+++
A. Symptoms and Signs
++
The clinical diagnosis of PE is notoriously difficult for two reasons. First, the clinical findings depend on both the size of the embolus and the patient’s preexisting cardiopulmonary status. Second, common symptoms and signs of pulmonary emboli are not specific to this disorder (Table 9–18).
++
++
Indeed, no single symptom or sign or combination of clinical findings is specific to PE. Some findings are fairly sensitive: dyspnea and pain on inspiration occur in 75–85% and 65–75% of patients, respectively. Tachypnea is the only sign reliably found in more than half of patients. A common clinical strategy is to use combinations of clinical findings to identify patients’ risk for PE. For example, 97% of patients in the original Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED I) study with angiographically proved pulmonary emboli had one or more of three findings: dyspnea, chest pain with breathing, or tachypnea. Wells and colleagues have published and validated a simple clinical decision rule that quantifies and dichotomizes this clinical risk assessment, allowing diversion of patients deemed unlikely to have PE to a simpler diagnostic algorithm (see Integrated Approach to Diagnosis of Pulmonary Embolism, below).
+++
B. Laboratory Findings
++
The ECG is abnormal in 70% of patients with PE. However, the most common abnormalities are sinus tachycardia and nonspecific ST and T wave changes, each seen in approximately 40% of patients. Five percent or less of patients in the PIOPED I study had P pulmonale, right ventricular hypertrophy, right axis deviation, and right bundle branch block.
++
ABGs usually reveal acute respiratory alkalosis due to hyperventilation. The arterial PO2 and the alveolar-arterial oxygen difference (A–a–DO2) are usually abnormal in patients with PE compared with healthy, age-matched controls. However, ABGs are not diagnostic: among patients who were evaluated in the PIOPED I study, neither the PO2 nor the A–a–DO2 differentiated between those with and those without pulmonary emboli. Profound hypoxia with a normal chest radiograph in the absence of preexisting lung disease is highly suspicious for PE.
++
Plasma levels of D-dimer, a degradation product of cross-linked fibrin, are elevated in the presence of thrombus. Its value is as a diagnostic tool to exclude PE. Using a D-dimer threshold between 300 and 500 ng/mL (300 and 500 mcg/L), a rapid quantitative enzyme-linked immunosorbent assay (ELISA) has shown a sensitivity for venous thromboembolism of 95–97% and a specificity of 45%. Therefore, a D-dimer less than 500 ng/mL (less than 500 mcg/L) using a rapid quantitative ELISA provides strong evidence against venous thromboembolism, with a likelihood ratio of 0.11–0.13. Due to much higher false-positive rates, D-dimer is not useful in the hospital setting.
++
Serum troponin I, troponin T, and plasma B-type natriuretic peptide (BNP) levels are typically higher in patients with PE compared with those without embolism; the presence and magnitude of the elevation are not useful in diagnosis, but correlate with adverse outcomes, including mechanical ventilation, prolonged hospitalization, and death.
+++
C. Imaging and Special Examinations
++
The chest radiograph is necessary to exclude other common lung diseases and to permit interpretation of the ventilation-perfusion (V̇/Q̇) scan, but it does not establish the diagnosis by itself. The chest radiograph was normal in only 12% of patients with confirmed PE in the PIOPED I study. The most frequent findings were atelectasis, parenchymal infiltrates, and pleural effusions. However, the prevalence of these findings was the same in hospitalized patients without PE. A prominent central pulmonary artery with local oligemia (Westermark sign) or pleural-based areas of increased opacity that represent intraparenchymal hemorrhage (Hampton hump) are uncommon (eFigure 9–21). Paradoxically, the chest radiograph may be most suggestive of PE when normal in the setting of hypoxemia.
++
+++
2. CT-pulmonary angiography (PA)
++
Helical CT-PA is used as the initial diagnostic study in North America for suspected PE (eFigure 9–22). CT-PA requires administration of intravenous radiocontrast dye but is otherwise noninvasive. A high-quality study is very sensitive for the detection of thrombus in the proximal pulmonary arteries. Comparing CT-PA to the V̇/Q̇ scan as the initial test for PE, detection of thrombi is roughly comparable, although more alternative pulmonary diagnoses are made with CT-PA scanning.
++
++
Test characteristics of CT-PA vary widely by study and facility. Factors influencing results include patient size and cooperation, the type and quality of the scanner, the imaging protocol, and the experience of the interpreting radiologist. The 2006 PIOPED II study, using multi-detector (four-row) helical CT and excluding the 6% of patients whose studies were “inconclusive,” reported sensitivity of 83% and specificity of 96%.
++
A 15–20% false-negative rate is high for a screening test and raises the practical question whether it is safe to withhold anticoagulation in patients with a negative CT-PA. Research data provide two complementary answers. The insight of PIOPED I, that the clinical assessment of pretest probability improves the performance of the V̇/Q̇ scan, was confirmed with CT-PA in PIOPED II, where positive and negative predictive values were highest in patients with concordant clinical assessments but poor with conflicting assessments. The negative predictive value of a normal CT-PA in patients with a high pretest probability was only 60%. Therefore, a normal CT-PA alone does not exclude PE in high-risk patients, and either empiric therapy or further testing is indicated.
++
A large, prospective trial, the Christopher Study, incorporated objective, validated pretest clinical assessment into diagnostic algorithms using D-dimer measurement. In this study, patients with a high pretest probability and a negative CT-PA who were not receiving anticoagulation had a low (less than 2%) 3-month incidence of subsequent PE. This low rate of complications supports the contention that many false-negative studies represent clinically insignificant, small distal thrombi and provides support for monitoring most patients with a high-quality negative CT-PA off therapy (see Integrated Approach to Diagnosis of Pulmonary Embolism below). The rate of false-positive CT-PA and overtreatment of PE has not been as well studied to date.
+++
3. Ventilation-perfusion lung scanning
++
A perfusion scan is performed by injecting radiolabeled microaggregated albumin into the venous system, allowing the particles to embolize to the pulmonary capillary bed. To perform a ventilation scan, the patient breathes a radioactive gas or aerosol while the distribution of radioactivity in the lungs is recorded. A defect on perfusion scanning represents diminished blood flow to that region of the lung. This finding is not specific for PE. Defects in the perfusion scan are interpreted in conjunction with the ventilation scan to give a high, low, or intermediate (indeterminate) probability that PE is the cause of the abnormalities. Criteria for the combined interpretation of ventilation and perfusion scans (commonly referred to as a single test, the V̇/Q̇ scan) are complex, confusing, and not completely standardized. A normal perfusion scan excludes the diagnosis of clinically significant PE (negative predictive value of 91% in the PIOPED I study). A high-probability V̇/Q̇ scan is most often defined as having two or more segmental perfusion defects in the presence of normal ventilation and is sufficient to make the diagnosis of PE in most instances (positive predictive value of 88% among PIOPED I patients). V̇/Q̇ scans are most helpful when they are either normal (eFigure 9–23) (eFigure 9–24) or indicate a high probability of PE. Such readings are reliable—interobserver agreement is best for normal and high-probability scans—and they carry predictive power. The likelihood ratios associated with normal and high-probability scans are 0.10 and 18, respectively, indicating significant and frequently conclusive changes from pretest to posttest probability.
++
++
++
However, 75% of PIOPED I V̇/Q̇ scans were nondiagnostic, ie, of low or intermediate probability. At angiography, these patients had an overall incidence of PE of 14% and 30%, respectively.
++
One of the most important findings of PIOPED I was that the clinical assessment of pretest probability could be used to aid the interpretation of the V̇/Q̇ scan. For patients with low-probability V̇/Q̇ scans and a low (20% or less) clinical pretest probability of PE, the diagnosis was confirmed in only 4%. Such patients may reasonably be observed off therapy without angiography. All other patients with nondiagnostic V̇/Q̇ scans require further testing to determine the presence of venous thromboembolism.
+++
4. Venous thrombosis studies
++
Seventy percent of patients with PE will have DVT on evaluation, and approximately half of patients with DVT will have PE on angiography. Since the history and physical examination are neither sensitive nor specific for PE and since the results of V̇/Q̇ scanning are frequently equivocal, documentation of DVT in a patient with suspected PE establishes the need for treatment and may preclude further testing.
++
Commonly available diagnostic techniques include venous ultrasonography, impedance plethysmography, and contrast venography. In most centers, venous ultrasonography is the test of choice to detect proximal DVT. Inability to compress the common femoral or popliteal veins in symptomatic patients is diagnostic of first-episode DVT (positive predictive value of 97%); full compressibility of both sites excludes proximal DVT (negative predictive value of 98%). The test is less accurate in distal thrombi, recurrent thrombi, or in asymptomatic patients. Impedance plethysmography relies on changes in electrical impedance between patent and obstructed veins to determine the presence of thrombus. Accuracy is comparable though not quite as high as ultrasonography. Both ultrasonography and impedance plethysmography are useful in the serial examination of patients with high clinical suspicion of venous thromboembolism but negative leg studies. In patients with suspected first-episode DVT and a negative ultrasound or impedance plethysmography examination, multiple studies have confirmed the safety of withholding anticoagulation while conducting two sequential studies on days 1–3 and 7–10. Similarly, patients with nondiagnostic V̇/Q̇ scans and an initial negative venous ultrasound or impedance plethysmography examination may be monitored off therapy with serial leg studies over 2 weeks. When serial examinations are negative for proximal DVT, the risk of subsequent venous thromboembolism over the following 6 months is less than 2%.
++
Contrast venography remains the reference standard for the diagnosis of DVT (eFigure 9–25). An intraluminal filling defect is diagnostic of venous thrombosis. However, venography has significant shortcomings and has been replaced by venous ultrasound as the diagnostic procedure of choice. Venography may be useful in complex situations where there is discrepancy between clinical suspicion and noninvasive testing.
++
+++
5. Pulmonary angiography
++
Pulmonary angiography is the historical reference standard for the diagnosis of PE. An intraluminal filling defect in more than one projection establishes a definitive diagnosis. Secondary findings highly suggestive of PE include abrupt arterial cutoff, asymmetry of blood flow—especially segmental oligemia—or a prolonged arterial phase with slow filling. Pulmonary angiography was performed in 755 patients in the PIOPED I study. A definitive diagnosis was established in 97%; in 3% the studies were nondiagnostic. Four patients (0.8%) with negative angiograms subsequently had pulmonary thromboemboli at autopsy. Serial angiography has demonstrated minimal resolution of thrombus prior to day 7 following presentation. Thus, negative angiography within 7 days of presentation excludes the diagnosis.
++
Pulmonary angiography it is a safe but invasive procedure with well-defined morbidity and mortality data. Minor complications occur in approximately 5% of patients. Most are allergic contrast reactions, transient kidney injury, or percutaneous catheter–related injuries; cardiac perforation and arrhythmias are reported but rare. Among the PIOPED I patients who underwent angiography, there were five deaths (0.7%) directly related to the procedure.
++
Pulmonary angiography is indicated in any patient in whom the diagnosis is in doubt when there is a high clinical pretest probability of PE or when the diagnosis of PE must be established with certainty, as when anticoagulation is contraindicated or placement of an inferior vena cava filter is contemplated.
++
MRI has sensitivity and specificity equivalent to contrast venography in the diagnosis of DVT. It has improved sensitivity when compared with venous ultrasound in the diagnosis of DVT, without loss of specificity. The test is noninvasive and avoids the use of potentially nephrotoxic radiocontrast dye. However, artifacts introduced by respiratory and cardiac motion have limited the use of MRI in the diagnosis of PE. New techniques have improved sensitivity and specificity to levels comparable with helical CT, but MRI remains primarily a research tool for PE.