The Diagnosis of Clinically Suspected Pulmonary Embolism*

Transcription

1 The Diagnosis of Clinically Suspected Pulmonary Embolism* Practical Approaches RusseilD. Hull, M.B.B.S., M.Sc., F.C.C.P.; Gary E. Raskob, B.Sc.(Hon.), M.Sc.; and Jack Hirsh, M.D. pulmonary embolism is a common complication of venous thrombosis that usually originates in the deep veins of the legs. It is now well recognized that the clinical diagnosis of pulmonary embolism is highly nonspecific. 1.7 Clinical diagnosis is nonspecific because none of the symptoms or signs of pulmonary embolism is unique, and all may be caused by a variety of other cardiorespiratory disorders. The common symptoms and signs of pulmonary embolism and the associated differential diagnoses are listed in Table 1. The nonspecificity of the clinical diagnosis of pulmonary embolism was strikingly demonstrated in the Urokinase/ Streptokinase Pulmonary Embolism Study (UPET) in which more than 60% of over 2,500 patients entered with clinically suspected pulmonary embolism had this diagnosis excluded by the finding of a negative perfusion lung scan. 5 6 The results of the UPET study are consistent with the findings of other studies,2 7 all of which indicate that more than half of all patients with clinically suspected pulmonary embolism do not have this diagnosis confirmed by objective testing. Thus, objective testing is mandatory either to confirm or to exclude a diagnosis of pulmonary embolism. Measurements of serum enzymes and bilirubin are both insensitive and nonspecific and should not be used in the diagnosis.7 Arterial blood gas measurements are equally nonspecific and should not be used for diagnostic purposes in patients with suspected pulmonary embolism A normal arterial Po2 (>80 mm Hg) does not exclude pulmonary embolism, and abnormal blood gas values occur in a wide variety of respiratory disorders. The radiologic abnormalities associated with pulmonary embolism are nonspecific and occur in many other pulmonary disorders. In addition, patients with pulmonary embolism may have normal chest x-ray film findings at presentation. The chest x-ray examination is helpful, however, in demonstrating other causes for the From the Departments of Medicine, and Clinical Epidemiology and Biostatistics, Chedoke-McMaster Hospitals, and McMaster University, Hamilton, Ontario, Canada. Reprsnt requests: Dr Hull, Chedoke Hospital, P0 Box 2000, Station A, Hamilton, Ontario, Canada L8N 3Z5 patient s condition (eg, pneumothorax) and is important in interpreting the lung scan findings. The ECG may be useful fur differentiating between pulmonary embolism and myocardial infarction. It is frequently normal or nonspecific, and the classic findings associated with pulmonary embolism (right axis shift, and S,. Q3, T3 pattern) are uncommon and also nonspecific. Lung scanning is extremely useful for excluding a diagnosis of pulmonary embolism, and when there is a large ventilation-perfusion mismatch, lung scanning can usually be used to rule in pulmonary embolism. Other findings by lung scanning do not have sufficiently high or low predictive power either to rule out or to rule in pulmonary embolism, and, therefure, further investigations are required. These include objective tests for venous thrombosis (because most pulmonary emboli are associated with deep vein thrombosis of the leg) and pulmonary angiography. Although there is some morbidity associated with the use of the invasive tests (pulmonary angiography and Table 1-Differential Diagnosis of the Clinkal Features of Pulmonary Embolism Dyspnea Atelectasis Pneumothorax Acute pulmonary edema Acute bronchitis Acute bronchiolitis Acute bronchial obstruction Hemoptysis Pneumonia Bronchial neoplasm Bronchiectasis Acute bronchitis Mitral Tuberculosis stenosis Acute right heart failure Myocardial infarction Myocarditis Cardiac tamponade Acute respiratory infection complicating lung disease chronic Pleuritic chest pain Pneumonia Pneumothorax Pericarditis Pulmonary Bronchiectasis Subdiaphragmatic neoplasm inflammation Myositis Muscle strain Rib fracture Cardiovascular collapse Myocardial infarction Acute massive hemorrhage Gram-negative septicemia Cardiac tamponade Spontaneous pneumothorax CHESTI89I5/MAY,l9e6ISupplsment 417$

2 venography), there is virtually none associated with noninvasive testing. Furthermore, the morbidity from unnecessary anticoagulant therapy and inappropriate hospitalization exceeds that caused by pulmonary angiography and venography, and these tests should be used when other approaches are inconclusive. PULMONARY ANGIOGRAPHY: THE DIAGNOSTIC REFERENCE STANDARD FOR PULMONARY EMBOLISM Pulmonary angiography is the accepted diagnostic reference standard for establishing the presence or absence of pulmonary embolism.11 Ip recent years, the diagnostic resolution of pulmonary angiography has been markedly improved by using selective angiography and magnification views. 3 These techniques have improved the accuracy of this invasive test and decreased its risk to the patient. Pitfalls and Limitations of Pulmonary Angiography Pulmonary angiography provides a means for direct visualization of filling defects caused by thromboemboli. A diagnosis of pulmonary embolism is made if there is a constant intraluminal filling defect seen on multiple films, or if sharp cut-offs can be seen in vessels greater than 2.5mm in diameter, which are constant in multiple films. Other abnormalities, such as oligemia, vessel pruning, and loss of filling of small vessels, are nonspecific and may occur in pneumonia, atelectasis, bronchiectasis, postinflammatory atrophy, primary pulmonary hypertension, pulmonary venous hypertension, emphysema, and pulmonary carcinoma. Loss of filling may also occur for technical reasons, but this artifact can often be avoided by careful attention to technique with repeated injection of small volumes of dye (eg, 20 ml). Both hypotension and arrhythmias resulting in death have been observed in patients undergoing main pulmonary outflow dye injection. These risks can be reduced by using selective pulmonary angiography with repeated injections of small volumes of dye. Selective pulmonary angiography is a safe technique in the absence of severe chronic pulmonary hypertension or severe cardiac or respiratory decompensation. 4 Although the risk of pulmonary angiography has been substantially reduced in recent years by the use of the selective technique, its invasive nature and the associated risks contraindicate its use in a significant number of very ill patients whose clinical course has been complicated by suspected pulmonary embolism. In our experience,2 approximately 20% of patients with clinically suspected pulmonary embolism and abnormal perfusion lung scan findings cannot undergo pulmonary angiography because of the severity of their primary illness. Clinically significant complications, including tachyarrhythmias, endocardial or myocardial injury, cardiac perforation, cardiac arrest, and hypersensitivity reactions to contrast medium, occur in up to 3-4% of patients undergoing pulmonary angiography. 4 Patients with a history of allergy to radiopaque dye should not have pulmonary angiography performed. One retrospective long-term follow-up study 3 has been performed to validate the negative predictive value of a negative pulmonary angiogram. Although none of the patients with negative pulmonary angiograms developed thromboembolic complications during follow-up, this study was flawed because 13% of the patients with negative pulmonary angiograms were lost to follow-up. The use of a negative pulmonary angiogram to rule out pulmonary embolism has been criticized, because angiography may have insufficient sensitivity to detect small emboli that can be detected by perfusion lung scanning. 9 Therefore, additional follow-up studies are required to evaluate the clinical significance of a negative pulmonary angiogram in patients with clinically suspected pulmonary embolism. ESSENTIAL METI-LODOLOGIC CRITERIA FOR THE EVALUATION OF LESS INVASIVE DIAGNOSTIC APPROACHES FOR SUSPECTED PULMONARY EMBOLISM Because of the limitations of pulmonary angiography, extensive efforts have been made to replace this invasive technique with less invasive diagnostic tests.2 The early studies with less invasive tests (LDH and arterial gases) were inadequately designed and the diagnostic recommendations drawn from these studies spurious. A falsely high specificity fur the diagnosis of pulmonary embolism was attributed to perfusion lung scanning, which was subsequently refuted by multiple studies. 1,,0,n The uncritical clinical acceptance of a diagnostic test for pulmonary embolism has serious implications, because it may result in inappropriate and potentially dangerous management. The major reason for the early inappropriate application of the above diagnostic tests for pulmonary embolism was a premature clinical acceptance of diagnostic efficacy based on studies that failed to include the essential design features required to adequately assess the efficacy of a diagnostic test. These essential design features are summarized in Table 2. The efficacy of a diagnostic test lies in its ability to indicate the presence or absence of disease. Efficacy is measured by 4 indices: sensitivity (proportion of positive test results among patients with the disease), specificity (proportion of negative test results among patients without the disease), positive predictive value (the likelihood that the patient with positive test results will have the disease), and negative predictive 418S Diagnosis of Clinically Suspected Pulmonary Embolism (Hull, Raskob, Hirsh)

3 Table 2-The Essential Design Features for Studies Evaluating the Efficacy of a Diagnostic Test 1. The test should be evaluated prospectively in consecutive patients, all of whom undergo both the diagnostic test under evaluation and the reference test, to determine the sensitivity, specificity, positive, and negative predictive values. 2, The evaluation of the diagnostic test should be performed in a broad spectrum of patients suspected to have the disease of interest (both with and without the disease), Failure to include a broad spectrum of patients may result ins falsely high estimate of efficacy. 3. Diagnostic suspicion bias should be avoided b evaluating consecutive patients and by interpreting the results of the diagnostic test and reference test independently, and without knowledge of each other or the patient s clinical findings, 4. The clinical validity of a negative test result should be evaluated by long-term clinical follow-up to determine the safety of withholding therapy on the basis of a negative test result, value (the likelihood that patients with negative test results will not have the disease). To determine adequately the efficacy of a diagnostic test, it is essential that the test be evaluated in a broad spectrum of patients suspected to have the disease of interest (both with and without the disease), all of whom undergo testing with a diagnostic reference test. In this way, it is possible to identify disorders that produce falsely positive and falsely negative results and to determine the clinical utility of the test in various patient subgroups. Failure to evaluate the test in a broad spectrum of patients may result in falsely high indices of efficacy, particularly when applied to certain subgroups. Bias can be avoided by performing the diagnostic test and the reference test in all eligible patients and by assessing the test results blindly, without knowledge of each other or the patient s condition.23 The final step in the process of evaluating a new diagnostic test is to confirm the clinical validity of a negative test result. Clinical validity should be determined by long-term follow-up in consecutive patients in whom treatment has been withheld on the basis of negative test results. PERFUSION LUNG SCANNING The history of perfusion lung scanning dates back to the early 1960s when Taplin and Poe described a technique to make 5-20.t-sized particles of human macroaggregated albumin (MAA) that could be injected safely into man. When injected intravenously, these particles labeled with I lodged in the pulmonary capillary bed, and their distribution, which was recorded with an external photoscanner, reflected the distribution of lung blood flow. Rapid improvements in instrumentation, with the development of the gamma camera, and in radiopharmaceuticals, with the development of technetium 99m (Tc)-labeled MAA, led to rapid acceptance of the perfusion lung scan for the investigation of a variety of lung diseases, particularly pulmonary embolism. Although perfusion lung scanning can detect regions of poor perfusion as small as 2 cm in diameter, an abnormal perfusion scan is nonspecific 7 and cannot identify the cause of the perfusion defect; disturbances in pulmonary blood flow from any cause produce an abnormal scan. This observation is of particular clinical relevance in patients with suspected pulmonary embolism, because in most reported series the majority of lung scan defects are produced by conditions other than pulmonary embolism. In the absence of pulmonary embolism, perfusion defects are usually secondary to ventilation abnormalities caused by disorders with regional hypoxia and consequent hypoxic pulmonary vasoconstriction or to loss of the vascular bed such as occurs in emphysema. Recent studies2 23 using improved imaging techniques have confirmed the poor specificity of perfusion lung scanning for the diagnosis of pulmonary embolism. In 2 of the earlier studies, pulmonary embolism by pulmonary angiography was present in only 40% and 34% of 167 patients and 146 patients, respectively, with abnormal perfusion scans and suspected pulmonary embolism.3 4 These findings were confirmed in a recent prospective study of 305 consecutive patients with clinically suspected pulmonary embolism and abnormal perfusion lung scan findings.2 23 The presence of pulmonary embolism by angiography was demonstrated in only 95 of 183 patients (52%) with abnormal perfusion lung scans and adequate pulmonary angiogram results. In all of these studies, exclusion from the analysis of patients who had abnormal chest x-ray film findings did not overcome the problems of the nonspecificity of the abnormal lung scan findings. Attempts were made to improve the specificity of the perfusion scan by classifying the defects according to size and number, but the probabilities obtained are unacceptable for making individual patient decisions.3 4 In our recent study, pulmonary angiography confirmed the presence of pulmonary embolism in only 65 of 90 patients (71%) with 1 or more segmental or greater perfusion defects; and in 25 of 68 patients (37%) with 1 or more subsegmental perfusion defects; and in 5 of 24 patients (21%) in whom the lung scan defects corresponded to the defect on chest x-ray film.#{176}the consistent finding that perfusion lung scanning is highly nonspecific is not surprising, since abnormalities of pulmonary blood flow distribution are seen in many common pulmonary disorders (eg, chronic obstructive lung disease, acute asthma, bronchitis, pneumonia, atelectasis, and pleural effusion). Due to the documented nonspecificity of an abnormal perfusion lung scan, it is no longer acceptable to make management decisions on the basis of perfusion scan- CHEST / 89 / 5 / MAY, 1986 / Supplement 419S

4 ning alone. VENTILATION-PERFUSION LUNG SCANNING Ventilation lung scanning is performed using either radioactive gases or radioactive aerosols that are inhaled and exhaled by the patient while a gamma camera records the distribution of radioactivity within the alveolar gas exchange units. Ventilation imaging was introduced into clinical practice for the diagnosis of pulmonary embolism based on the premise that ventilation is preserved in areas of reduced perfusion due to pulmonary embolism (ventilation-perfusion mismatch), whereas ventilation is abnormal when perfusion defects result from the physiologic response to primary parenchymal disease (ventilation-perfusion match). jan Thus, it was assumed that the addition of ventilation imaging would improve the specificity of an abnormal perfusion lung scan by differentiating embolic occlusion of the pulmonary vasculature from perfusion defects occurring secondary to a primary disorder of ventilation. The basic premise that perfusion defects that ventilate normally are due to pulmonary embolism, whereas matching ventilation-perfiision abnormalities are due to other conditions, was not supported by early studies in experimental animals, 23 and has recently been shown to be incorrect based on the findings of a prospective clinical trial.2 23 VENTILATION LUNG SCANNING WITH RADIOACTIVE GASES Much of the current understanding of the physiology of regional pulmonary ventilation is based on studies performed with the radioactive gases such as xenon 133 ( 23Xe) or xenon 127 ( 27Xe) There are practical problems with the use of radiactive xenon in clinical practice. 9 2#{176} With all radioxenons, the ventilation technique requires the patient to rebreathe the gas from a closed circuit spirometer or bag system. The complexity of the technique limits the imaging to only 1 view. With 23Xe, the ventilation image is traditionally performed from the posterior view before the SSmTc MAA perfusion scan, because the Tc gamma rays degrade the 23Xe images. With this approach, the ventilation image may not be obtained from the view that best demonstrates the perfusion defect. Another potential problem in the interpretation of ventilationperfusion scans is that the spatial resolution with 23Xe is much worse than the resolution obtained with Tc. As a consequence, small defects in perfusion may appear to ventilate well with 23Xe when in fact, the region is poorly ventilated but too small to be resolved with 33Xe Several approaches have been taken to improve the ventilation images with different radioactive gases such as 21Xe and krypton 81m. With 27Xe the ventilation image can be obtained after the perfusion lung scan from whichever view best demonstrates the lesion, but the technical difficulties inherent in the xenon ventilation technique still apply. For those institutions within easy reach of a cyclotron, krypton 81m has the potential to be a superior agent. The spatial resolution of krypton 81m is comparable to Tc, and multiple views of the lungs are routinely obtained. 9 The expense and lack of availability of 81 ICr and the inadequacies of radioxenons have prompted investigation into the use of other agents for measuring regional ventilation and has led to the recent major interest in the use of radioactive aerosols. 9 2#{176} RADIOAEROSOL VENTILATION IMAGING Submicron aerosols, when inhaled into the lungs, lodge mainly in peripheral airways and have a distribution pattern essentially the same as radioxenons and sthkt The advent of inexpensive disposable aerosol systems to nebulize mtc radiopharmaceuticals has made aerosol ventilation scans available to all nuclear medicine departments. The use op#{176} Tc-labeled aerosols (either Tc DTPA or #{176} Tcsulfur colloid) has obvious advantages in terms of image resolution and availability. 9 In addition, once deposited in the lung, the aerosol remains for at least 1 hour, permitting multiple views of the lungs to be obtained. DIAGNOSTIC APPROACHES FOR SUSPECTED PULMONARY EMBOLISM USING VENTILATION- PERFUSION LUNG SCANNING Historically, a variety of diagnostic approaches using ventilation-perfusion lung scanning have been used for patients with clinically suspected pulmonary embolism. The correct approach remained uncertain until recently, because the respective roles of ventilationperfusion lung scanning, pulmonary angiography, and objective testing for deep-vein thrombosis had not been adequately evaluated by properly designed and executed clinical trials, and because opinions differed about the specificity of ventilation-perfusion lung scanning Consequently, divergent and inherently contradictory diagnostic approaches for patients with clinically suspected pulmonary embolism emerged. The divergent recommended approaches were based on the following concepts: 1. That ventilation scans are only occasionally helpful and pulmonary angiography is the most accurate diagnostic means currently available ;9 2. That ventilation-perfusion mismatch correlates to a high degree with pulmonary embolism in patients undergoing angiography, 3 and in individual patients, the ventilation-perfusion patterns can be assigned estimates of probability on which decisions concerning management can be based. The presence of a ventilation-perfusion match (in an area that is normal on chest roentgenogram) virtually rules out the possibility of 420S Diagnosis ci Clinically Suspected Pulmonary Embolism (Hull, RSSICOb, Hirsh)

5 pulmonary embolism.3 3. That mismatch with perfusion defects is (virtually) diagnostic of acute embolism and that the main role for pulmonary angiography is in patients with nondiagnostic scans.27 The results of recent prospective clinical studies2 23 of the diagnosis of pulmonary embolism are presented in detail in this section and provide the basis for a practical approach to diagnosing pulmonary embolism which is outlined later in this article. Retrospective Studies and Nonconsecutive Patient Series The published data3 4 2 supporting the clinical application of ventilation-perfusion lung scanning were, until recently, taken largely from retrospective studies or from nonconsecutive prospective patient series, none of which satisfied the design criteria outlined in Table 2. The initial studies, which included only small numbers of patients, reported a falsely high degree of efficacy for ventilation-perfusion lung scanning. 621 The results of subsequent larger retrospective surveys reported false-positive rates for ventilationperfusion mismatches of 20% and 48%, respectively.3 4 Attempts were made to improve the specificity of ventilation-perfusion lung scanning by classifying the perfusion defects according to their size, number, and the presence of matched or mismatched ventilation defects Multiple large defects with normal ventilation were associated with a very high probability of pulmonary embolism, while other lung scan patterns were reported to be associated with a lower frequency of pulmonary embolism, leading to the concept of low-probability patterns. Subsequently, the concept that a low-probability lung scan pattern could be used to rule out pulmonary embolism has been shown to be incorrect. 2,22 Prospective Consecutive Patient Series The results of our recent prospective study have provided new data concerning the predictive value of the individual ventilation-perfusion lung scan patterns.2 23 In this study, a consecutive series of patients with clinically suspected pulmonary embolism and an abnormal perfusion lung scan were entered prospectively in a protocol requiring ventilation-perfusion lung scanning, pulmonary angiography and venography in all patients (unless these tests were contraindicated because of concurrent life-threatening cardiac or respiratory illness). The results of ventilation-perfusion lung scanning, therefore, did not influence the decision to perform pulmonary angiography and venography, thus avoiding work-up bias that would have occurred if pulmonary angiography was done selectively on the basis of the lung scan findings. Bias due to diagnostic suspicion (in which knowledge of one test Table 3-Frequency of Pulmonary Embolism (PE) Associated with the Individual Ventilation-Perfusion Scan Patterns* Ventilation-Perfusion Scan Pattern Frequency of PE, No. (%) One or more segmental or greater defects Mismatch 51/59 (86) Match 10/28 (36) One or more subsegmental defects Mismatch 16)4.0 (40) Match 6/24 (25) Indeterminate 5/24 (21) *Hull et al21 finding may influence the interpretation of another) was avoided by interpreting all of the test findings independently and without knowledge of each other or the patient s clinical status. The findings of our study indicate that patients with large perfusion defects (1 or more segmental or greater defects) and a ventilation mismatch have a high probability of pulmonary embolism; 51 of 59 patients (86%) in this category had pulmonary embolism by angiography (Table 3). This observation is consistent with the findings previously reported in the literature Our results differ, however, from previous findings in patients with a ventilation-perfusion match and in those with small perfusion defects. In these latter 2 groups, the frequency of pulmonary embolism was not sufficiently low to rule out pulmonary embolism. In patients with small perfusion defects (1 or more subsegmental defects), pulmonary angiography confirmed the presence of pulmonary embolism in 16 of 40 patients (40%) with ventilation mismatch and in 6 of 24 patients (25%) with ventilation match (Table 3). Thus, the addition of ventilation lung scanning is helpful only in patients with large perfusion defects, where it markedly increases the probability of pulmonary embolism if a mismatch is found. On the basis of this study, the procedure of assigning probability estimates to ventilation-perfusion scan patterns is clinically useful only if the perfusion defect is large and is associated with a ventilation mismatch. The presence of a ventilation-perfusion match does not rule out the possibility of pulmonary embolism. The presence of small perfusion defects, irrespective of ventilation, indicates neither a high probability nor a low probability of pulmonary embolism. Most of the subgroup of patients with ventilationperfusion match and pulmonary embolism by angiography did not have clinically obvious asthma or chronic obstructive lung disease. The ventilationperfusion match seen in these patients may have been due to bronchospasm occurring early in the course of pulmonary embolism. It has been suggested that a ventilation-perfusion match due to pulmonary embo- CHEST / / MAY, 1986 I Supplement 421S

6 Table 4-Frequency of Pulmonary Embolism (PE) andlor Proximal Vein Thrombosis (PROX-DVT) As8ociated with the individual Ventilation-Perfusion Scan Patterns* Ventilation-Perfusion Frequency of PE Scan Pattern and/or PROX-DVT, No. (%) One or more segmental or greater defects Mismatch 53/59 (90) Match 13/28 (46) One or more subsegmental defects Mismatch 17/40 (43) Match 7/24 (29) Indeterminate 9/24 (38) 6Hull et al lism may be transient, and thus repeated ventilationperfusion lung scanning done several days later may demonstrate ventilation-perfusion mismatch, but the clinical value of this suggested approach requires evaluation in a formal study. Contrary to current clinical practice, our findings indicate that the strategy of using a low probability lung scan pattern to rule against pulmonary embolism is incorrect and should be abandoned. The observed frequencies of venous thromboembolism (Table 4) associated with those lung scan patterns which have been traditionally regarded as low probability ranged from 29 to 46%.223 The use of an improved method of ventilation scanning ( Tc aerosol ventilation imaging), which provided excellent ventilation imaging, did not improve the specificity of ventilationperfusion lung scan abnormalities, suggesting that, contrary to current expectations, the diagnostic dilemma will not be resolved by refinement of ventilation imaging. Our findings clearly indicate that it is inappropriate to withhold anticoagulant therapy solely on the basis of the results by ventilation-perfusion lung scanning in patients with abnormal perfusion scans, and further objective testing is required to establish or refute the diagnosis of venous thromboembolism. THE ASSOCIATION BETWEEN DEEP VENOUS THROMBOSIS AND PULMONARY EMBOLISM The Role of Objective Testing for Venous Thrombosis in the Diagnostic Work-up of Patients with Suspected Pulmonary Embolism Postmortem studies have shown that most patients with pulmonary embolism have deep vein thrombosis of the legs. These autopsy findings, however, may not reflect the relation between venous thrombosis and pulmonary embolism in the living patient. Several investigators have examined the association between deep vein thrombosis and pulmonary embolism in patients with clinically suspected pulmonary embolism.2 2 Some of the earlier studies reported that up to 50% of patients with pulmonary embolism did not have detectable deep vein thrombosis. This impression was based on the use of an abnormal perfusion lung scan as the diagnostic end point for pulmonary embolism and is of doubtful validity, since it is now recognized that more than 50% of patients with an abnormal perfusion lung scan do not have pulmonary embolism confirmed by pulmonary angiography #{176} In our recent prospective study, deep vein thrombosis was present in 70% of patients with pulmonary embolism documented by pulmonary angiography.2 The demonstration of silent venous thrombosis in patients with clinically suspected pulmonary embolism is clinically useful, since in most cases the treatment of deep vein thrombosis and pulmonary embolism is the same. Thus, detection of deep vein thrombosis could circumvent the need for pulmonary angiography, a distinct advantage because objective testing for deep vein thrombosis is less invasive, less complex, and more readily available. Both impedance plethysmography and venography have now been formally evaluated prospectively in patients with suspected pulmonary embolism and abnormal perfusion lung scans.2 23 Impedance plethysmography has the potential advantage that it is nonin-. vasive and free of morbidity, and can easily be perfbrmed in the emergency room or doctor s office, and is readily repeatable. Impedance plethysmography was positive in approximately 45% of patients with pulmonary embolism by pulmonary angiography.23 Others have reported a higher frequency. The results of impedance plethysmography were also compared with the venographic findings in these patients with clinically suspected pulmonary embolism. Even though most of the proximal vein thrombi were silent, almost 90% were detected by impedance plethysmography, and a positive IPG result was highly predictive of venous thromboembolism (a positive predictive value of greater than 95%).2 THE FREQUENCY OF VENOUS THROMBOSIS ASSOCIATED WITH THE INDIVIDUAL VENTILATION-PERFUSION SCAN PATFERNS A Biologic Gradient A gradient was noted for the frequency of proximal vein thrombosis among patients with a range of ventilation-perfusion defects, and this frequency differed sharply from that found in patients with normal lung scans (<1%). 2 Proximal vein thrombosis was present in 49% of patients with large perfusion defects and ventilation mismatch; in 27% of patients with large perfusion defects and ventilation match; in 15% of patients with subsegmental perfusion defects; and 17% of patients with indeterminate findings on perfusion lung scan.2 23 These findings therefore indicate that patients presenting with clinically suspected pulmonary embolism and abnormal findings by perfusion lung scan- 422S Diagnosis of Clinically Suspected Pulmonary Embolism (Hull, Raskob, Hirsh)

7 fling, including those scan patterns that have been traditionally regarded as low probability, have a substantial frequency of extensive deep vein thrombosis. The presence of proximal vein thrombosis in these patients has important management implications because recent randomized clinical trials have shown that failure to treat proximal deep vein thrombosis is associated with a high risk of recurrent venous thromboembo1ism.30 Although most patients with pulmonary embolism shown by pulmonary angiography had deep vein thrombosis by venography, the frequency of a negative venogram associated with pulmonary embolism by pulmonary angiography was 30%. Patients with negative findings by venography but with pulmonary embolism shown by angiography may have had their source of embolism in the deep pelvic veins, renal veins, inferior vena cava, or right atrium. Alternatively, the pulmonary emboli may have been derived from the deep veins of the legs, but all or most of the thrombi embolized, leaving no residual thrombi detectable by venography. Thus, although a positive result by venography or impedance plethysmography can be used as the basis for commencing therapy, a negative result cannot be used to exclude venous thromboembolism.2 23 A PRACTICAL DIAGNOSTIC STRATEGY FOR CLINICALLY SUSPECTED PULMONARY EMBOLISM A diagnostic algorithm for the management of clinically suspected pulmonary embolism is shown in Figure 1. Following a history and physical examination, ECG, and chest x-ray examination, all patients should undergo perfusion lung scanning. The finding of a negative perfusion lung scan can be considered to rule out clinically significant pulmonary embolism, Clinically Suspected Pulmonary EmbolIsm I V.0 Lung Scan I I I V.0 Scan V-a Scan V.0 Scan NORMAL HIGH.PROBABILITY NONHlGH PROBABIUTY 40% 17% 43% 1 1 PE Excluded Treat IPG POSITIVE IPO NEGATIVE 1 Tr.at FlGunz 1. Practical diagnostic approach for clinically suspected pulmonary embolism. V-Q ventilation-perfusion; IPG = impedance plethysmography. The percentages refer to the proportion of all patients with suspected pulmonary embolism based on the results of our recent prospective study. and anticoagulant therapy is withheld unless the patient also presents with clinically suspected venous thrombosis, in which case objective testing fur venous thrombosis should be performed. In our recent study,2 approximately 40% of patients with suspected pulmonary embolism had a normal perfusion lung scan. The management of an abnormal perfusion lung scan is more complex. If the perfusion lung scan demonstrates one or more segmental (or greater) perfusion defects, ventilation lung scanning should be performed because the probability of pulmonary embolism is markedly increased if a mismatch is found (positive predictive value 86%), providing an end point for commencing anticoagulant therapy in the majority of patients. The presence of a ventilation-perfusion match does not rule out the possibility of pulmonary embolism, and further objective testing is required in these patients. In patients with small perfusion defects (one or more subsegmental defects) or in patients with indeterminate lung scan findings (in which the perfusion scan defects correspond to a defect on chest x-ray film), the predictive values obtained from these ventilation-perfusion scan patterns are neither sufficiently high nor low to confirm or exclude the presence of pulmonary embolism. Alternative approaches are available which would reduce the need fur pulmonary angiography in patients with abnormal but non-high probability ventilation-perfusion lung scans. In these patients, venography or impedance plethysmography could be performed as the initial step of the diagnostic work-up. If objective testing confirms the presence of deep vein thrombosis, anticoagulant therapy can be commenced without the further procedure of pulmonary angiography. If venography is negative, pulmonary angiography is required to confirm the presence or absence of pulmonary embolism, as a negative venogram occurs in up to 30% of patients with pulmonary embolism by angiography and therefore may not be used to exclude venous thromboembolism. The correct approach to patients with non-high probability lung scan patterns who have a negative result by impedance plethysmography or venography at presentation (and, therefore, either do not have venous thrombosis or have calf vein thrombosis) remains to be adequately defined (Fig 1). One approach would be to perform pulmonary angiography in all of these patients to detect the 15-50% of patients who have pulmonary embolism. An alternative strategy that we are currently exploring in patients with good cardiorespiratory reserve, low probability, or indeterminate lung scans, and negative impedance plethysmography at presentation is to use surveillance with serial impedance plethysmography testing to detect recurrent or extending venous thrombosis. The rationale of this approach is based on the premise that CHEST I 89 / 5 I MAY, 1986 / Supplement 423S

8 clinically significant recurrent pulmonary embolism is very unlikely in patients who do not have proximal vein thrombosis and that serial impedance plethysmography testing can be used to detect extending deep vein thrombosis.23 Serial impedance plethysmography has been used successfully to detect clinically important venous thrombosis in patients with clinically suspected deep vein thrombosis that is inapparent at presentation23 and, therefore, holds promise in patients with suspected pulmonary embolism who are stable clinically. This approach is likely to be more successful than venography alone because, in patients with negative venography at presentation, the putative thrombus may have embolized completely but, in the absence of further testing, could recur undetected and lead to serious recurrent pulmonary embolism. Furthermore, because of its invasive nature, venography cannot be readily repeated. Noninvasive testing with impedance plethysmography has a practical role at the bedside in the diagnostic work-up of patients with clinically suspected pulmonary embolism and abnormal perfusion scans. The use of impedance plethysmography for diagnosing proximal vein thrombosis at the time of presentation obviates pulmonary angiography in 20-30% of patients with clinically suspected pulmonary embolism and abnormal perfusion scans.23 If anticoagulant therapy is started on the basis of documented deep vein thrombosis, the patient s respiratory illness should be closely monitored to detect a nonembolic disorder that may be present. The objective confirmation of deep vein thrombosis provides an indication for anticoagulant therapy, but does not necessarily establish a diagnosis of pulmonary embolism because venous thrombosis may have occurred in association with another primary respiratory illness. By closely monitoring the patient s respiratory status, other diseases, such as pneumonia, that initially may not have been an obvious component of the diagnosis can be detected and managed appropriately. If the cause of the respiratory disorder remains uncertain, pulmonary angiography will distinguish between pulmonary embolism and other respiratory problems. Anticoagulant therapy is withheld in patients who have normal results by both pulmonary angiography and venography. REFERENCES 1 Urokinase Pulmonary Embolism Trial. A national co-operative study. 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9 prevention by oral anticoagulants. Am J Med 1962; 33: Sasahara AA, Sharma CVRK, Parisi AR New developments in the detection and prevention of venous thromboembolism. Am J Cardiol 1979; 43: Hull R, Delmore T, Genton E, et al. Warfarin sodium versus lowdose heparin in the long-term treatment of venous thrombosis. N Engi J Med 1979; 301: Hull R, Delmore T, Carter C, et al. Adjusted subcutaneous heparin versus warfarmn sodium in the long-term treatment of venous thrombosis. N Engl J Med 1982; 306: Hull R, Hirsh J, Carter C, et al. Different intensities of oral anticoagulant therapy in the treatment of proximal vein thrombosis. N Engl J Med 1982; 307: Moser KM. Lemoine JR. Is embolic risk conditioned by location of deep venous thrombosis? Ann Intern Med 1981; 94: Wheeler HB, Anderson FA Jr. Can non-invasive tests be used as the basis for treatment of deep-vein thrombosis? In: Berstein EF, ed. Non-invasive diagnostic techniques in vascular disease. 2nd ed. St. Louis: CV Mosby Co, 1982: Hull R, Hirsh J, Carter CJ, et al. Diagnostic efficacy of impedance plethysmography fur clinically suspected deep-vein thrombosh: a randomized trial. Ann Intern Med 1985; 102:21-28 CHEST I 89 / 5 / MAY / Supplement 425$