with the perfusion images are obtained.

Glycoprotein Ilb-llla Receptor Imaging

More recently, there has been considerable interest in antibody fragments and radiolabeled peptides directed against glycoprotein Irb-IIIa receptors on the surface of activated platelets.lO, 38, 73 The Food and Drug Adminis-


Figure 5. Coronal single photon emission computed tomography (SPECT) images through the midthorax demonstrate increased accumulation of DMP-444 (99mTc-GP IlbAlla antagonist) in a patient with documented PE within the right main and lower lobe pulmonary arteries.

tration has recently approved Acutetec, a Tc 99m-labeled synthetic peptide that binds to the glycoprotein 1%-IIIa receptors for evaluation of patients with suspected DVT. The main advantage of this agent is its ability to distinguish between acute and chronic DVT. Several Tc 99m-labeled peptides directed against activated platelets are currently under investigation for the evaluation of patients with suspected PE (Fig. 5).

PROSPECTIVE TRIALS

Data from multiple prospective and outcome-based large studies have reported on the efficacy of V/Q scanning in patients suspected of having acute PE.26-28, 30, 34, 45, 73 In a prospective study by Hull et al,27 874 patients suspected of having PE were enrolled. V/Q scan interpretations were grouped into three diagnostic categories: (1) normal; (2) non- high probability; and (3) high probability (mismatch defect involving at least 75% of a segment). The purpose of the study was to determine if anticoagulation therapy could be withheld in patients with a non-high probability V/Q scan, adequate cardiorespiratory reserve, and absent proximal vein thrombosis as determined by negative serial impedance plethysmography (IPG). This diagnostic approach emphasized the importance of the basic pathophysiologic concept that venous thromboembolism is a systemic disease proc- ess and that PE was merely the respiratory manifestation of venous thromboembolism. High probability and normal V/Q scans were interpreted in 8% and 36% of patients, respectively. Nine percent of patients had non-high probability V/Q scans and inadequate cardiorespiratory reserve defined by the presence of pulmonary edema, right ventricular failure,

systolic blood pressure less than 90 mm Hg, syncope, acute tachyarrhythmia, and severely abnormal spirometry or arterial blood gases. Most patients (47%) had non-high probability V/Q scans and adequate cardiorespiratory reserve. The outcome in each group was assessed during a 3-month follow-up period. In patients with non-high probability lung scan interpretation, adequate cardiorespiratory reserve, and negative serial IPG studies, antico- agulants were withheld. Only 2.7% of these patients had evidence of venous thromboembolism on follow-up. The conclusion from this study was that patients with a non-high probability V/Q scan, adequate cardiorespiratory reserve, and negative serial IPG studies could be managed safely without anticoagulation. In addition, these results also confirm findings from previous studies that suggested that the incidence of recurrent PE is very low in the absence of proximal lower extremity venous thrombus. Unfortunately, the interpretation criteria used to categorize the probability of PE were to some extent unconven- tional (normal, nondiagnostic, or high). Consequently, comparison of these results with the PIOPED study is not directly possible.

In a separate study, Hull et alZ8 prospectively examined 1564 consecutive patients with suspected PE who underwent both V/Q scanning and IPG of the lower extremities. In 40% (627 of 1564) V/Q scans were interpreted as nondiagnostic and serial IPG studies were negative. All of these patients had an adequate cardiorespiratory reserve and were managed without anticoagulation. Using this algorithm, only 1.9% (12 of 627) had evidence of either DVT or PE on follow- up. As Hull et alZGz8 have demonstrated, the combination of V/Q scan findings and IPG can be very useful in selecting patients who


have not had substantial PE and in whom there is no evidence of proximal lower extremity venous thrombi. In these patients the risk of recurrent embolic events is low and anticoagulation may not be 30

More recently, Wells et al” prospectively examined 1239 patients with PE. The clinical model categorized pretest probability of PE as low, moderate, or high, and V/Q scanning and bilateral deep venous ultrasound were performed. Using this approach, only 3 (0.5%) of the 665 patients with low or moderate pretest probability and a non-high probability scan had PE or DVT during the 90-day follow-up period. Their conclusion was that patients with suspected PE can be managed safely based on pretest probability and results of V/Q scanning.

Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis

The prospective investigative study of acute PE diagnosis (PISA-PED) used perfusion scanning alone in conjunction with the chest radiographs in 890 consecutive patients. The sensitivity and specificity of scintigraphy were 92% and 87%, respectively.M The prevalence in their population was relatively high at 39%. By combining the clinical assessment of the likelihood of PE (very likely, possible, or unlikely), the positive predictive value of a positive perfusion scan was 99%. A near normal or abnormal perfusion scan without segmental defects combined with a low clinical likelihood of PE had a negative predictive value of 97%.

Prospective Investigation of Pulmonary Embolism Diagnosis Study

To date, the most comprehensive prospective study addressing the role of V/Q scanning in the diagnosis of PE has been the PIOPED The prospective investigation of PE diagnosis (PIOPED) study was a multi-institutional study designed to evaluate the efficacy of V/Q scanning for diagnosing acute PE. The PIOPED study also provided an opportunity to assess the validity of pulmonary angiography for diagnosing acute PE and to determine the incidence of complications related to t h s procedure.

In the PIOPED study, the sensitivity, specificity, and positive predictive value of a high-probability V/Q scan interpretation for detecting acute PE are 40%, 98%, and 87%, respectively. The diagnostic accuracy of V/ Q scanning was not significantly different in women compared with men.47 Similarly, the overall diagnostic performance of the V/Q scan was similar among patients with varying ages.63, 76 The diagnostic use of V/Q scanning for detecting PE was similar among patients with pre-existing cardiac or pulmonary disease compared with patients with no underly- ing cardiac or pulmonary In a subset of patients with COPD, the sensitivity of a high-probability V/Q scan interpretation was significantly lower compared with patients with no pre-existing cardiopulmonary disease.31 The positive predictive value of a high-probability V/Q scan interpretation was loo%, however, and the negative predictive value of a low- or very-low-probability V/Q scan interpretation was 94%.

Although the clinical diagnosis of PE is not diagnostic in most instances, the results from the PIOPED study emphasized the importance of incorporating the clinical assessment when evaluating patients suspected of having acute PE. As expected, combining clinical assessment with the V/Q scan interpretation improved the diagnostic accuracy. In PIOPED, however, most patients had intermediate-probability V/Q scans and an intermediate clinical likelihood of PE. For these patients, the combination of clinical assessment and V/Q scan interpretation does not provide adequate information to direct patient management accurately, and further investigations with peripheral venous studies, CT angiography, or pulmonary angiography are usually required. In the more recent PISA- PED study combining the clinical estimates of PE with an independent perfusion lung scan, interpretation restricted the need for angiography to a minority of patients with suspected PE.35

Interpretation Pitfalls

False-negative lung scan interpretations (low probability and PE present) do occur, and patients who have a recent history of immobilization (bed rest for 3 days), recent surgery, trauma to the lower extremities, or central venous instrumentation are particularly at risk for this finding. In patients with


Table 1. PIOPED STUDY

0 Risk Factors* 1 Risk Factor* 2 2 Risk Factors’ V/Q Scan PE +/No. of Patients PE +/No. of Patients PE+/No. of Patients

Interpretation (“w (%I High 63/77 (82) Intermediate 52/207 (25) Low or very low Normal 0/28 (0)

14/315 (4)

41/49 (84) 40/107 (37) 19/155 (12) 0/7 (0)

56/58 (97) 77/173 (45) 37/179 (21) 0/4 (0)

*Risk factors include immobilization for more than 3 days before presentation, history of surgery, trauma to the lower extremities,

Datafrom Worsley DF, Alavi AJ: Comprehensive analysis of the results of the PIOPED study Prospective Investigation of Pulmonary and central venous instrumentation within 3 months of presentation.

Embolism Diagnosis Study Nucl Med 36238&2387,1995.

low- or very-low-probability V/Q scan interpretations and no history of immobilization, recent surgery, trauma to the lower extremities, or central venous instrumentation, the prevalence of PE was only 4.5y0.~ In patients with low- or very-low-probability V/Q lung scan interpretations and one or more than one of the previously mentioned risk factors, the prevalences of PE were 12% and 21%, respectively (Table 1). Patients with false-negative lung scan interpretations tend to have nonocclusive subsegmental thrombi with low pulmonary clot burden. In recent years, con- cern has been raised that a low-probability lung scan interpretation may be misleading and result in unnecessary mortality as a se- quelae of PE. The prognostic value of a low probability is excellent, particularly in patients with a low clinical pretest likelihood of disease or negative ultrasound. In a recent series of 536 consecutive patients with this finding, there was no evidence that PE was a causative or contributing factor among patients who died within 6 months of imaging.&

The most common cause of V/Q mismatch in patients who do not have acute PE is related to chronic or unresolved PE (see Fig. 4). Other causes of V/Q mismatch in the absence of PE (false-positive V/Q study) include compression of the pulmonary vasculature (mass lesions, adenopathy, or mediastinal fibrosis); vessel wall abnormalities (pulmonary artery tumors or vasculitis); intraluminal obstruction (tumor emboli or foreign body emboli); and congenital vascular abnormalities (pulmonary artery agenesis or hypoplasia). In patients with unilateral V/Q mismatch (hypo- perfusion or absent perfusion) within an entire lung or multiple contiguous segments, and normal perfusion in the contralateral lung, extrinsic compression of the pulmonary vasculature, congenital abnormalities, and proximal PE all need to be considered in the

differential diagnosis (Fig. 6). These patients often require further imaging with CT or angiography.

INTERPRETATION CRITERIA

Several diagnostic criteria have been suggested for the interpretation of V/Q lung scans. In a study comparing the various interpretation algorithms, the PIOPED criteria had the highest likelihood ratio for predicting the presence of PE on pulmonary angiography. The PIOPED criteria, however, also had the highest proportion of V/Q scans interpreted as representing an intermediate probability of acute PE.” Several revisions of the original PIOPED criteria have been made based on the observations from the PIOPED study. By using a number of these revisions it is possible to decrease the number of intermediate V/Q scan interpretations and correctly inter- pret them as low probability of acute PE. The use of revised PIOPED criteria has already been shown to provide a more accurate assessment of angiographically proved PE compared with the original criteria.l7> 59

The nuclear medicine physician’s subjective estimate of the likelihood of PE (without using specific interpretation criteria) correlated well with the fraction of patients with angiographic evidence of PE.58 Experienced readers can provide an accurate estimate of the probability of PE based on radiographic and scintigraphic findings.

VENTILATION-PERFUSION LUNG SCANNING IN THE EVALUATION OF PULMONARY HYPERTENSION

Chronic pulmonary thromboembolism is a serious and potentially surgically treatable


Figure 6. Tc-99m DTPA aerosol (A) and Tc-99m MAA perfusion (B) images demonstrate unilateral, markedly decreased activity within the entire left lung. Ventilation within the left upper lung zone is markedly decreased. V/Q mismatch, however, is present within the left lower lung zone (unilateral VI Q mismatch). A single transaxial slice from the CT angiogram (C) demonstrates a large left upper lobe mass and associated left hilar adenopathy that is causing encasement of the left lower lobe pulmonary vasculature (solid arrow). The left lower lobe bronchus (dotted arrow) is compressed; however, it remains patent. Although PE may rarely present as unilateral V/Q mismatch, the presence of this finding more typically indicates extrinsic compression of the pulmonaty artery or vein.

cause of PHT. It has been estimated that between 0.5% and 4% of patients with acute PE eventually develop chronic thromboembolic PHT.37 Unfortunately, the clinical features, laboratory investigations, and other noninvasive investigations are often unreliable in dis- tinguishing chronic thromboembolic PHT from primary and nonthromboembolic secondary PHT. Evaluation with pulmonary angiography is usually required to confirm the diagnosis and to determine whether surgical intervention is indicated. Although some authors have reported that pulmonary angiography can be performed safely in patients with severe PHT, others have documented a higher frequency of complications, including death.41,61 V/Q lung scanning provides a safe, noninvasive technique that effectively selects which patients with PHT require pulmonary angiography to confirm the diagnosis of chronic PE and determine surgical accessibil- ity. Both V/Q lung scanning and pulmonary

angiography, however, may underestimate the severity of chronic thromboembolic mate- rial within the pulmonary vasculature as determined during thromboendartere~torny.5~

When performing the V/Q lung scan in patients with PHT it is important to avoid any adverse hemodynamic effects by reducing the number of Tc 99m MAA particles that are injected. In patients with known PHT, the authors routinely inject 90,000 to 150,000 particles. Several studies have documented the safety of perfusion lung scanning in patients with PHT when the number of particles is reduced.54,78 In patients with chronic thromboembolic PHT, most V/Q lung scans demonstrate multiple segmental perfusion defects with relatively normal ventilation, indicating a high probability of PE (Fig. 7). Most patients with primary PHT and nonthromboembolic secondary PHT have low-probability V/Q lung scan interpretations that demonstrated diffuse inhomogeneous distribution of Tc 99m


Figure 7. Xenon (Xe)-133 ventilation (A) and Tc-99m MAA perfusion (B) images in a young female patient with pulmonary hypertension demonstrate multiple segmental and subsegmental regions of V/Q mismatch within both lungs most suggestive of chronic thromboembolic pulmonary hypertension. CT angiography demonstrated diffuse intimal hypertrophy within the pulmonary arteries and was interpreted as representing primary pulmonary hypertension. Subsequent pulmonary angiography and surgical thrombectomy (C) confirmed the presence of chronic PE. A follow-up perfusion lung scan (0) demonstrated marked improvement in pulmonary perfusion.

MAA within both lungs. Patients with PHT rarely if ever have normal or very-low-probability V/Q lung scan interpretations, and a low-probability V/Q lung scan interpretation effectively excludes chronic thromboembolism as the cause of PHT.78 In PHT, pulmonary angiography is justified in patients with intermediate- or high-probability V/Q lung scan interpretations to confirm the diagnosis of chronic PE and determine surgical accessi- bility.

COMPUTED TOMOGRAPHY ANGIOGRAPHY IN PULMONARY EMBOLISM

Both spiral and helical CT angiography and electron beam CT have been used to visualize

and diagnose PE 51, 53, 66, 67, 69, 70 With spiral CT angiography data are continuously and rapidly collected as the patient moves through the gantry. Volumetric datasets of the entire lungs can generally be acquired during a single breath, which eliminates respiratory misregistration. Electron beam CT is less widely available and has superior temporal resolution but inferior spatial resolution compared with spiral CT. Electron beam CT does not acquire a true volumetric dataset but rather acquires overlapping transaxial images that can be reformatted to be viewed as multiplanar or three-dimensional images. In animal models, CT angiography has been shown to detect thrombi in central to fourth division (segmental) pulmonary arteries.1s* 6o

The sensitivity and specificity of CT angiography for detecting central PE are 86% to


95% and 75% to 97%, respectivelyz1, 52, 53, b6, 67,

70, 71 In a single study of patients with angiography-documented PE, the sensitivity and specificity of spiral CT for detecting-PE were 6% and 8l%, re~pective1y.l~ The diagnostic performance of CT for detecting subsegmental thrombi is lower. In a prospective comparison of spiral CT and pulmonary angiography in 20 patients, Goodman et alZ1 reported that the sensitivity for detecting PE decreased from 86% to 63% when all vessels (segmental and subsegmental) were included. Similarly, Teigen et al,’j7 using ultrafast CT, reported that the sensitivity for the detection of PE decreased from 88% to 65% when subsegmental vessels were included. In a prospective study comparing spiral CT angiography with V / Q scintigraphy, Mayo et a133 reported that spiral CT angiography had a higher sensitivity compared with a high-probability V / Q scan interpretation. The specificity, positive predictive value, and negative predictive value were similar between the two modal- ities. Another advantage of spiral CT angiography compared with V/Q scanning is higher

interobserver agreement and the ability to provide an alternative diagnosis for patients with suspected PE (Fig. 8).33,53

The performance of optimum CT angiography for detection of PE is technically de- manding, and several examination parame- ters need to be considered. Scans are generally performed from the level of the aor- tic arch to below the inferior pulmonary veins. Imaging with multiring detectors can be performed during a single breath-hold or during shallow respiration. Scan volumes are generally 12 to 15 cm and can be performed in either the caudal-cranial or reverse direc- tion. For optimum reporting, images should be viewed on both pulmonary vascular and lung parenchymal settings on a workstation.

Acute PE appears as an intraluminal filling defect that -partially or completely occludes the pulmonary artery (Fig. 9). Commonly, mild vascular distention is present within the affected vessel at the site of the thrombus. Segmental pulmonary arteries are located in close proximity to their accompanying bronchus on the corresponding lung window. Up-

Figure 8. A, Tc-99m aerosol ventilation and Tc-99m MAA perfusion images from a young male patient demonstrate generalized mild matching decreased activity within the left hemithorax. No pleural- based regions of V/Q mismatch to suggest acute PE were present. 6, Chest radiograph was interpreted as normal. C, Single transaxial slice from CT angiogram demonstrated a left pneumothorax with normal opacification of the pulmonary arteries.


Figure 9. Tc-99m Pertechnegas (top row) and Tc-99m MAA perfusion (bottom row) images (A) demonstrate a matching ventilation, perfusion, and chest radiograph opacity within the right middle and lower lobes (Q defect = V defect = chest radiograph opacity). Within the left lower lobe and lingula, the perfusion abnormalities (arrow) appear more extensive than the corresponding ventilation and chest radiograph (6) opacity (Q defect > V defect > chest x-ray opacity). The corresponding spiral CT (C) on vascular windows demonstrates partially occlusive thrombus within the left lower lobe pulmonary artery (arrow).

per and lower lobe arteries run perpendicular to the scan plane, whereas lingular and right middle lobe arteries tend to run parallel to the scan plane, and in these vessels the sensitivity for detecting PE is lower (Fig. 66

Other limitations of CT angiography include technical failures and incomplete examinations. Patient-related factors that can result in incomplete or suboptimal examinations include orthopnea, poor intravenous access, and severe shortness of breath. In patients who are unable to breath-hold, respiratory misregistration may occur and degrade image quality. Poor signal-to-noise ratio or vascular enhancement may occur in patients with right heart failure, large right-to-left shunts, or ex- travasated intravenous lines. An imaging artifact called flow phenomenon, which produces a central low density within the vessels ori- ented perpendicular to the scan, has been de- scribed. This is most often seen in vessels scanned either too early or too late following

intravenous contrast. The mechanisms causing this artifact have not been fully eluci- dated; however, it is likely in part caused by laminar flow and uneven mixing of contrast within the vessel. Despite the technical de- mands, CT angiography can provide a prompt and accurate diagnosis of PE in most patients.

Proponents suggest that spiral CT should be used as the first-line imaging test in patients with suspected PE. Others suggest that V/Q scanning should remain as the first-line diagnostic imaging test and that CT angiography should be used in patients in whom the diagnosis remains uncertain. Currently, more experience and outcome data exist for V/Q scanning. Other factors influencing the choice. of diagnostic tests are cost, availability, and expertise.

Two recent meta-analy~es~”~~ on the role of CT angiography in the diagnosis of PE have concluded the following:


Figure 10. Tc-99m DTPA ventilation (A) and Tc-99m MAA perfusion (6) images demonstrate a single segmental V/Q mismatch (arrow) within the superior lingular segment in this patient three days following surgery for a fractured hip. Matching decreased ventilation and perfusion was also present within multiple segments of the left lower lobe. A spiral CT performed within 1 hour of the ventilation- perfusion scan was normal. C, A subsequent pulmonary angiogram demonstrated an intraluminal filling defect and abrupt vascular cutoff within a lingular artery (arrow), confirming PE.

1. CT angiography is sensitive and specific for diagnosing central PE, but relatively insensitive for diagnosing subsegmental PE.

2. The safety of withholding anticoagulant treatment in patients with negative results on CT angiography is uncertain.

3. Use of spiral CT in the diagnosis of PE has not been adequately evaluated.

4. Further prospective studies to evaluate the sensitivity, specificity, and safety of CT angiography are required.

PULMONARY ANGIOGRAPHY IN PULMONARY EMBOLISM

Pulmonary angiography has remained the definitive gold standard test for the diagnosis or exclusion of PE. The angiographic diagnosis of acute PE in PIOPED was based on the identification of an intraluminal filling defect

or the trailing edge of a thrombus obstructing a vessel. In patients who had angiographic evidence of PE, reader agreement among an- giographers was noted to be 86% (331 of 383) of cases. In patients with angiograms interpreted as negative or uncertain, PE reader agreement was noted to be 80% (544 of 681) and 40% (14 of 35) of cases, respectively. In PIOPED, pulmonary angiography was completed in 99% (1099 of 1111) of patients who consented to undergo the procedure.61 In most patients in whom angiography was not completed, a complication was encountered during the procedure. Nondiagnostic pulmonary angiograms were obtained in only 3% (35 of 1111) of patients.

The validity of pulmonary angiography was assessed by the outcome classification committee. In 681 patients whose angiograms were interpreted as being negative for PE, only 4 patients had their diagnosis reversed by the outcome classification committee. A


negative pulmonary angiogram excluded the diagnosis of acute PE in 99% (667 of 681) of cases. Because angiography was considered the gold standard in the PIOPED study, the validity of a positive angiogram representing PE could not be assessed. In one patient with an angiographic diagnosis of PE, however, the outcome classification committee failed to document PE at autopsy.

Ventilation-perfusion lung scanning has been shown to provide useful information for the angiographer before the procedure. In a review of 104 patients with angiographically proved PE, V/Q imaging before angiography predicted unilateral and segmental PE in most patients and provided an accurate guide for determining the initial approach for pulmonary angiography.13

The complications related to pulmonary angiography have been well documented by Stein et a1.61 Death attributed to pulmonary angiography occurred in 0.5% (5 of 1111) of patients. Nonfatal major complications, including respiratory distress, severe renal failure, and hematoma requiring transfusion, occurred in 1% (14 of 1111) of patients. The frequency of major complications was higher in patients from the medical intensive care unit compared with patients from other wards. Minor complications, which were not life threatening and responded promptly to pharmaceutical therapy, occurred in 5% (60 of 1111) of patients. The most common minor complications were urticaria or pruritus and mild renal dysfunction. The frequency of complications was not related to patient age, the presence of PE, or pulmonary artery pressure.

SUMMARY

From the prospective and outcome-based studies that have been carried out in the past few years, the following conclusions regarding the diagnostic evaluation of patients with suspected PE can be made:

1.

2.

3.

A normal V/Q scan interpretation excludes the diagnosis of clinically significant PE. Patients with a very-low- or low-probability V/Q scan interpretation and a low clinical likelihood of PE do not require angiography or anticoagulation. Patients with a very-low- or low-probability V/Q scan interpretation, an inter-

mediate or high clinical likelihood of PE, and negative serial noninvasive venous studies of the lower extremities do not require anticoagulation or angiography. If serial noninvasive venous studies of the lower extremities are positive, patients should be treated. Clinically stable patients with an intermediate-probability V/Q scan interpretation require noninvasive venous studies of the legs and, if negative, require CT angiography or pulmonary angiography for a definite diagnosis. Clinically stable patients with a high- probability V/Q scan interpretation and a high clinical likelihood of PE require treatment and need no further diagnostic tests to confirm the diagnosis. Clinically stable patients with a high- probability V/Q scan interpretation and a low or intermediate clinical likelihood of PE require noninvasive venous studies of the legs and, if negative, often require CT angiography or pulmonary CT for a definitive diagnosis.

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Address reprint requests to Daniel F. Worsley, MD

University of British Columbia Division of Nuclear Medicine

Vancouver General Hospital 899 West 12th Avenue

Vancouver, BC Canada

V5Z 1M9

e-mail: Wors1eyBtriumf.ca

radionuclide imaging of acute pulmonary embolism

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