Diagnosing Pulmonary Embolism: A Medical Masquerader
MAJ Jerald L. Wells, MPAS, PA-C, and CPT Steven W. Salyer, PhD,
[Clinician Reviews 11(2):66-79, 2001. © 2001 Clinicians Publishing Group]
IntroductionPulmonary embolism (PE), one of the great masqueraders in medicine, is notoriously difficult to diagnose. Even in serious cases, its manifestations are nonspecific, and the diagnosis is missed with disturbing frequency -- or made only at autopsy. Yet it typically occurs in patients with specific risk factors. A high index of suspicion and a detailed history and physical examination constitute the starting place for a sound evaluation. While no single diagnostic test short of pulmonary angiography gives definitive results in all patients with suspected PE, noninvasive tests such as ventilation-perfusion lung scanning and compression ultrasonography are reliable in many patients. The clinician who combines such test data with pretest probability of disease stands to lessen morbidity, reduce resource utilization, and save lives.
Pulmonary embolism (PE), a common and potentially lethal condition with varied and often subtle manifestations, has an estimated annual incidence of 600,000 and is believed to cause between 50,000 and 200,000 deaths each year. This range is wide because PE-related deaths are so often attributed to other causes, including myocardial infarction and old age. Known, reversible risk factors and effective prophylactic options make PE a preventable disease.
Patients with untreated PE face an extremely high risk of death. Overall mortality is generally estimated at 30% -- in part because the diagnosis has previously been missed in as many as two thirds of patients. Appropriate treatment, initiated promptly, can reduce mortality to between 2% and 8%. Among patients with relatively mild PE, the one-year mortality rate is reported at 5%.
Preparedness on several fronts is important. The primary care clinician should be aware of the risk factors for PE, familiar with its typical and atypical forms, prepared to assign pretest probability of PE, and well versed in what tests should be ordered, and in what sequence.
PathophysiologyEmbolism in the lungs is most common in the lower lobes, where multiple smaller emboli predominate. Unless PE is massive and catastrophic, death usually is due to recurrent multiple embolization of the lungs.
Origins and SourcesPE usually results from deep venous thrombosis (DVT) -- formation of thrombi in the deep veins of the lower extremities, primarily in the proximal veins of the iliofemoral system. While thrombi in the saphenous or deep veins of the calf often resolve spontaneously, these thrombi can propagate to the popliteal and femoral veins; from there, a clot can dislodge and embolize, then travel to a lung. Thrombi may also develop in the pelvic, renal, and upper extremity veins. The right cardiac chambers can be foci of thrombus formation in the patient with atrial fibrillation or flutter.
Thrombi formed in the deep venous system may propagate to the bifurcation of the main pulmonary artery, the lobar or segmental lung regions, or the subsegmental branches of the pulmonary circulation. Emboli in the major vessels (eg, saddle embolus in the main pulmonary artery) may cause rapid and extreme hemodynamic compromise. Patients with embolism involving more distal vessels may present with only mild or exertional dyspnea or mild pleuritic chest pain.
Pulmonary ResponsesPulmonary responses to PE vary greatly. In complete vascular obstruction, lung zones are ventilated but not perfused -- a state known as ventilation-perfusion mismatch. Distal alveolar hypocapnia may lead to pneumoconstriction. Within 24 hours of total occlusion, loss of pulmonary surfactant will result in atelectasis. Hyperventilation of lung zones will lead to pulmonary vasoconstriction. In the presence of vasoconstriction and hypoxia, pulmonary artery pressure increases, possibly leading to perfusion of inadequately ventilated lung zones. In patients with massive PEs that obstruct central vessels, acute right ventricular failure and myocardial ischemia may develop. Impaired cardiac output further contributes to an increasing alveolar-to-arterial oxygen gradient.
However, only about 10% of PE patients experience complete vascular obstruction and pulmonary infarction. Only patients with pulmonary infarction experience pleuritic chest pain (possibly from irritation of pain fibers in the parietal pleura); in most cases, PE does not cause pleuritic chest pain.
Clinical RecognitionIdentification of PE is based on a constellation of risk factors, historical and physical findings, and pretest probability of disease. A high degree of suspicion is appropriate when the clinician sees a patient with significant risk factors and suggestive signs and symptoms.
Risk FactorsThe risk factors for both PE and DVT (see Table 1[5-8]) are generally explained in terms of hypercoagulability, stasis of blood flow, and (less importantly), vascular injury. Hypercoagulability may result from deficiencies in protein C, protein S, or antithrombin III. Presence of the factor V Leiden mutation can also cause a hypercoagulable state, thus increasing the risk of PE or DVT.
PE may occur in patients who need anticoagulation therapy but who are not receiving it or are taking inadequate doses. (The effects of warfarin, it should also be noted, may be influenced by diet, certain other medications, and patient noncompliance -- all of which contribute to fluctuations in patients' prothrombin time and propensity to coagulate, even when warfarin is being taken in "therapeutic doses.")
In a year 2000 population-based study of 625 patients with PE or DVT over a 15-year period, independent risk factors for PE included hospital or nursing home confinement, surgery, trauma, malignant neoplasm, chemotherapy, neurologic disease with paresis, presence of a central venous catheter or a pacemaker, varicose veins, and superficial vein thrombosis. According to the investigators, venous thromboembolism is likely to recur, especially within the first six to 12 months -- but patients are at heightened risk of recurrences for at least 10 years. Other researchers have reported the recurrence rate of symptomatic DVT at 21.5%.
PresentationRecognizing PE in its varied clinical presentations is a considerable challenge. Although 65% to 90% of PEs arise from the lower extremities and a reported 50% of patients with proximal DVT have asymptomatic PE, fewer than 30% of patients with confirmed PE have signs or symptoms of DVT. In fact, physical findings are notoriously unreliable for confirming or excluding the diagnosis; they are merely suggestive (see Table 2). Even normal arterial blood gas values (including the alveolar-to-arterial oxygen gradient) do not rule out PE.
Much of our knowledge about PE's clinical presentation comes from the landmark Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED), published in 1990.[13,16] This multicenter study included almost 1,000 patients with possible PE, followed over 20 months. The most common presenting signs and symptoms in patients without preexisting cardiopulmonary disease were nonspecific: dyspnea (in 73% of patients with PE), tachypnea (70%), pleuritic chest pain (66%), rales (51%), cough (37%), tachycardia (30%), and hemoptysis (13%). On cardiac auscultation, an S4 was present in 24% and an accentuated P2 was noted in 21%.
While PE has no characteristic or pathognomonic presentation, several clinical syndromes suggest its presence (see Table 3, page 73).
Chronic progressive dyspnea without chest pain suggests recurrent pulmonary emboli. Recurrent emboli with unresolved clot burden in the proximal pulmonary arteries may lead to chronic exertional dyspnea with pulmonary hypertension. Circulatory collapse or syncope implies massive embolization of the proximal pulmonary arteries; when this occurs, the patient may develop hypotension, chest pain from myocardial ischemia, and rightventricular dilatation and failure from acute pulmonary hypertension.
Pretest ProbabilityLaboratory testing and imaging are expensive and, when used alone, have limited positive or negative predictive value - unless the patient's probability for PE has first been established. Pretest probability, based on the clinical assessment, is most reliable as a predictor when scores are extremely high or extremely low.
In the PIOPED study, 68% of patients in the high-pretest probability group subsequently received confirmed diagnoses of PE. But in patients with both a high pretest probability and a high-probability ventilation/perfusion (V/Q) scan, the diagnosis was confirmed in 96%. Similarly, a low pretest probability of PE combined with a low-probability V/Q scan correctly identified 96% of patients without PE. However, although the PIOPED scientists based their assessments on history, physical examination, arterial blood gas values, chest x-ray studies, and electrocardiographic data, criteria were not uniform and no standardized algorithm was used by all the participating institutions.
More recently, Wells and associates developed such an algorithm (see page 72). They tested this clinical model in a prospective cohort study of 1,239 patients with suspected PE; 78.4% of patients in the high- pretest probability group had confirmed PE, as did 27.8% of those in the moderate-probability group and 3.4% of patients in the low-probability group. During 90 days' follow-up, only 0.5% of patients with low or moderate pretest probability and a non-high-probability V/Q scan received a diagnosis of PE or DVT.
Laboratory TestingOnce pretest probability has been established, the clinician may select appropriate diagnostic tests for thromboembolic disease. Options include V/Q scanning, pulmonary angiography, compression ultrasonography, impedance plethysmography, D-dimer assay, and spiral (helical) computed tomography (CT). Other diagnostic measures currently under investigation include magnetic resonance imaging of DVT; transthoracic and transesophageal echocardiography (to diagnose "hemodynamically significant PE"); and determination of alveolar dead space, alveolar-arterial oxygen gradient, and the late pulmonary dead space fraction.
Ventilation/Perfusion ScanningThis is the most frequently used diagnostic test for PE. Patients with results that are not normal are stratified into very low, low, intermediate, or high probability of PE. Interpretation is based on the presence or absence of perfusion defects and associated ventilation defects (see Figure 1). Mismatches between areas of poor perfusion and poor ventilation are significant; the larger the mismatched perfusion defect, the higher the probability of PE. Figure 1. Multiple segmental or greater perfusion defects shown at the right apex, the right base anterior, and the right base posterior. (Courtesy, Michael W. Peterson, MD, and Virtual Hospital®)
A normal or nearly normal V/Q scan virtually excludes the diagnosis of PE. In the PIOPED study, a V/Q scan that is showing no more than three small, segmental perfusion defects (combined with normal chest x-ray findings) was assigned very low probability. Scans interpreted differently between investigators were classified as "nearly normal." PE was later confirmed by angiography in only 4% of PIOPED patients with normal or nearly normal V/Q scans.
By contrast, a high-probability scan is highly predictive of PE -- which was confirmed in 87% of PIOPED patients with high-probability scans (however, these scans had a sensitivity of just 42%). Intermediate-probability and low-probability scans are neither sufficiently sensitive nor specific to be of value; PE was present in 30% and 14%, respectively, of patients with these results. Thus, only normal and high-probability scans are considered reliable; these and nondiagnostic scans are reported.
When a facility does not offer V/Q scanning, patient transfer may be avoided if compression ultrasonography or bilateral ultrasonography results or results of D-dimer assay (by enzyme-linked immunosorbent assay [ELISA]) are negative for thromboembolic disease.
Pulmonary AngiographyGenerally accepted as the gold standard for accurate diagnosis of PE, pulmonary angiography is safe; in one recent five-year study, Wallis et al reported procedure-related mortality at 0.0% and morbidity at 0.4%. In patients who receive thrombolytic therapy or who have renal failure, the risk of complications may increase. An angiogram (see Figure2) can be diagnostic as long as two weeks after an acute embolic event; resolution of an embolism before then is unlikely. Figure 2. Pulmonary angiogram showing filling defects in the right lower lobe and no perfusion to the right middle lobe. (Courtesy, Michael W. Peterson, MD, and Virtual Hospital®)
Adjunctive techniques (cineangiography, digital subtraction angiography, superselective injection) may be useful "when there is an area of concern in small vessels," suggested a 1998 statement from the American College of Chest Physicians (ACCP) Consensus Committee on Pulmonary Embolism.
Because pulmonary angiography is highly invasive, expensive, and not available in all hospitals, other diagnostic choices are generally considered first.
Compression UltrasonographyA compression ultrasonogram that reveals lower-extremity DVT (see Figure 3) is considered indirect evidence of PE, and anticoagulant therapy should begin immediately. Figure 3. This color-flow Doppler ultrasound shows a vein with a noncompressible filling defect (arrow) consistent with deep-vein thrombosis. (Courtesy, Michael W. Peterson, MD, and Virtual Hospital®)
In this test, a thrombus in the proximal lower extremity is demonstrated by abnormal Doppler color flow in an incompressible vein. The test has a sensitivity of 89% and a specificity of 100% in symptomatic patients, but sensitivity drops to approximately 38% when signs and symptoms of DVT are absent. Accuracy is highly operator dependent, and plaster leg casts preclude use of the procedure.
Bilateral lower-extremity venous ultrasonography appears less reliable than compression ultrasonography. Daniel and colleagues recently found that in 156 patients with nondiagnostic V/Q scan findings and negative results on a bilateral leg ultrasonographic study, the diagnosis of PE could not be excluded.
Impedance PlethysmographyIn this noninvasive test for venous thrombi, a partially obstructing thigh cuff is inflated; impedance falls as blood pools in the lower extremities. The cuff is rapidly deflated, and the velocity of venous outflow is then measured.
Impedance plethysmography is highly sensitive and specific for DVT. Though less expensive (as a single test) than compression ultrasonography, however, it is also less specific. False-positive results are more common in patients with increased central vascular pressure (as in vascular disease or congestive heart failure) and in those receiving mechanical ventilatory support.
Because the legs must be kept bent and motionless for about two minutes, this procedure is uncomfortable for some patients.
D-Dimer AssayThe fibrin-specific product D-dimer has been extensively studied in the diagnosis of DVT and PE. Elevated levels, as measured by ELISA or by whole-blood assay, are detectable in nearly all patients with PE -- but elevations are not considered diagnostic for PE; rather, a low level may be used to exclude the diagnosis. In one analysis of 1,177 patients with suspected PE, a normal whole-blood D-dimer assay (<500 µg/L), combined with a low pretest probability, had a negative predictive value of 99%. This test, estimate Owings et al, could be substituted for more expensive, invasive testing in about one third of surgical patients with possible PE or DVT.
Researchers conducting a prospective management study involving 308 patients found that a combination of pretest probability, lung scanning, D-dimer ELISA, and compression ultrasonography (in that order) correctly confirmed or excluded the diagnosis of PE in 62% of patients in whom lung scanning was nondiagnostic. Angiography was required in the remaining 38%.
The D-dimer assay is highly sensitive but not specific; it may be positive in postoperative patients, and results can be misleading in patients with cancer. Although the ACCP Consensus Committee statement acknowledges the ELISA test's "high negative predictive value for PE," the authors do not recommend widespread use "until D-dimer testing is standardized and more widely validated in prospective outcome studies."
Specialized CT ScanningUsing contrast material injected into a peripheral vein, spiral (helical) or electron-beam CT scanning allows visualization of proximal and segmental emboli, as well as other relevant thoracic structures. Spiral CT has a sensitivity of 65% to 98% for PE, and a specificity greater than 90%; it has been shown to reliably exclude clinically important PE. Baile et al consider it comparable to pulmonary angiography in detecting subsegmental emboli. In one French trial, interobserver agreement favored spiral CT over V/Q scanning for initial diagnostic testing of suspected acute PE.
According to the ACCP Consensus Committee statement, spiral CT may be useful in diagnosing central PE when more established tests are not available; otherwise, further study is needed.
Among its drawbacks, spiral CT is expensive and calls for a large volume of contrast material, thus increasing the likelihood of allergic reaction. Spiral CT also requires patients to hold their breath for 15 to 25 seconds.
Other Ancillary StudiesChest x-ray studies, electrocardiography (ECG), and arterial blood gas values are generally required because of other entities in the differential diagnosis (see Table 4).
In the PIOPED study, 12% of patients with PE had normal chest x-ray findings; if proximal blood flow is obstructed, no pulmonary infiltrates will be seen, and signs of pulmonary infarction may be absent. Investigators for the International Cooperative Pulmonary Embolism Registry recently reported that the most common chest film abnormality in patients with acute PE was cardiomegaly -- which is not associated with increased acute PE-related mortality risk.
Among PIOPED patients with confirmed PE, atelectasis or parenchymal abnormalities were noted in 69%, compared with 58% of patients without PE. Significant hypoxemia with a normal or relatively normal chest x-ray film should raise the suspicion of PE. Other chest x-ray findings suggestive of PE include pulmonary artery enlargement, pleural effusion, and elevated hemidiaphragm.
An absence of ECG abnormalities has no significance; in 25% of patients with proven PE, ECGs are unchanged from baseline. The most common PE-related ECG abnormalities are tachycardia and nonspecific ST-T-wavechanges. Of other common ECG abnormalities that may suggest PE (eg, right-axis deviation, right bundle-branch block, supraventricular arrhythmias), none is sensitive or specific for PE.
In patients with suspected PE, a normal PaO2 (>80 mm Hg) cannot exclude the diagnosis; other conditions that can be mimicked by PE usually cause greater decreases in the PaO2. These include pneumonia, chronic obstructive pulmonary disease, and congestive heart failure.
Diagnostic StrategiesSeveral practical strategies have been proposed to help clinicians meet the challenge of diagnosing PE. Perhaps the most widely accepted diagnostic sequence begins with determining pretest probability andobtaining a V/Q scan. If both suggest low likelihood of PE, no further evaluation is considered necessary.[18,35]
Next, compression ultrasonography may be performed. If the result is positive for DVT, anticoagulant therapy is started, as if for PE. If the result is negative for DVT and the V/Q scan suggests low probability of PE, the evaluation ends; but if the V/Q scan is indeterminate, pulmonary angiography is ordered.
For certain patients, serial noninvasive leg studies over two weeks may be appropriate. In one study, therapy was withheld safely during these studies from 874 patients with suspected PE who had good cardiopulmonary reserve and non-high-probability V/Q scans. Hull et al showed that V/Q scanning combined with serial impedance plethysmography is cost-effective because it obviates pulmonary angiography in the greatest number of patients. However, the advisability of withholding therapy in patients with compromised cardiopulmonary reserve has not been determined.
ConclusionMortality associated with PE can be reduced significantly by timely diagnosis, leading to prompt treatment. History and physical examination findings are often nonspecific in patients with PE; V/Q lung scans are diagnostic only when results are normal or suggest a high probability of disease. Noninvasive studies such as compression ultrasonography may be helpful, limiting the need for pulmonary angiography -- which, though accurate and safe, is invasive and costly.
Table 1. Risk Factors for PE[5-8]
Cardiac disease (especially heart failure and related cardiac decompensatory
conditions; myocardial infarction)
Pelvic or lower-extremity fractures
High-dose estrogen use (eg, hormone replacement therapy, oral contraceptives)
Indwelling femoral catheter
Major surgery (especially involving the abdomen, spine, hip, or knee)
Poorly controlled anticoagulation therapy, atrial fibrillation, or
Pregnancy and the postpartum state
Prior thromboembolic disease
Prolonged air travel
Right central venous and right heart catheterization
Table 2. Physical Findings Suggestive of Pulmonary Embolism
Chest pain (especially pleuritic)
Pulmonary crackles and rales
Table 3. Syndromes that Suggest Pulmonary Embolism
Chronic progressive dyspnea
Progressive dyspnea with pulmonary hypertension
Pleuritic chest pain without preexisting cardiopulmonary disease
Table 4. Differential Diagnosis of Pulmonary Embolism
Asthma or chronic obstructive pulmonary disease
Cardiac disease (congestive heart failure, myocardial infarction)
Chest wall pain
Pericardial disease (pericarditis or tamponade)
Pulmonary edema or hypertension
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