Acute pulmonary thromboembolism (PE) is a common,

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1 Role of Echocardiography in the Diagnosis and Treatment of Acute Pulmonary Thromboembolism David Leibowitz, MD, Jerusalem, Israel The diagnosis and treatment of acute pulmonary thromboembolism (PE) remains a complex clinical challenge. Many studies have used both transthoracic and transesophageal echocardiography as a diagnostic and/or prognostic tool in this common disorder. In patients with central, hemodynamically significant PE, echocardiography can directly visualize thrombus or demonstrate the hemodynamic consequences of PE, whereas in the majority of patients, the sensitivity of echocardiography appears limited. Echocardiography may be useful in assessing the prognosis of patients with PE as well as their response to therapy. Further studies are needed in larger populations of patients to clarify the role of echocardiography in the assessment of patients with clinically suspected PE. (J Am Soc Echocardiogr 2001;14:921-6.) Acute pulmonary thromboembolism (PE) is a common, life-threatening illness that is an important cause of morbidity and mortality. Population-based studies estimate that there are approximately 170,000 new cases of PE in the United States alone, with a 1-year mortality rate of up to 25%. 1,2 The diagnosis of this common disorder remains a clinical challenge despite the extensive use of ventilationperfusion scintigraphy, pulmonary angiography, Doppler ultrasound of the lower extremities, and newer techniques such as spiral/helical computed tomography, serum D-dimer, and magnetic resonance imaging. Although many reports have investigated the potential role of transthoracic (TTE) and transesophageal (TEE) echocardiography in the diagnosis and treatment of PE, the clinical utility of these techniques in this setting remains unclear. This review will examine the role of TTE and TEE in the diagnosis and treatment of acute pulmonary thromboembolism. From the Coronary Care Unit, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel. Reprint requests: David Leibowitz, MD, Coronary Care Unit, Hadassah University Hospital, p.o.b , Mount Scopus, Jerusalem, Israel ( oleibo@hadassah.org.il). Copyright 2001 by the American Society of Echocardiography /2001/$ /1/ doi: /mje TEE IN THE DIAGNOSIS OF PULMONARY EMBOLISM TEE directly images the right-sided cardiac structures, the main pulmonary artery, a significant portion of the right pulmonary artery, and the proximal portion of the left pulmonary artery. The ability of TEE to directly visualize central pulmonary emboli, initially described by Nixdorf et al 3 in 1988, has since been documented in several case reports and small series 4-7 (Figures 1 and 2). One prospective study of 32 patients referred for TEE with clinical or TTE suspicion of pulmonary embolism and documentation of right ventricular overload on TTE noted a sensitivity of 80% and a specificity of 100% for acute PE. 8 Pruszcyk et al 9 prospectively compared the value of TEE and spiral computed tomography (CT) in 49 consecutive patients with clinical suspicion of PE and right ventricular overload noted on TTE. PE was diagnosed in 40 patients by means of reference diagnostic methods (lung scan in 27, angiography in 13). Sensitivity was noted to be 90% for spiral CT and 80% for TEE (not significant), with 100% specificity for both methods.the relatively low negative predictive value (52.9%) of TEE led the authors to caution that TEE could not reliably exclude the diagnosis of PE. In another study of 30 patients with clinically suspected PE and right ventricular overload on TTE, the sensitivity of TEE was 58% when compared with helical CT or angiography. 10 The authors noted that the sensitivity of TEE was limited primarily by difficulty in imaging the left pulmonary and lobar arteries. 921

2 922 Leibowitz September 2001 T Figure 1 Thrombus seen attached to right atrial free wall demonstrated by transesophageal echocardiography. T, Thrombus. Figure 2 Thrombus seen on transesophageal echocardiography in right pulmonary artery in patient with acute shortness of breath and right heart failure. T, Thrombus. Other studies have shown TEE to be an effective diagnostic tool for major PE.In the study of Krivec et al, patients with unexplained shock and distended neck veins admitted to the medical intensive care unit were examined with TEE, and evidence of central pulmonary emboli was noted in 13.The sensitivity of TEE was 92% and specificity was 100% for PE in those patients with right ventricular dilation noted on TTE. 11 In addition,wittlich et al 12 noted a sensitivity of 97% and a specificity of 88% for TEE in detecting central PE when compared with ventilation-perfusion scan and pulmonary angiography. In conclusion, in some but not all studies, TEE appears to be a specific and relatively sensitive diagnostic tool in patients with clinically or echocardiographically suspected central PE. The role of TEE in the more common clinical scenario of peripheral pulmonary emboli is limited because of its inability to image the more distal pulmonary vessels as well as the invasive nature of the procedure. TTE IN THE DIAGNOSIS OF PULMONARY EMBOLISM Although the ability of TTE to directly image the proximal pulmonary arteries is limited, several case reports and series have documented findings of right-sided or pulmonary thrombi by TTE in patients with suspected PE. 13 Chartier et al 14 demonstrated free-floating right-heart thrombi in 38 patients with suspected PE over a 12-year period. Thirty-two patients were in New York Heart Association class IV, and mortality rate was 44.7%.Although these authors did not report the incidence of free-floating thrombi among the general population of patients with sus- pected PE, other studies have suggested that they occur in 7% to 18% of patients. 15,16 Because the number of patients with PE who have directly visualized thrombus on TTE is small, the utility of TTE as a diagnostic test in PE is mainly related to its ability to demonstrate secondary changes in cardiac size and function caused by the hemodynamic effects of PE (Table 1). Kasper et al 17 in 1986 reviewed echocardiographic studies performed in 105 patients with confirmed PE. In their study, right ventricular dilation was found in 70 (75%) patients, reduced left ventricular diameter in 38 (42%) patients, dilated right pulmonary artery in 78 (77%) patients, and abnormal motion of the septum in 41 (44%) patients (Figures 3 and 4). Of note, echocardiographic parameters were normal in 19 (18%) patients. It is also important to note that 33 of the patients in their series had recurrent or chronic pulmonary emboli and so might be expected to have a higher incidence of echocardiographic findings than patients with a single, acute PE. Several prospective studies have examined the utility of TTE as a primary diagnostic tool for PE (Table 2). Cheriex et al 18 studied 60 consecutive patients seen with clinically suspected PE including 11 with cardiovascular collapse who were referred for cardiological consultation. Corroborative investigations, which were not performed systematically, included ventilation-perfusion scanning, pulmonary angiography, surgery, and autopsies but did not confirm the diagnosis of PE in all patients. In this series, 56 (94%) patients had elevated pulmonary systolic pressures as measured by velocity of the tricuspid regurgitation jet. In 56 patients, right ventricular end-diastolic diameter was enlarged, and diastolic bulging of the septum toward the left ventricle

3 Volume 14 Number 9 Leibowitz 923 Figure 3 Short-axis transthoracic view showing dilated right ventricle and septal flattening in patient with pleuritic chest pain and tachycardia. Spiral computed tomography confirmed diagnosis of acute pulmonary thromboembolism. noted. Intracardiac or vascular thrombi were noted in 10 patients. The authors concluded that echocardiography is a sensitive technique for the identification of right ventricular overload in PE.The applicability of this study to the general population of patients with PE is limited because it incorporated a highly selected population, a high proportion of which had hemodynamic abnormalities. In addition, many patients did not undergo definitive diagnostic procedures, and the diagnosis of PE remained unconfirmed. Another prospective study was reported by Nazeyrollas et al. 19 The authors examined 132 patients admitted to the cardiac intensive care unit with suspected pulmonary embolism, excluding patients with previously known cardiac disease. Seven patients died before completion of the protocol, and 55 had other diagnoses (mainly reduced left ventricular function) established by echocardiographic study. Of the final group of 70 patients, 31 had PE documented on pulmonary angiography, and 39 had negative pulmonary angiograms. Significant differences in several echocardiographic variables were noted between the two groups including right ventricular diameter >25 mm (70% versus 14%), ratio of right ventricular diameter to left ventricular diameter >0.5 (85% versus 22%), and tricuspid velocity >2.5 m/s (93% versus 18%). When combined in an echocardiographic logistic model, these echocardiographic parameters had a sensitivity of 93%, specificity of 81%, positive predictive value of 78%, and negative predictive value of 93%.This study was limited to patients admitted to the cardiac intensive care unit, again leading to a selection bias in favor of Figure 4 Apical 4-chamber view (same patient as in Figure 3) showing dilated right ventricle and right atrium. Table 1 Echocardiographic signs used in diagnosis of acute pulmonary thromboembolism 1. Direct visualization of thrombus in the right-sided chambers or the pulmonary artery 2. Right ventricular dilation 3. Reduced right ventricular function 4. Reduced left ventricular cavity size 5. Dilated pulmonary arteries 6. Abnormal septal motion/systolic flattening of the septum 7. Significant (moderate to severe) tricuspid regurgitation 8. Increased velocity of tricuspid regurgitation jet 9. Dilation of the inferior vena cava sicker, more compromised patients who would be expected to have more significant hemodynamic and hence echocardiographic abnormalities than the general population of patients with PE. Several studies have examined the use of TTE as a diagnostic tool for patients with suspected PE who are examined in the emergency department, a more generalized population of patients. Perrier et al 20 prospectively studied 50 patients with suspected PE referred primarily from the emergency ward. The diagnostic gold standard was a sequential noninvasive strategy including lung scan, D-dimers, and lower-extremity Doppler. The prevalence of PE was 36% (18 of 50 patients).the combination of echocardiographic criteria of right ventricular dilation and tricuspid regurgitation velocity of >2.7 m/s yielded a sensitivity of 67% and specificity of 94% when compared with the gold standard. Another prospective study of patients examined in the emergency department was recently reported by Jackson et al. 21 TTE was performed on all patients with suspected PE, with a combination of noninvasive testing considered diagnostic. They reported a sensitivity of only

4 924 Leibowitz September 2001 Table 2 Prospective studies of transthoracic echocardiography as a diagnostic tool in acute peripheral pulmonary thromboembolism Positive Negative No. of Source of Diagnostic predictive predictive Author patients patients gold standard Sensitivity Specificity value value Nazeyrollas et al 70 CCU Pulmonary angiography 93% 81% 78% 93% Perrier et al 50 ED Noninvasive testing 67% 94% 86% 83% Jackson et al 124 ED Pulmonary angiography or noninvasive testing 41% 91% NS NS Grifoni et al 117 ED Pulmonary angiography or noninvasive testing 51% 87% 82% 60% Steiner et al 35 NS Helical CT 59% 77% 81% 37% NS, Not stated; CT, computed tomography; CCU, coronary care unit; ED, emergency department. 41% and concluded accordingly that TTE was not a sensitive test for the diagnosis of acute PE. Grifoni et al 22 studied 117 consecutive patients with suspected PE in the emergency department. Sixty-three of these patients had a diagnosis of PE confirmed by either lung scan or angiography. Echocardiography had a sensitivity of 51%, with a relatively high specificity of 87%. 22 A study by Steiner et al 23 prospectively examined 35 consecutive patients with clinically suspected PE with TTE, TEE, and helical CT. Twenty-two (63%) of this patient sample had PE documented on helical CT that was defined as the diagnostic gold standard. The sensitivity and specificity of the combination of both echocardiographic studies (relying on both direct and indirect signs of PE) were relatively low,at 59% and 77%,respectively.When including only patients with central PE (50% of the total sample), the sensitivity and specificity rose to 82% and 92%,respectively.The relatively low sensitivity in these studies indicates that echocardiography cannot reliably exclude the diagnosis of PE. Limitations of these studies include the small sample sizes and use of noninvasive testing as the gold standard instead of pulmonary angiography. McConnell et al 24 described a regional pattern of right ventricular dysfunction in patients with PE with akinesia of the right ventricular free wall but normal motion at the right ventricular apex. This finding was in contrast to patients with right ventricular dysfunction secondary to other causes in which wall motion was abnormal in all segments. In their validation cohort that included 13 patients with PE and 72 patients with right ventricular dysfunction from any cause, this finding had a sensitivity of 77% and 94% specificity, with a positive predictive value of 71% and negative predictive value of 96%. The authors postulated several potential mechanisms for this finding including tethering of the right ventricular apex to a hyperdynamic left ventricle or localized ischemia of the free wall caused by increased wall stress. ECHOCARDIOGRAPHY IN THE ASSESSMENT OF PROGNOSIS OF PATIENTS WITH PE Several studies have examined the prognostic role of TTE in patients with PE. In a short-term study, Grifoni et al 25 studied 209 consecutive patients with acute PE diagnosed by lung scan, CT, or pulmonary angiography by TTE within 1 hour of admission. Patients who were normotensive were divided into 2 groups, based on the presence or absence of right ventricular dysfunction.the group of patients with right ventricular dysfunction (31% of the total cohort) had a 10% rate of PE-related shock, with a 5% mortality rate in the hospital. PE-related death was 0 in the normal right ventricular function group.the negative predictive value of echocardiography for PE-related death was 100%; however, the positive predictive value was low (5%), leading to the authors conclusion that echocardiography was most effective as a screening test for the identification of low-risk patients. 25 Ribeiro et al 26 studied 126 patients with PE by TTE on the day of diagnosis. The study noted a significantly higher mortality rate in the group with moderately or severely reduced right ventricular function (7% versus 21%,P =.04).Seventy-eight members of this study population underwent repeated follow-up TTE during the first year after diagnosis. 27 More than 90% of patients had stabilization of pulmonary pressures and right ventricular function within 30 days after diagnosis. Multiple logistic regression analysis of variables associated with persistent pulmonary hypertension/right ventricular dysfunction showed an odds ratio of 3.3 for patients with pulmonary artery systolic pressure >50 mm Hg at the time of diagnosis. The authors concluded that early echocardiography may predict long-term outcome in patients with PE. Kasper et al 28 prospectively studied 317 patients with clinically suspected PE with TTE, of whom 87 (27%) had evidence of right ventricular afterload stress. One-year mortality rate from PE was 13% in this group versus 1.3% in the group without right

5 Volume 14 Number 9 Leibowitz 925 ventricular afterload stress. A major limitation of this study was the absence of confirmation of the diagnosis of PE in a significant number of patients. Wolfe et al 29 examined the relation between right ventricular hypokinesis assessed by echocardiography and the degree of perfusion scan defects in 90 patients with PE. The degree of perfusion defect was greater in the patients with right ventricular dysfunction (54% versus 30%, P <.001). Interestingly, all of the patients with recurrent PE were in the group with right ventricular dysfunction at baseline (13% versus 0%, P <.01), suggesting a strong association between echocardiographic demonstration of right ventricular dysfunction and the risk of recurrent PE. Ribeiro et al 30 demonstrated a correlation between echocardiographically determined right ventricular dysfunction and perfusion defects but noted wide variability in both groups, with large confidence intervals. Miller et al 31 failed to show a correlation between right ventricular dysfunction and perfusion defects in a group of 64 patients with acute PE.The mixed results of these studies suggest that the extent of perfusion defects cannot accurately predict the presence of RV dysfunction. The prevalence of a patent foramen ovale (PFO) detected by contrast echocardiography is increased in patients with PE.In a study of 40 patients with PE diagnosed primarily with high-probability nuclear scans, Miller et al 32 noted an association between the presence of a PFO and extent of perfusion abnormalities. The study was not powered to assess the effect of PFO on prognosis. Konstantinides et al 33 prospectively examined 139 patients with a diagnosis of PE based on defined clinical criteria and findings on echocardiography of right-sided pressure overload and/or pulmonary hypertension. All patients underwent contrast echocardiography, and PFO was diagnosed in 35%. Patients with a PFO had a 33% mortality rate as opposed to a 14% mortality rate in patients with a negative contrast study.a PFO was an independent predictor of death on logistic regression analysis. Because the diagnosis of PE required evidence of pulmonary hypertension, this was a high-risk population, as evidenced by the overall mortality rate of 21%, and as such may not reflect the general population of patients with PE. ECHOCARDIOGRAPHY AND THROMBOLYTIC THERAPY FOR PE Thrombolytic therapy has emerged as a therapeutic option not only in patients with shock but in hemodynamically stable PE as well. Several small studies have studied the effect of thrombolytic therapy on right ventricular function as assessed by TTE. Come et al 34 serially examined 7 patients by TTE before and after (mean 9 hours) therapy with tissue-type plasminogen activator for pulmonary embolism and noted significant decreases in pulmonary artery systolic pressure, right ventricular diameter, and systolic septal flattening after lytic therapy. Metz et al 35 used an automated boundary detection system to examine changes in right ventricular function within 1 hour after thrombolysis in patients with PE.In accordance with the findings of Come et al, decreases in right ventricular diastolic diameter and area and increased right ventricular fractional area change was noted post thrombolysis. Nass et al, 36 in a retrospective study of 18 patients with acute PE and right ventricular dysfunction who received thrombolytic therapy, noted normalization of right ventricular function in most patients after therapy. Follow-up studies were performed at varying intervals, but normalization was reported as early as 3 days after therapy in this series.these small studies support the concept that thrombolytic therapy in acute PE results in prompt improvement in right ventricular function and reduction of pulmonary pressures and that TTE can be used to assess the response to thrombolytic therapy in patients with acute PE. CONCLUSION In summary, in patients with central or massive pulmonary emboli, echocardiography may directly visualize the embolus or, more commonly, provide evidence of its hemodynamic sequelae with reasonable sensitivity. In the majority of patients with clinically suspected PE, the limited sensitivity of echocardiography restricts its role as a primary diagnostic tool. Limitations of the published studies include selected populations, varying diagnostic gold standards, and small numbers of patients. Echocardiography appears to be useful in the assessment of prognosis of patients with PE, particularly in the identification of a low-risk population, and in the hemodynamic response to thrombolytic therapy if used. Further studies incorporating echocardiography as part of a diagnostic algorithm in large, unselected populations of patients with suspected PE are necessary to further delineate the role of echocardiography in this common, frustrating diagnostic dilemma. REFERENCES 1. Hansson PO, Welin L, Tibblin G, Eriksson H. Deep vein thrombosis and pulmonary embolism in the general population: the Study of Men Born in Arch Intern Med 1997; 157:

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