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Optimal Strategy for Diagnosis and Treatment of Pulmonary Embolism Due to Right Atrial Thrombus

1988; Elsevier BV; Volume: 63; Issue: 12 Linguagem: Inglês

10.1016/s0025-6196(12)65416-0

1942-5546

Samuel Z. Goldhaber,

Blood properties and coagulation

Pulmonary embolism (PE) due to right atrial (RA) thrombus is gaining increasing recognition as a common clinical problem. In fact, the diagnosis of RA thrombus often is a surprise to the clinician who obtains an echocardiogram to evaluate breathlessness attributed to left-sided heart failure.1Goldhaber SZ Nagel JS Théard M Levine JD Sutton MGStJ Treatment of right atrial thrombus with urokinase.Am Heart J. 1988; 115: 894-897Abstract Full Text PDF PubMed Scopus (42) Google Scholar Quite often, no predisposition for RA thrombus (for example, an indwelling central line) is apparent. For patients with dyspnea of unknown cause, no apology is needed when an echocardiogram is requested. Imaging and Doppler echocardiographic findings can either confirm the presence of left-sided heart dysfunction or suggest pulmonary arterial disease attributable to acute pulmonary hypertension (most often due to acute PE), chronic pulmonary hypertension, or primary pulmonary hypertension.2Come PC Echocardiographic recognition of pulmonary arterial disease and determination of its cause.Am J Med. 1988; 84: 384-394Abstract Full Text PDF PubMed Scopus (35) Google Scholar Thus, the diagnosis of PE can be strongly suggested by echocardiographic findings, even in the absence of RA thrombus. Because PE is justifiably known as the "great masquerader," the echocardiographer is in a strategic position to alert the clinician to the possibility of PE. Although not pathognomonic, the major echocardiographic findings in acute PE have been elucidated by Come2Come PC Echocardiographic recognition of pulmonary arterial disease and determination of its cause.Am J Med. 1988; 84: 384-394Abstract Full Text PDF PubMed Scopus (35) Google Scholar and include a dilated, hypokinetic right ventricle, systolic septal flattening, and tricuspid regurgitation. Often the patient has an increased flow velocity within the tricuspid regurgitant jet that is compatible with mild to moderate elevation of pulmonary arterial systolic pressure. When no prior PE has occurred, right ventricular hypertrophy is absent. Unless left-sided heart disease coexists, the left ventricle will appear compressed but structurally normal. More widespread use of echocardiography will lead inevitably to more frequent establishment of the diagnosis of PE. The initial clinical manifestations of a large PE almost always include dyspnea; however, the absence of pleuritic chest pain may obscure the diagnosis of PE. My colleagues and I have observed that an anatomically smaller, more peripheral PE tends to be associated with pleuritic chest pain, whereas an anatomically large PE is more often associated with syncope or presyncope. Therefore, the differential diagnosis of dyspnea and presyncope should include PE (as well as arrhythmia). If an echocardiogram in a dyspneic patient suggests PE, the diagnosis should then be confirmed with a lung scan or pulmonary angiogram. Once the diagnosis of RA thrombus (often with concomitant PE) has been established, what strategy constitutes optimal management? Among patients without contraindications to thrombolytic therapy, a reasonable approach is to use a lytic agent in an attempt to dissolve the thrombus in situ. (The fear of lysing a RA thrombus just enough to cause embolization to the right ventricle and pulmonary arteries has not been substantiated.) If lytic therapy is used, it should then be followed by heparin anticoagulation and warfarin. Another approach that can result in a good clinical outcome is standard heparin and warfarin therapy, without thrombolysis.3Mancuso L Marchì S Mizio G Iacona MA Celona G Echocardiographic detection of right-sided cardiac thrombi in pulmonary embolism.Chest. 1987; 92: 23-26Crossref PubMed Scopus (26) Google Scholar Although my colleagues and I manage RA thrombus with lytic therapy whenever contraindications to thrombolysis are not prohibitive, our approach is based solely on clinical intuition. We strongly believe that a controlled clinical trial should be undertaken to determine which approach (that is, thrombolysis or heparin alone) is more effective and safer.1Goldhaber SZ Nagel JS Théard M Levine JD Sutton MGStJ Treatment of right atrial thrombus with urokinase.Am Heart J. 1988; 115: 894-897Abstract Full Text PDF PubMed Scopus (42) Google Scholar Currently, two lytic drugs have been approved by the Food and Drug Administration (FDA) for thrombolysis of PE: (1) streptokinase in a dose of 250,000 U (bolus), followed by 100,000 U/h for 24 hours, or (2) urokinase in a dose of 2,000 U/lb (bolus), followed by 2,000 U/lb per hour for 12 to 24 hours. Both drugs are approved for peripheral intravenous administration, not local administration through a superior vena caval, RA, or pulmonary arterial catheter. A third drug, recombinant human tissue-type plasminogen activator (rt-PA), seems promising in the treatment of PE, but it has not yet been approved by the FDA for this condition. In a dosing regimen of 100 mg as a continuous peripheral intravenous infusion for a period of 2 hours, rt-PA lysed PE more rapidly and more safely than a 24-hour infusion of peripheral intravenously administered urokinase.4Goldhaber SZ Kessler CM Heit J Markis J Sharma GVRK Dawley D Nagel JS Meyerovitz M Kim D Vaughan DE Parker JA Tumeh SS Drum D Loscalzo J Reagan K Selwyn AP Anderson J Braunwald E Randomised controlled trial of recombinant tissue plasminogen activator versus urokinase in the treatment of acute pulmonary embolism.Lancet. 1988; 2: 293-298Abstract PubMed Scopus (304) Google Scholar This recently completed randomized controlled clinical trial of 45 patients resulted from a multicentered cooperative effort at six institutions. The Mayo Clinic, under the leadership of John A. Heit, M.D., has been a key contributor to this collaborative undertaking. Our multicentered PE Research Group is now testing peripheral intravenous administration of rt-PA in comparison with a novel dosing regimen of peripheral intravenous administration of urokinase (3,000,000 U/2 h, with the first 1,000,000 U as a bolus) that is similar to a urokinase dosing regimen used successfully to lyse coronary arterial thrombi in patients with acute myocardial infarction.5Neuhaus K-L Tebbe U Gottwik M Weber MAJ Feuerer W Niederer W Haerer W Praetorius F Grosser K-D Huhmann W Hoepp H-W Alber G Sheikhzadeh A Schneider B Intravenous recombinant tissue plasminogen activator (rt-PA) and urokinase in acute myocardial infarction: results of the German Activator Urokinase Study (GAUS).J Am Coll Cardiol. 1988; 12: 581-587Abstract Full Text PDF PubMed Scopus (157) Google Scholar In the myocardial infarction trial, conducted in West Germany, 3,000,000 U of peripheral intravenously administered urokinase was as efficacious and safe as 70 mg of peripheral intravenously administered rt-PA. A common denominator in all the aforementioned thrombolysis trials is that the lytic agent was administered through a peripheral vein. One investigative group tested directly the strategy of intrapulmonary versus peripheral intravenous administration of rt-PA for PE.6Verstraete M Miller GAH Bounameaux H Charbonnier B Colle JP Lecorf G Marbet GA Mombaerts P Olsson CG Intravenous and intrapulmonary recombinant tissue-type plasminogen activator in the treatment of acute massive pulmonary embolism.Circulation. 1988; 77: 353-360Crossref PubMed Scopus (353) Google Scholar In a randomized trial of 34 patients with PE, recruited from eight centers in five European countries, intrapulmonary administration of rt-PA offered neither improved efficacy nor improved safety in comparison with peripheral intravenous administration of rt-PA. Thus, on the basis of available evidence, it seems that peripheral intravenous thrombolysis should be used in preference to local thrombolysis. Even among patients who require a pulmonary arterial catheterization for pulmonary angiography, my colleagues and I advocate infusion of the lytic agent through a peripheral vein. After pulmonary angiography, a pulmonary arterial catheter should remain in place only if needed for serial measurements of pulmonary artery capillary wedge pressure in the presence of coexisting left-sided heart disease. In our PE clinical trials, we leave the pulmonary arterial catheter in place for 2 hours to facilitate a follow-up, research pulmonary angiogram at 2 hours to assess the early dissolution of pulmonary arterial thrombus. Even in this research setting, however, we always administer the lytic agent through a peripheral vein. Among patients with RA thrombus, a central line might unintentionally dislodge clot and result in its embolization. Patients with a patent foramen ovale or atrial septal defect might then suffer an embolic stroke, in lieu of or in addition to PE. Furthermore, if one wished to establish a subclavian or internal jugular venous line specifically for local administration of a thrombolytic agent, a failed venipuncture attempt could result in substantial internal hemorrhage when the lytic agent is eventually infused. In our experience, peripheral intravenous administration of urokinase can be effective in lysing RA thrombus (Fig. 1) and in restoring pulmonary perfusion impaired by PE due to RA thrombus (Fig. 2).Fig. 2Lung scans of same patient as depicted in Figure 1. A, Initial scan demonstrates multiple segmental perfusion defects (arrows) involving right middle lobe (right lateral view), base of right lower lobe (right posterior oblique view), anterobasal left lower lobe (left posterior oblique view), and lingula (left lateral view). The ventilation images were normal, an indication that the perfusion defects are "mismatched," consistent with a high probability of pulmonary emboli. B, Follow-up perfusion lung scan demonstrates substantial improvement in pulmonary perfusion, consistent with resolving pulmonary emboli.(From Goldhaber and associates.1Goldhaber SZ Nagel JS Théard M Levine JD Sutton MGStJ Treatment of right atrial thrombus with urokinase.Am Heart J. 1988; 115: 894-897Abstract Full Text PDF PubMed Scopus (42) Google Scholar By permission of The C. V. Mosby Company.)View Large Image Figure ViewerDownload (PPT) In the case series reported by Proano and associates in this issue of the Proceedings (pages 1181 to 1185), RA thrombus was successfully lysed in three patients who received central (local) thrombolytic infusions of streptokinase. The three patients had PE (diagnosed angiographically in two and clinically in one) that was caused by the RA thrombus. At the time of initial examination, each of the three patients had dyspnea and two of the three had presyncope, indicative of an anatomically large PE. Two of the three patients received the FDA-approved 250,000-U bolus of streptokinase before a continuous intravenous infusion of 100,000 U/h for 24 to 48 hours. As the authors state, it is highly likely that similar improvement would have occurred with peripheral intravenous administration of streptokinase. On the basis of available evidence, thrombolysis should be administered through a peripheral vein, not centrally. For patients with dyspnea, echocardiography should be used when the cause of the breathlessness cannot be established by less expensive diagnostic modalities (for example, sputum Gram stain in combination with chest roentgenography). If echocardiography suggests PE or demonstrates RA thrombus, ventilation-perfusion lung scanning or pulmonary angiography should be performed. In the treatment of patients with RA thrombus, peripheral intravenous lytic therapy is an attractive and useful strategy. In the management of these patients, however, a controlled clinical trial should be undertaken to compare the efficacy and safety of thrombolysis versus heparin alone. In the management of PE (with or without concomitant RA thrombus), a megatrial is needed to determine whether thrombolysis, by reversing right-sided heart failure in patients with PE, can also reduce the mortality rate in comparison with standard heparin anticoagulation.