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AJR 2000; 174:1489-1497
© American Roentgen Ray Society

Centennial Dissertation

Pulmonary Embolism

What's Wrong with This Diagnosis?

Tony P. Smith1

1 Department of Radiology, Rm. 1502, Duke University Medical Center, Erwin Rd., Durham, NC 27710.

Received December 7, 1999; accepted after revision February 3, 2000.

 
Honoring Percy Brown, MD and Frederick H. Baetjer, MD

This is the sixth in a series of Centennial Dissertations that the AJR is publishing this year in honor of the former presidents of the American Roentgen Ray Society, two of whom are pictured above.

Address correspondence to T. P. Smith.


Introduction
Top
 Introduction
Autopsy Issues
 Clinical and Laboratory Issues
 Imaging Issues
 Perspective
 References
 
The first description of pulmonary embolism is attributed to Laennec [1] in 1819 and what probably represents the first case description to Helie [2] in 1837. However, it was von Virchow [3] in 1846 who first described the connection between venous thrombosis and pulmonary embolic disease, even using the term "embolis." The first radiographic description of pulmonary embolism is that of Wharton and Pierson [4] of a chest radiograph in 1922. Since that time, virtually all areas of radiology—most notably chest radiography, angiography, nuclear scintigraphy, and, more recently, CT and MR imaging—have participated in the diagnosis of pulmonary embolic disease.?,?



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  		Percy Brown 12th President of ARRS 1911-1912

 


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  		(Courtesy of the American College of Radiology) Frederick H. Baetjer 13th President of ARRS 1912-1913

 

The prevalence of thromboembolic pulmonary disease is usually the first topic addressed in any diagnostic or therapeutic treatise on the subject. It has been estimated that pulmonary embolism occurs in approximately 650,00 patients annually in the United States and contributes to as many as 50,000 deaths [5, 6]. Pulmonary embolism is said to be responsible for as many as 15% of all in-hospital deaths [7]. Although these are staggering numbers, they are for the most part imprecise. Many studies of the incidence of pulmonary embolism are quite dated, often relied on the clinical diagnoses alone, and incorporated various design flaws. Given such difficulties, wide variations in published incidence figures are not surprising. Certainly, pulmonary embolism remains a clinical problem. Silverstein et al. [8] recently published a retrospective review of records from a population-based study and found the incidence of pulmonary embolism to be 69 in 100,000. Although studies such as this provide a better understanding of the scope of the problem, in the final analysis these figures are reliable only when a confident and sure diagnosis of pulmonary embolism can be reached. The current diagnostic measures for acute pulmonary embolism consist of autopsy results, clinical data, laboratory testing, and imaging studies.


Autopsy Issues
Top
 Introduction
 Autopsy Issues
Clinical and Laboratory Issues
 Imaging Issues
 Perspective
 References
 
Massive pulmonary embolic disease obstructs the pulmonary arteries, thus decreasing return to the left heart and resulting in a lowering of the systemic blood pressure [9]. This decreases the circulation to the coronary and cerebral beds and causes sudden death. At autopsy, the embolus is most often found straddling the bifurcation of the pulmonary trunk. The chambers of the right heart and vena cavae are distended, the left-sided chambers are contracted, and the lungs are pale in appearance. Large emboli located centrally in the pulmonary arteries have a coiled appearance when removed, and it is this coiling that distinguishes embolic thrombi from those formed primarily in the pulmonary arteries. Thrombi formed in situ and thrombotic emboli are firm and friable and show striae of Zahn, which represent successive layers of platelets and fibrin-enmeshed blood cells, indicating that the thrombus was formed premortem rather than postmortem.

If the autopsy represents the true gold standard for the diagnosis of pulmonary embolism, it is not without a degree of tarnish. First, the mechanism of death from pulmonary embolism is not as straightforward as simple mechanical obstruction; other causes such as reflex and humoral mechanisms have also been implicated [10]. Second, emboli may be easily missed if the pulmonary artery and its branches are not opened with care during autopsy [11]. Large emboli obstructing the pulmonary trunk or main pulmonary arteries will not go undetected if these vessels are opened; however, lobar and segmental vessels are often not systematically cut, and emboli in these vessels often escape detection [12]. The frequency of pulmonary embolism in autopsy patients ranges from 52% to 64% when meticulous dissection techniques with microscopic correlation are used [13,14,15]. However, the positivity rate may approach 90% when a large number of lung tissue blocks are studied [16]. Third, despite this discussion, it is not always possible to distinguish premortem from postmortem thrombus or even thromboemboli from thrombi formed primarily in small pulmonary arteries, in which primary thrombosis is far more common than small thromboemboli [17]. In addition, Morpurgo and Rustici [18] found in a review of 49 instances of sudden and unexpected death from pulmonary embolism, 10 involved only peripheral and unilateral branches. These findings are especially disconcerting because small peripheral arteries are also the areas that are difficult to image radiographically.

One can see how questions arise as to the true incidence of pulmonary embolism when it is based on autopsy numbers. Stein and Henry [19] published autopsy data regarding the prevalence of acute pulmonary embolism among patients in a general hospital and reported that pulmonary embolism was interpreted as the cause of death if no other explanation was found. Such reporting clearly increases the mortality statistics of pulmonary embolism and may seem errant, but is understandable when one looks at autopsy reports. When the embolic material is small (assuming it is even found), determining its role in the patient's demise may be difficult or even impossible. Pulmonary embolic disease at autopsy is therefore often reported as either the cause, a contributing factor, or incidental in the death of the patient. In many instances, this distinction may be relatively easy, whereas in others it may be difficult or even impossible. In a series of 538 autopsies with pulmonary emboli found, Morpurgo and Schmid [20] estimated that without having suffered pulmonary embolism, 21% of the patients had a favorable survival prognosis and an additional 39% would probably have survived, whereas 39% would probably have died from their baseline disease within a few months. Overall, although I am about to discuss many problems with the clinical diagnosis of pulmonary embolism, the autopsy diagnosis of this disease can often be perplexing.


Clinical and Laboratory Issues
Top
 Introduction
 Autopsy Issues
 Clinical and Laboratory Issues
Imaging Issues
 Perspective
 References
 
Pulmonary embolism was a clinically vexing problem for early investigators in the 1800s and remains almost as difficult a problem in the 2000s. Much has been published about the usefulness (or uselessness) of the signs and symptoms associated with pulmonary embolism [21]. The problems originate from two sources: the pulmonary system has limited possible presentations, and it is the site of many maladies. The manifestations of pulmonary embolism are associated intimately with the degree and extent of vessel occlusion, ranging from small nonocclusive thrombi to massive occlusions to areas of infarction. In addition, presenting signs and symptoms are associated with the basic constitution of the patient. For example, patients with compromised pulmonary reserve or right heart dysfunction will present with more profound findings than young patients with a high cardiopulmonary reserve.

Two large prospective studies of pulmonary embolic disease based on clinical and imaging data have been conducted. The first, originally published in 1990, is the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) performed in the United States [22]. The second, the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis, whose original findings were published in 1995, was performed in Europe [23]. A number of publications continue to surface from these studies. Stein et al. [24] reviewed patients in PIOPED with pulmonary embolism and evaluated their clinical presentation. Dyspnea, tachypnea, or pleuritic chest pain was present in as many as 97% of patients with pulmonary embolism. However, the same combinations of clinical characteristics occurred with nearly the same frequency among patients in whom pulmonary embolism was excluded. Miniati et al. [25] recently presented the clinical diagnostic criteria for pulmonary embolism from the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis and found three symptoms: sudden onset of dyspnea, pleuritic chest pain, and fainting were significant for the presence of pulmonary embolism, particularly when combined with specific findings on ECG and chest radiography. Again, however, the signs and symptoms were much more predictive when in combination and occurred independently in patients with and without pulmonary embolism. Despite the evaluation and reevaluation of data even when collected prospectively, the clinical diagnosis of pulmonary embolism remains one of clinical suspicion at best and must be used simply as an indicator for further testing.

The most widely applied laboratory test in the diagnosis of pulmonary embolism has been the partial pressure of oxygen in the arterial blood (PaO2) while the patient is breathing room air. Although this value is often decreased for patients with pulmonary embolism, it is also decreased in a host of other pulmonary disorders, making it very nonspecific. Stein et al. [26] found no significant difference in the distribution of the levels of PaO2 for patients with and without pulmonary embolism in PIOPED. A second laboratory evaluation, alveolar-arterial oxygen gradient (P[A-a]O2), was the subject of much controversy a number of years ago when published results suggested that a normal P[A-a]O2 could be used to exclude pulmonary embolism [27]. These findings have been subsequently refuted by other publications that included a number of editorials, as is often the case in the controversial world of pulmonary embolism diagnosis [28].

The laboratory test that currently receives the greatest attention is the plasma level of fibrin D-dimer, a degradation product released into the circulation after the breakdown of cross-linked fibrin. Fibrin D-dimer levels have been shown to be increased in patients with thrombosis, including pulmonary embolism, and a host of studies have been published. Becker et al. [29] reviewed 29 of these studies for the strength of the study and the results. Of the 13 studies deemed to possess strong research designs, sensitivity ranged from 72% to 100% and specificity from 31% to 100%. Variations were caused by the type of assay method used, the discriminate levels for positivity, and the methods used to validate the presence of pulmonary embolism. More recently, Heit et al. [30] attempted to validate D-dimer testing performed by various methods and to discriminate levels using pulmonary angiography in 105 patients. The researchers found the sensitivity and negative predictive value to be greatest for the enzyme-linked immunosorbent assay method but both depend largely on the discriminate levels chosen (>500 µg/l) and the length of time since onset of symptoms. Using these methods, researchers have described D-dimer testing as having a negative predictive value of 99% [31]. In general, D-dimer levels appear to be clinically useful if they are negative, which effectively excludes thrombosis, including pulmonary embolism. Elevated values must be interpreted using clinical acumen and imaging to exclude false-positives for thrombosis in general and, more specifically, to diagnose pulmonary embolism. D-dimer levels are noninvasive, easily obtained during routine blood drawing, and inexpensive when compared with imaging studies. D-dimer testing represents the first hopeful step in future diagnostic laboratory examinations for pulmonary embolism.

Genetic risk factors for acute pulmonary thromboembolic disease are now being investigated and may play a role in future laboratory testing. Currently, the best known is the factor V Leiden mutation, which is linked to the clinical state known as activated protein C resistance. Factor V Leiden has a prevalence of 3-6% in the Caucasian population and is associated with a significantly increased risk of venous thrombosis, although possibly not with acute pulmonary embolism [32, 33]. Unfortunately, genetic links as understood today exist in a very small portion of the overall population of patients with pulmonary embolism.


Imaging Issues
Top
 Introduction
 Autopsy Issues
 Clinical and Laboratory Issues
 Imaging Issues
Perspective
 References
 
The impact of radiology on pulmonary thromboembolic disease has been immense, mostly because of nonspecific clinical and laboratory findings. In general, imaging has focused directly on the diagnosis of pulmonary embolism. However, some have suggested that diagnostic protocols for suspected acute pulmonary embolism should initially include lower extremity evaluation for venous thrombus [34]. This concept is predicated on the notion that pulmonary thromboemboli originate from veins in the lower limbs. Unless there are associated symptoms, this concept has always been confusing to this author, who prefers to approach a problem directly. The concept resembles the old story of a man looking for his lost coin. When asked "Where did you lose it?" the man replies, "Over there, but I am searching here because the light is better." It makes more sense empirically to look at the lungs if one suspects pulmonary embolism, especially because fewer than 50% of patients with documented pulmonary embolism have positive findings on lower limb studies for thrombus [35]. Proponents, however, point to some merits of the approach. If venous thrombus is present, further testing for pulmonary embolism is unnecessary because treatment can be instituted. However, a negative study is not as useful because one does not know whether thrombus was never present and no pulmonary embolism exists; or whether pulmonary embolism does exist and the lower limb thrombus has embolized completely to the lungs or is from another source such as the pelvic or upper limb veins. Negative findings do imply absence of a large thrombus burden in the legs awaiting embolization to the lungs. Overall, lower limb venous evaluation remains at best an indirect study that can complement patient therapy but does not address the problem of pulmonary embolism diagnosis.

Chest Radiography and Ventilation-Perfusion (V/Q) Lung Scintigraphy
Chest radiography is performed in almost all patients suspected of pulmonary embolism and almost always has abnormal findings (Fig. 1A,1B). Ninety-two percent of patients with acute pulmonary embolism had abnormal findings on chest radiographs in a subset of the PIOPED study [36]. However, chest radiography alone is notoriously inexact for the diagnosis of pulmonary embolism. True-positive rates of 39% and false-negative rates of 61% have been reported when compared with results of pulmonary angiography [37]. Radiographic findings tend to be nonspecific and varied, all of which occur alone or in combination with other diseases. However, the chest radiograph remains valuable in the examination of patients with suspected pulmonary embolism for two major reasons: to exclude diagnoses of disorders that clinically mimic pulmonary embolism and to aid in the interpretation of other imaging studies, most notably V/Q lung scintigraphy.



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  		Fig. 1A. —77-year-old man found unresponsive. Frontal chest radiograph reveals marked paucity of pulmonary vasculature to right lung base.

 


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  		Fig. 1B. —77-year-old man found unresponsive. Enhanced helical CT chest scan reveals marked intraluminal filling defect involving right pulmonary artery (black arrowhead) and extending into interlobar artery (white arrowhead), representing extensive pulmonary embolism. (Courtesy of McAdams HP, Durham, NC)

 

V/Q lung scintigraphy was widely used since the 1960s for the diagnosis of acute pulmonary embolism when, in 1977, Robin [38], in his classic and controversial publication, questioned its diagnostic capability, seemingly voicing the concerns of many at the time. Robin believed the only use of V/Q lung scintigraphy was in excluding pulmonary embolism, which was, in his opinion, being overdiagnosed and overtreated. At that time, a number of diagnostic schemes were used and opinion varied regarding the overall reliability, usefulness, and interpretation of V/Q lung scintigraphy for the diagnosis of acute pulmonary embolism.

In an effort to address many of the uncertainties of V/Q lung scintigraphy, a large multicenter prospective study (PIOPED) was performed in 1985-1986 [22]. The purpose of PIOPED was to determine the sensitivity and specificity of V/Q lung scintigraphy for acute pulmonary embolism. The PIOPED investigators further defined categories for the probability of pulmonary embolism based on the number and degree of segmental ventilation and perfusion abnormalities, laying probabilities for the presence of pulmonary embolism as normal or near normal, low, intermediate, or high, similar to that of other schemes used at the time (Fig. 2A,2B,2C,2D). In addition, patients were assigned a clinical science probability based on the clinical likelihood of pulmonary embolism (Table 1). The PIOPED results were published in 1990, and there have been many subsequent publications from these data. In the interpretation of V/Q lung scintigraphy, PIOPED criteria and their recent modifications are used today in most centers, although disagreement exists among those interpreting the studies as to the best available set or sets of such criteria.



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  		Fig. 2A. —63-year-old man with dyspnea for 24 hr. Chest radiograph revealed loss of volume in middle and lower lobes and small right pleural effusion. Left lung was normal. Perfusion lung scintigram reveals perfusion defect in right lung base (solid arrow) and smaller defect in left lung base (open arrow).

 


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  		Fig. 2B. —63-year-old man with dyspnea for 24 hr. Chest radiograph revealed loss of volume in middle and lower lobes and small right pleural effusion. Left lung was normal. Ventilation lung scintigram shows defects that are matched to perfusion abnormalities and delayed washout in left lung base (arrow). This study was given intermediate probability for pulmonary embolism on basis of PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) criteria. (Courtesy of Coleman RE, Durham, NC)

 


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  		Fig. 2C. —63-year-old man with dyspnea for 24 hr. Chest radiograph revealed loss of volume in middle and lower lobes and small right pleural effusion. Left lung was normal. Selective right pulmonary artery angiogram reveals decreased flow to right lung base (arrows) that correlates well with findings on scintigraphy. No evidence of pulmonary embolism is seen.

 


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  		Fig. 2D. —63-year-old man with dyspnea for 24 hr. Chest radiograph revealed loss of volume in middle and lower lobes and small right pleural effusion. Left lung was normal. Selective left pulmonary angiogram reveals intraluminal filling defects in branches to left lower lobe (arrows), representing acute pulmonary embolism.

 

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  		TABLE 1 Correlation of Ventilation-Perfusion Lung Scintigraphy and Clinical Science Probabilities in PIOPED [22]

 

In the PIOPED population of patients suspected of having pulmonary embolism, 39% had intermediate-probability scans and 34% had low-probability scans [22]. Only 14% and 13% had normal or near normal and high-probability scans, respectively. In patients with pulmonary embolism, 87% had high-probability scans, 30% intermediate probability, 14% low probability, and 4% normal or near normal scans. When a high clinical suspicion was combined with a high-probability scan, 96% of patients had pulmonary embolism (Table 1) [22]. Conversely, when a low clinical suspicion was combined with a near normal or normal scan, only 2% of patients had pulmonary embolism.

It is easy to appreciate why a great deal of confusion exists among many referring physicians as to the meaning of the generated nuclear medicine report [39]. Scans interpreted as high probability and normal or near normal are viewed by most as diagnostic and, when coupled with the clinical context, no further testing is usually necessary for instigating or withholding therapy. Unfortunately, all other situations must be regarded as nondiagnostic, a scenario that occurs far too frequently. In PIOPED, only 27% of patients had their scans interpreted as high probability or normal or near normal [22]. In addition, only 12% of patients with pulmonary embolism seen on angiography had high-probability scans, and most patients (57%) with pulmonary embolism had intermediate- or low-probability scan interpretations. Disagreement among observers occurred in more than 20% of the interpretations in the PIOPED study, increasing to 25% and 30% for intermediate- and low-probability scans, respectively [22]. The Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis used a simpler algorithm of positive or negative for pulmonary embolism and assessed perfusion imaging only. Although 92% of patients with angiographically proven emboli had abnormal findings on scans, 12% of patients with negative scan findings also had pulmonary embolism [40]. However, the simpler criteria allowed much greater interobserver agreement (97%) in assigning lung scans to the normal or near normal or to the abnormal category.

For acute pulmonary embolism, V/Q lung scintigraphy is based on some autopsy and follow-up data, but for the most part, on pulmonary angiography. Considerable questions have arisen regarding the V/Q scan relative to the angiogram. Alderson et al. [41] in 1976 reviewed 136 vessel segments with thrombus on angiography and compared the findings with V/Q images. Interestingly, 22% of these segments had normal perfusion and 38% showed matched abnormalities on V/Q images. Meyer et al. [42] found the angiographic defects were underestimated by lung scintigraphy when embolic involvement was extensive, and a number of the pulmonary thrombolytic trials have also reported a poor correlation between the degree of thrombus and the findings on scintigraphic perfusion imaging [43, 44].

The problem with V/Q lung scintigraphy is that it does not directly visualize thromboembolism but rather visualizes its effects on perfusion and ventilation. This problem causes the need for probability criteria, which in turn causes confusing results and high interobserver disagreement. Nowhere in radiographic imaging is there more confusion with a diagnostic test than with V/Q lung scintigraphy for the diagnosis of acute pulmonary embolism. Nowhere in radiology is the diagnosis provided purposefully and prospectively in such vague and obscure terms. The entire probability process resembles a lottery in which one is simply "playing the odds." Unfortunately, this has long been known and accepted by the medical community because no noninvasive alternative exists. V/Q imaging has therefore been used as the diagnostic imaging screening tool for the patient suspected of having pulmonary embolism. The probability reading is then used for evidence to initiate or withhold treatment or as a guide for another study that directly visualizes the thromboembolus. Until recently, that study was pulmonary angiography.

CT and MR Imaging
The diagnosis of pulmonary embolism using conventional CT scanners was initially made incidentally, visualizing large central emboli. However, volumetric and fast scanners have prompted investigators to look at CT as a primary imaging technique for the diagnosis of pulmonary embolism (Fig. 3A,3B). Remy-Jardin et al. [45] published the first prospective study of 42 patients for the diagnosis of pulmonary embolism comparing the results of helical CT with those of angiography. These researchers concluded that helical CT was a safe procedure and could be used in patients thought to be at high risk for angiography, to complement angiography, and to monitor patients with documented central emboli. As a follow-up, Teigen et al. [46] used electron beam CT to image the pulmonary vascular system in 86 patients and found comparable results with a sensitivity and a specificity of 95% and 80%, respectively. However, these studies were in controlled patient populations and were not applied to difficult clinical situations. Goodman et al. [47] examined patients in whom clinical data and V/Q studies failed to answer the question of pulmonary embolism and found helical CT was only 63% sensitive, with subsegmental emboli being the most difficult to diagnose. Those researchers concluded that CT had a limited role in the evaluation of pulmonary embolism and that pulmonary angiography remained the study of choice.



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  		Fig. 3A. —59-year-old man with history of metastatic lung and renal carcinoma and deep venous thrombosis involving both lower limbs who presented with dyspnea, cough, and low-grade fever. Helical CT chest scan reveals extensive intraluminal filling defects in both pulmonary arteries (arrows), which is diagnostic of pulmonary embolism.

 


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  		Fig. 3B. —59-year-old man with history of metastatic lung and renal carcinoma and deep venous thrombosis involving both lower limbs who presented with dyspnea, cough, and low-grade fever. Lower sections of helical CT chest scan reveal thrombus extending into segmental and subsegmental branches (arrows). (Courtesy of Erasmus JJ, Durham, NC)

 

Since these beginnings, CT has rapidly grown in popularity as an imaging tool for the diagnosis of acute pulmonary embolism, particularly as equipment has improved and techniques have been refined. Remy-Jardin and Remy [48] recently reviewed the available literature for the accuracy of helical CT for the diagnosis of pulmonary embolism. In their review of the literature (11 studies involving 1578 patients), sensitivity ranged from 53% to 100% and specificity from 81% to 100% for the evaluation of acute thrombi to the segmental level. Suboptimal examinations occurred in only 2-4% of patients and were usually caused by severe dyspnea and inability to breath-hold adequately. However, the validation of these data remains somewhat dubious. Of the 11 studies, two are in abstract form only and have not yet been subjected to peer review and full publication. The remaining nine entail 807 patients, only 643 (80%) of whom received pulmonary angiography as the standard for diagnosis. The reminder used a variable combination of clinical and imaging information.

CT has obvious advantages. Fast scanners have become readily available. CT is essentially noninvasive, requiring only iodinated contrast material and interpretative skills. It can be performed expediently, requiring little patient preparation and recovery. CT reveals other structures in the thorax and can visualize conditions leading to alternate diagnoses in a relatively high percentage of patients [49]. Most important, like angiography, CT directly visualizes thrombus, which provides an assessment of the location and degree of clot burden, and shows pulmonary arteries distal to occlusions (Fig. 3A,3B). CT has disadvantages in that it is not as useful in patients who are severely short of breath, and it may not be very accurate for small peripheral emboli [47]. However, the major shortcoming of CT is that it is essentially unproven at this time. The available reports are based on a combination of clinical, scintigraphic, and angiographic findings, all of these having a host of problems of their own as described in this article [48, 50, 51]. In addition, available studies are for the most part single-center, independent trials. However, large collaborative studies are planned in both the United States and Europe to evaluate CT for the diagnosis of pulmonary embolism. Although they will be based on the same standards as the PIOPED and the Prospective Investigative Study of Acute Pulmonary Embolism Diagnosis, the data will be accrued in a controlled, prospective manner and will be independently evaluated without bias. In the final analysis, the role of helical CT for the diagnosis of pulmonary embolism has yet to be fully determined, although its popularity is growing. The future appears bright as continued technical modifications and improvements occur and further clinical research is performed. If the current trends continue, CT will most assuredly become the imaging study of choice, relegating V/Q lung scintigraphy and pulmonary angiography to only selected instances.

If any imaging study is to challenge CT for the diagnosis of acute pulmonary embolism, it will be MR imaging (Fig. 4). Like CT, MR imaging can visualize the pulmonary circulation and other structures in the chest and mediastinum. It does not require catheterization as angiography does and does not require iodinated contrast material as CT does. Even more than CT, it has the potential to provide three-dimensional display of vessels. MR imaging, with its ability to quantitate blood flow and provide velocity mapping, can also provide physiologic information. MR imaging techniques have been shown to be as effective as scintigraphic imaging for the assessment of relative and absolute differential pulmonary perfusion [52]. In addition, MR imaging also reveals the lower extremity, pelvic, and central veins, in effect diagnosing pulmonary embolism and potential sources in the same study.



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  		Fig. 4. —58-year-old man with deep venous thrombosis seen on MR venography. During same sitting, contrast-enhanced axial gradient-recalled echo MR pulmonary angiogram was obtained and reveals absence of signal in main pulmonary artery extending into right pulmonary artery, which is diagnostic of pulmonary embolism (arrowheads). (Courtesy of Spritzer CE, Durham, NC)

 

At this time, MR imaging has not been widely applied to the diagnosis of pulmonary embolism, although early results show potential. In a prospective analysis by Grist et al. [53] in which 20 studies were interpreted by observers who were unaware of the confirmatory imaging, the sensitivity of MR imaging for diagnosing pulmonary embolism was 100%; unfortunately, the specificity was 62%. Erdman et al. [54] compared V/Q imaging with MR imaging using catheter angiography for correlation. MR imaging had a sensitivity of 90%, a specificity of 77%, a positive predictive value of 86%, and a negative predictive value of 83%. However, visualized emboli were limited to large- and medium-sized arteries and, despite using careful techniques, vessels smaller than 4 mm could not be identified. This inability to visualize emboli in small vessels is in keeping with other studies that have been unable to detect peripheral emboli on MR imaging [55]. Contrast agents tend to increase the visualization of the pulmonary vessels. Gupta et al. [56] recently compared gadolinium-enhanced MR angiography with pulmonary angiography in 36 patients. MR imaging was found to have a high accuracy for depicting lobar and segmental emboli but was unable to depict subsegmental emboli in most cases, which is in keeping with previously reported series [57]. Hurst et al. [58] recently compared gadolinium-enhanced MR imaging with CT in a canine model and found helical CT to be more sensitive for the detection of pulmonary emboli. However, both techniques were highly specific for pulmonary embolism and had high interobserver agreement.

MR imaging has its shortcomings. Unfortunately, it depends on the degree of flow, and slow flow can provide confusing artifacts, as can adjacent air-containing bronchi. Current magnet designs and protocols are difficult for patients who are short of breath and severely ill. MR imaging is not yet widely used for the diagnosis of pulmonary embolism, so current data are preliminary and large series and controlled trials are nonexistent. Studies that do exist, as already described in this article, display low specificity and difficulty visualizing peripheral emboli. That is not to say that MR imaging does not have a future role in the diagnosis of pulmonary embolism, particularly as technical advancements are made. Even with such advancements, however, as with CT, reservations exist about the reliability of the gold standard with which it is being compared.

Pulmonary Angiography
The role of pulmonary angiography for the diagnosis of acute pulmonary embolism has changed significantly since its inception in the 1960s. Its current role can best be defined by examining its diagnostic advantages and disadvantages, particularly in relation to other imaging techniques. The major disadvantages of pulmonary angiography include its expense, its requirement for highly trained angiographers, its invasive nature, and the risks of complications. Because of these factors, it is often unavailable in some centers. Pulmonary angiography is an expensive test, particularly when compared with noninvasive techniques. It is physician-intensive, requiring catheters, sterile trays, and patient preparation and recovery, all of which make it costly. Although expertise is needed, pulmonary angiography is for the most part simple to perform today in the hands of reasonably experienced angiographers with modern catheterization tools and radiographic equipment. However, because it is an invasive procedure, pulmonary angiography suffers from two inherent disadvantages: a finite rate of complications, and patient dissatisfaction with an invasive procedure. Patients prefer a less invasive study that is painless and does not require extensive preparation or recovery.

Much of the dissatisfaction with pulmonary angiography, at least from the referring physician's perspective, stems from concerns for patient safety. These concerns originated from the 1980 publication by Mills et al. [59], who reported three deaths from pulmonary angiography in patients with elevated right ventricular pressures. Although this report has little in the way of scientific merit, it has become fixed in the minds of many. Acknowledging a difference in reporting standards, Smith [60] reviewed 10 studies totaling 7111 patients. The overall mortality rate from pulmonary angiography was 0.1% (9/7111). Interventionists now uniformly agree that modern pulmonary angiography is safe, particularly with the use of nonionic low-osmolar contrast material [61, 62].

Pulmonary angiography has advantages. It allows visualization of the venous system and provides hemodynamic data and the opportunity for treatment in the same clinical setting. Most important, pulmonary angiography is still considered the imaging gold standard for the diagnosis of pulmonary embolism because it has traditionally been the only imaging technique able to directly visualize thrombus (Fig. 2D). Although it is possible to visualize the pelvic and central venous system, this is rarely done in practice. Hemodynamic data are useful but can just as easily be obtained from central venous catheters without the need for angiography. Although one can perform inferior vena cava filter placement or catheter-directed thrombolysis after routine diagnostic pulmonary angiography, these procedures represent a small number of cases. The overwhelming reason to perform pulmonary angiography is to confirm the diagnosis of pulmonary embolism.

So how does one validate the gold standard for the diagnosis of pulmonary embolism? Three basic methods have been used: correlation with autopsy data, clinical assessment of patients, and reproducibility of findings. Autopsy data have their own inadequacies, as I have noted. Autopsy studies have been performed assessing the premortem methods of pulmonary embolism diagnosis, including pulmonary angiography [63]. However, the greatest limitation is that, fortunately, most patients with pulmonary embolism who also receive angiography, do not die. Fewer than 30% of massive pulmonary embolisms obstructing the pulmonary arteries are diagnosed before the patient's death, and only a small number of these patients have had angiography for comparison with autopsy findings [64]. Although a fatal embolus can be relatively small but poorly tolerated and result in death, such a situation, fortunately, is rare [64]. Regrettably, small peripherally located emboli are also the more difficult diagnostic imaging cases and the ones most in need of validation.

Clinical assessment of patients has been used to determine the diagnostic accuracy of imaging studies, most notably pulmonary angiography, although the CT diagnosis of pulmonary embolism seems to be following this same track [65]. The concept is quite simple: monitor patients with negative study findings to see how they do. This is not a new concept. Novelline et al. [66] in 1978 presented a series of 167 untreated patients with normal findings on pulmonary angiograms and a minimum of 6 months of clinical follow-up. None of their patients had documented pulmonary emboli, although 20 died from unrelated causes. Cheely et al. [67] monitored 154 patients with negative findings on pulmonary angiograms for a mean of 13 months, and four patients developed symptoms or had thrombus at autopsy. Stein et al. [68] reviewed 675 patients from PIOPED who were untreated and had normal angiographic findings and found four deaths (0.6%) from pulmonary embolism within 4 days of angiography. A total of 380 patients from PIOPED were followed up for 1 year, and six were found to have pulmonary embolism on V/Q scanning [69]. A recent series also confirmed this data [70]. Patients with negative pulmonary angiographic findings do well clinically. Unfortunately, the data are actually less clear than they initially appear to be. Stein et al. [71] described 20 untreated patients with autopsy (n = 1) or angiographically proven (n = 19) pulmonary embolism who escaped treatment for a period of 3 months. One of these patients died from the effects of the original embolus, and a second suffered a nonfatal recurrent embolism. All other patients had no evidence of further pulmonary embolism. Although this group of patients did have only segmental or smaller arterial involvement on angiography, the data clearly raise questions regarding the lethality of pulmonary embolism. Egermayer [72] reviewed available data regarding the follow-up of patients with pulmonary embolism who were untreated. He found that only two prospective trials have been performed that assessed recurrence of pulmonary embolism [73, 74]. Both studies found higher recurrence rates in treated than in untreated groups. These findings put into question the anticoagulation schemes currently used, especially the more aggressive measures such as inferior vena cava filters. As pointed out by Egermayer, if significant numbers of diagnostic errors occur, it is assumed that treatment will be inappropriately withheld, resulting in adverse effects. To determine the accuracy of diagnostic measures, including angiography, a clear difference must be seen in outcomes between treated and untreated groups.

Attempts have been made to assess the reliability of pulmonary angiography on the basis of interobserver agreement. Quinn et al. [75] assessed the reliability of pulmonary angiography and found the mean interobserver agreement among three observers to be 86%, but only 13% for subsegmental emboli. Stein et al. [68] found the copositivity of two interpreters to be 98% and 90% for lobar and segmental pulmonary emboli, respectively, but only 66% for subsegmental emboli. Diffin et al. [76] examined the anatomic distribution of emboli on pulmonary angiography to determine the relationship of vessel size to interobserver agreement and found initial agreement among three observers to be only 45%. Like CT, pulmonary angiography appears to have excellent reproducibility for larger, more centrally located thrombi but not necessarily those at the subsegmental level. Unfortunately, pulmonary angiography is now being used as the gold standard for these peripheral thrombi and is the study to which all others are compared. Much like autopsy as the gold standard, pulmonary angiography as the imaging gold standard is abundantly tarnished.


Perspective
Top
 Introduction
 Autopsy Issues
 Clinical and Laboratory Issues
 Imaging Issues
 Perspective
References
 
The clinical and laboratory diagnosis of pulmonary embolism remains arduous and the issues regarding the imaging diagnosis are many. V/Q lung scintigraphy remains a major screening tool that is fraught with confusion. Pulmonary angiography remains the imaging gold standard but has high interobserver variability, especially for small peripheral emboli, and is clearly not the diagnostic tool we have so long thought. CT is the current imaging rage because it has greater diagnostic capability than V/Q lung scintigraphy and is much less invasive than angiography, but CT needs further validation. The role of MR imaging for the diagnosis of acute pulmonary embolism is essentially unknown at this time.

Although we have made advances in imaging techniques, we seem only to be replacing invasive studies with less invasive studies. This is an improvement, but are we striving to answer the questions regarding pulmonary embolism as a disease process? Maybe our difficulties with diagnosis are based on a misunderstanding, or at least misrepresentation, of the disease itself. Efforts must be made to improve our knowledge of the pathophysiology of pulmonary embolism rather than just altering the methods of diagnosis. Serendipitously, less invasive imaging may answer some of these questions. If less invasive imaging of direct thrombus, such as CT or MR imaging, can be applied to large population studies, a clearer picture of pulmonary embolism may evolve.

From a diagnostic standpoint, most interventionists have found pulmonary embolism to be a clinically baffling disease requiring middle-of-the-night pulmonary angiography for a definitive diagnosis, inferior vena cava filter placement for treatment, and catheter-directed thrombolysis as a lifesaving emergency procedure.

Recently, however, a number of interventional procedures have begun to raise questions about pulmonary embolism, particularly its clinical presentation, pathophysiology, and lethality. The most pertinent of these procedures is the declotting of dialysis arteriovenous accesses wherein thrombus is often pushed into the lungs. Although certainly many have worried about fatal pulmonary emboli from such procedures, apart from rare exceptions these patients do well without clinical or often even imaging evidence of pulmonary embolism [77,78,79]. Additionally, these are often ill patients in need of dialysis and possessing an overall poor constitution. Several reasons have been proposed as to why these patients fare so well, including the possibility that only a small amount of clot is deposited in the lungs, these interventions are only a single episode, and the thrombus bound for the lungs is saturated with a thrombolytic agent or has been broken up mechanically into small fragments [80, 81]. The latter two conditions are what is attempted during the interventional procedure. However, as all interventionists know, a good deal of thrombus is pushed to the lungs. Although many explanations are possible as to why patients tolerate pulmonary embolism during these procedures, one must at least include that pulmonary embolism is not the horrific disease we have long believed. That is certainly not to say people do not die from pulmonary embolism. But why else is it so hard to prove as the cause of death at autopsy? Why do patients with angiographically proven emboli have little clinical sequelae despite absence of treatment? Are our imaging studies really that bad? If but for an instant one considers that may be pulmonary embolism is not quite the assassin we have been taught, then many of these issues are easier to reconcile. It will take a new and thoughtful approach without preconceived biases to begin addressing these issues. Pulmonary embolism...what's wrong with this diagnosis?


References
Top
 Introduction
 Autopsy Issues
 Clinical and Laboratory Issues
 Imaging Issues
 Perspective
 References
 

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D. Luciani, S. Cavuto, L. Antiga, M. Miniati, S. Monti, M. Pistolesi, and G. Bertolini
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