Pulmonary Embolism: New Diagnostic Tools and Treatment Paradigms

Venous thromboembolism is a spectrum of diseases that includes deep vein thrombosis and pulmonary embolism. It is a common source of morbidity and an avoidable cause of mortality that typically occurs in high-risk persons or in specific clinical situations. The diagnosis of deep vein thrombosis or pulmonary embolism can be challenging because of their nonspecific signs and symptoms. As a result, they are underdiagnosed and undertreated. Over the past decade, new diagnostic tools have been developed that obviate the need for invasive pulmonary angiography. Concurrently, new treatment paradigms have become available since the introduction of low-molecular-weight heparin for initial therapy. Long-term warfarin anticoagulation guidelines tailored to specific clinical situations have been developed by expert consensus.

Jeffrey Wuhl, MD,

Senior Resident, Internal Medicine; Mark G. Graham, MD, FACP, Clinical Assistant Professor of Medicine, Associate Director, Division of Internal Medicine and Primary Care, Department of Medicine, Jefferson Medical College, Philadelphia, Pa

Pulmonary embolism is part of the spectrum of diseases that, along with deep vein thrombosis (DVT), falls under the umbrella of venous thromboembolism (VTE). Pulmonary embolism is a common clinical entity, affecting approximately 1 in 1000 Americans each year. It is estimated that as many as 600,000 episodes of pulmonary embolism occur annually in the United States, resulting in 100,000 to 200,000 deaths.¹ With the exception of cases presenting with hemodynamic compromise, recurrent pulmonary embolism and death are uncommon after the diagnosis is made and effective therapy is started. Most deaths can be attributed to missed diagnosis rather than to inadequate treatment.² The clinical presentation is quite variable, and signs and symptoms are neither sensitive nor specific. Autopsy series show that the vast majority of pulmonary emboli arise from the lower extremities, yet less than 30% of patients have antecedent leg symptoms.³ Accordingly, much has been written about how to best diagnose this potentially fatal yet very treatable condition. This article addresses current concepts in diagnosis, risk stratification, and management.

Pathophysiology

Pulmonary emboli most often arise from thrombi that originate in the deep venous system of the lower extremities. Dislodged thrombi travel through the right heart and become wedged in the pulmonary arterial circulation. The size of the thrombus determines the clinical picture. Large thromboemboli obstruct the pulmonary artery bifurcation or the left or right main pulmonary artery, causing massive pulmonary embolism and circulatory collapse. Smaller emboli wedge in distal pulmonary arteries and cause less hemodynamic compromise but more pleuritic chest pain and, occasionally, pulmonary infarction. Ineffective gas exchange occurs at the arteriolar-alveolar level, leading to hypoxemia. Most pulmonary emboli are multiple.

Risk Factors for VTE

The 1990 landmark study Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) identified the most common risk factors for pulmonary embolism as immobilization, surgery within the past 3 months, stroke, history of VTE, and malignancy.⁴ The Nurses' Health Study noted 3 additional risk factors for VTE?obesity, cigarette smoking, and hypertension.⁵ Other risk factors include extended travel, lower-extremity trauma, increasing age, hormone replacement therapy, pregnancy, recent delivery, oral contraceptive use, status post-joint replacement, pelvic fracture, and lower-extremity fracture (Table 1).

Patients with VTE but with no apparent risk factors may have one of the genetic or acquired causes of thrombophilia, namely, antithrombin III deficiency, protein C or protein S deficiency, prothrombin G20210A mutation, factor V Leiden, anticardiolipin syndrome, or lupus anticoagulant. Evaluation for these conditions should be limited to patients with recurrent VTE or a strong family history of VTE.

Signs and Symptoms of Acute Embolism

The PIOPED investigators illustrated the limitations of relying on signs and symptoms to diagnose pulmonary embolism. The most common symptoms and signs included dyspnea (73%), tachypnea (70%), pleuritic pain (66%), rales (51%), cough (37%), tachycardia (30%), fourth heart sound (24%), increased pulmonic component of second heart sound (23%), fever less than 102?F (14%), and hemoptysis (13%).⁴ However, these events occurred with similar frequency in the PIOPED patients who did not have pulmonary embolism. Therefore, a definitive diagnosis cannot be made on the basis of clinical findings alone. The clinical suspicion must be confirmed by one or more of the following tests.

Diagnosis: Basic Tests

Thorough history and physical examination are key to the clinician's assessment of the pretest probability of pulmonary embolism. Several scoring systems are available for estimating risk level for VTE. Table 2 summarizes one such clinical prediction system. Although these prediction rules are not in and of themselves sufficient, they are necessary to formulate a clinical gestalt about the likelihood of the presence of pulmonary embolism. This information can then be used as a powerful component of the diagnostic algorithm (Figure 1).

Imaging tests are the most useful tools for diagnosing pulmonary embolism, but, with the exception of chest radiography, they are rarely the first to be performed. The chest radiograph, electrocardiogram (ECG), arterial blood gas measurements, general serum chemistries, and evaluation of complete blood cell count, D-dimer, troponin, and brain-type natriuretic peptide (BNP) levels are typically performed before the more sophisticated imaging techniques.

Though useful clues can be gathered from these tests, poor specificity and sensitivity limit their role as stand-alone diagnostic tools. However, collectively they can add to or detract from the clinical suspicion of pulmonary embolism, and in some instances can provide information about the severity of the condition.

A mild leukocytosis and elevated erythrocyte sedimentation rate are commonly found by whole blood evaluation. Serum chemistries may show elevated aspartate aminotransferase and lactate dehydrogenase levels.

A normal ECG is unusual in pulmonary embolism. Sinus tachycardia and ST-segment and T-wave changes are the most commonly noted findings. With massive pulmonary embolism, ECG evidence of acute cor pulmonale (eg, S1Q3T3 pattern, right bundle-branch block, P pulmonale, or right-axis deviation) are common. A normal chest radiograph is also unusual, occurring in only 16% of patients in PIOPED.⁴ Findings include areas of focal oligemia, atelectasis, and cardiomegaly. Small pulmonary emboli wedged in the distal portions of the pulmonary arterial tree can produce pulmonary infarction, evidenced radiographically as a small peripheral infiltrate. The most useful role of chest radiography is in its ability to provide an alternative diagnosis, such as pneumonia, congestive heart failure, or malignancy.

Arterial blood gases typically demonstrate hypoxia, an increased alveolar-arterial oxygen gradient, and respiratory alkalosis. Metabolic acidosis occurs in massive pulmonary embolism with circulatory collapse. It is important to remember that a normal PO2 does not rule out a pulmonary embolism, particularly in young, otherwise healthy persons. The alveolar-arterial gradient is more universally abnormal in patients proven to have a pulmonary embolism.

Troponin concentration is elevated in nearly half the patients with a large pulmonary embolism, probably because of massive right ventricular (RV) overload. Although not useful in diagnosis, an elevated troponin level may have some prognostic value (see risk stratification below).

Brain-type natriuretic peptide is also elevated in patients with a large pulmonary embolism, presumably as a result of RV dysfunction. Its role as a prognostic indicator is currently under study.

D-dimer bears special mention, since it is an indicator of fibrin degradation, a process that is hyperactive in VTE states. On the surface, it may appear to be a useful tool for diagnosing VTE. However, it is important to recognize that D-dimer is also elevated in many clinical situations unrelated to VTE, such as inflammatory states, postsurgery, trauma, cancer, or pregnancy. Thus, D-dimer is too nonspecific to be relied upon to diagnose pulmonary embolism, but it is a useful test for excluding VTE. The absence of D-dimer has a strong negative predictive value in patients suspected of VTE.

The absence of D-dimer has been shown to have negative likelihood ratios similar to those of normal ventilation/perfusion (V/Q) scans and negative deep vein Doppler ultrasound examination.⁶ Evidence suggests that pulmonary embolism can be safely ruled out if D-dimer is negative in a patient with a low or moderate pretest clinical probability.⁶ However, these conclusions are specifically dependent on the use of the ELISA D-dimer assay, not the whole blood agglutinin test that is commonly used. If negative, the latter test is useful in ruling out pulmonary embolism in patients with low pretest probability, according to the 2003 British Thoracic Society guidelines.⁷

Definitive Imaging Studies

Pulmonary angiography

Pulmonary angiography remains the definitive test to diagnose or rule out pulmonary embolism. It requires right-heart catheterization and 4 injections of iodinated contrast. Although its sensitivity and specificity approach 100%, the technique is cumbersome and expensive and has been associated with a 5% morbidity and 0.5% mortality rate.⁸ Pulmonary angiography is reserved for cases in which suspicion is high but less-invasive testing is either unavailable or inconclusive.

Ventilation/perfusion scans

Ventilation/perfusion scanning has been a mainstay of the diagnostic algorithm for pulmonary embolism for years. The PIOPED study showed that a high-probability scan was 97% specific for pulmonary embolism and had a predictive value of 95% in patients with high clinical probability.⁴ Normal V/Q scans were sufficient to rule out the diagnosis, regardless of pretest probability.⁴ However, it is troubling that almost three quarters of V/Q scans demonstrate either intermediate or low probability of pulmonary embolism; these studies are neither sensitive nor specific and thus have limited use in diagnosing or ruling out pulmonary embolism. Furthermore, there is a 14% false-positive rate among high-probability V/Q scans.⁴ Such lack of certainty can only be cleared up after additional imaging with helical computed tomography (CT) scanning or pulmonary angiography.

Unlike the ventilation portion of the V/Qscan, the perfusion portion (Figure 2) is easy to perform and requires very little patient cooperation. Note that a normal perfusion lung scan alone virtually excludes the diagnosis of pulmonary embolism.

CTPA

Computed tomographic pulmonary angiography (CTPA), or helical CT scanning, (Figure 3) is becoming a widely used modality for diagnosing pulmonary embolism and is considered a first-line modality by some clinicians. A positive test is fairly specific (81%- 97%) but not very sensitive (53%-60%).⁹ In contrast, a prospective study reported only a trivial (<2%) incidence of pulmonary embolism in a 3-month followup period among patients who had a negative CTPA for pulmonary embolism in the presence of established DVT.¹⁰ CTPA allows the direct visualization of pulmonary emboli, and, like chest radiography, has the added benefit of suggesting alternative diagnoses. Whereas a positive result on CTPAis a clear indication for initiating anticoagulation, regardless of pretest probability, a negative result on its own is often insufficient to exclude pulmonary embolism in moderate-or high-risk patients. In these cases, perform lower-extremity evaluation for proximal DVT.

Other studies

Magnetic resonance pulmonary angiography has minimal value in the diagnosis of pulmonary embolism. Sensitivity is very high in the large lobar and segmental vessels but is less than 50% in the smaller subsegmental vessels.¹¹ Motion artifact, limited availability, and high cost further limit its usefulness.

Lower-extremity evaluation for DVT is useful when clinical suspicion for pulmonary embolism is high and V/Q scan results are equivocal (eg, 1:48). It is now well known that compression ultrasound with Doppler color flow has a more than 90% sensitivity for proximal DVT. Impedance plethysmography (IPG) is also highly sensitive and less costly. In the high-risk setting, a positive IPG or Doppler study is tantamount to the diagnosis of pulmonary embolism, whereas negative results provide a rational basis to withhold anticoagulation. There is only a 3% false-positive rate for the detection of DVT in patients suspected of pulmonary embolism, but the false-negative rate approaches 30%.¹² Thus, a single negative IPG or Doppler study is insufficient to rule out DVT.

Risk Stratification

BNP/troponin

The most significant marker of poor prognosis in pulmonary embolism is RV dysfunction, which, if progresses to RV failure can result in hemodynamic instability, shock, or death. The pathophysiology of RV dysfunction is related to the abrupt increase in pulmonary vascular resistance that can occur with massive pulmonary embolism. The workload of the RV is acutely increased and results in RV dilatation, hypokinesis, increased RV wall tension and, in extreme instances, RV failure. Ultimately, RV failure can lead to left ventricular (LV) failure as a result of insufficient RV output and impaired diastolic filling of the LV secondary to alterations in RV structure as well as RV-LV interdependence.

Cardiac troponin and BNP have been studied as indicators of RV dysfunction in patients with known pulmonary embolism. Troponin elevation is thought to occur secondary to RV ischemia and "micro-infarction" resulting from the increased wall stress. Compression of the right coronary artery may also play a role. Cardiac troponin has a high negative predictive value (97%- 100%) for in-hospital death and thus may be useful for identifying low-risk patients. The positive predictive value of an elevated troponin level for adverse outcomes is not as good, with one study showing it to be 70% for a troponin T value of more than 0.1 ng/mL.¹³

Elevated BNP and pro-BNP levels may also be seen with RV dysfunction, as they reflect myocyte stretch from RV overload. Like cardiac troponin, BNP has a high negative predictive value for adverse outcomes in pulmonary embolism but a low positive predictive value (97% and 48%, respectively, in a study using a cutoff value of 50 pg/mL).¹⁴ Pro-BNP also falls in line with this trend, with negative and positive predictive values for adverse outcomes of 97% and 45%, respectively (cutoff value, 500 pg/mL).¹³

Echocardiography

Echocardiography is useful mainly as a tool for risk stratification in patients who are hemodynamically unstable. Rarely, a large, central pulmonary embolism can be visualized directly with echocardiography. However, the most common findings are related to RV dysfunction and include RV dilation and hypokinesis, septal flattening and paradoxical septal motion, tricuspid regurgitation, pulmonary hypertension, and patent foramen ovale. One study showed that the McConnell sign?normal contraction of the RV apex despite moderate- to-severe RV-free wall hypokinesis?was 94% specific for pulmonary embolism.¹⁵

The benefit of echocardiography is its ability to select patients with the poorest prognoses who may need more aggressive treatment, such as thrombolysis or embolectomy. One study showed that RV dysfunction was the most powerful predictor of in-hospital death among patients with pulmonary embolism.¹⁶ In the International Cooperative Pulmonary Embolism Registry, 90- day mortality was increased in patients with RV dysfunction on presentation.¹⁷ In a study by the European Society of Cardiology, echocardiography was used to stratify patients with pulmonary embolism into 3 prognostic groups: low-risk (no RV dysfunction; hospital mortality, <4%), submassive (RV dysfunction without hemodynamic instability; hospital mortality, 5%-10%), and massive (RV dysfunction with cardiogenic shock; hospital mortality, 30%).¹⁸

Treatment

Immediate anticoagulation with heparin is the initial treatment for patients with pulmonary embolism. If the suspicion is very high, heparin should be started even before the diagnosis is confirmed by imaging techniques. Once therapeutically anticoagulated with heparin, prolonged anticoagulation with warfarin sodium (Coumadin, Jantoven) is begun, and the heparin is discontinued once the patient is therapeutically anticoagulated with warfarin. The latter should be continued for at least 3 to 6 months, or longer in some circumstances. In patients with a contraindication to anticoagulation with heparin or warfarin (eg, gastrointestinal [GI] bleeding, intracranial hemorrhage, very recent surgery) the placement of an inferior vena cava filter (ie, umbrella or Greenfield filter) is recommended.

Initial anticoagulation with heparin

Traditionally, unfractionated heparin was the treatment of choice for pulmonary embolism. A 5000 to 10,000 U bolus was followed by a constant infusion starting at 1000 U/h, with a goal partial thromboplastin time (PTT) of 1.5 to 2.5 over baseline. Adjustments to the rate of infusion were made after monitoring PTT results at 4-to 6-hour intervals. Complications occurred because of unacceptable delays in achieving therapeutic anticoagulation (ie, recurrent VTE) and supratherapeutic anticoagulation (ie, bleeding).

In 1993, some of the delay to therapeutic goal was circumvented by using a weight-based unfractionated heparin. In a study of 115 patients with pulmonary embolism, 77% of those receiving traditional unfractionated heparin achieved the anticoagulation goal at 24 hours compared with 97% of those receiving weight-based heparin.¹⁹ VTE recurrences occurred in 25% of the traditional group and in only 5% of the weight-based group.

Low-molecular-weight heparin (LMWH) was developed in the 1990s and represents the next great advance in the treatment of VTE. It can be administered subcutaneously; has a long half-life, permitting once or twice daily dosing; requires no monitoring; and immediately anticoagulates patients to their therapeutic goal. A 2000 review demonstrated that LMWH was better than or equal to unfractionated heparin for treating VTE, caused less major bleeding and less thrombocytopenia than unfractionated heparin, and could safely and effectively be used in the outpatient setting.²⁰

The 2004 Seventh American College of Chest Physicians (ACCP) Conference on Antithrombotic and Thrombolytic Therapy further has shown that use of LMWH has therapeutic equivalency to unfractionated heparin in proximal DVT and VTE.²¹

Chronic anticoagulation with warfarin

Once initial anticoagulation with heparin is therapeutically established, chronic oral anticoagulation can begin with warfarin. The international normalized ratio (INR) goal is 2 to 3. When the INR is at goal, heparin therapy can be discontinued. The optimal duration of oral anticoagulation is controversial, but the 2004 ACCP consensus statement provides the following guidelines for long-term treatment²¹:

1. Patients with a first episode of pulmonary embolism caused by a reversible (time-limited) risk factor should receive at least 3 months of warfarin therapy.

2. Patients with a first episode of idiopathic pulmonary embolism should be treated with warfarin therapy for at least 6 to 12 months and be considered for indefinite anticoagulation therapy.

3. Patients with pulmonary embolism and cancer should be treated with LMWH for the first 3 to 6 months and then with warfarin therapy indefinitely, or until the cancer is resolved.

4. Patients with a first episode of pulmonary embolism who have antiphospholipid antibodies or 2 or more thrombophilic conditions (eg, combined factor V Leiden and prothrombin G20210A gene mutations) should be treated for 12 months; indefinite anticoagulation therapy is suggested.

5. Patients with a first episode of pulmonary embolism who have antithrombin deficiency, protein C or S deficiency, factor V Leiden or prothrombin G20210A gene mutation, homocystinemia, or high factor VIII levels should be treated for 6 to 12 months; indefinite anticoagulation therapy is suggested for patients with idiopathic pulmonary embolism.

6. Patients with 2 or more episodes of pulmonary embolism should be considered for indefinite treatment.

Thrombolytic therapy

Thrombolytic therapy is dangerous and should be reserved for hemodynamically unstable patients with massive pulmonary embolism, in whom it provides a more rapid resolution of the clot and restoration of hemodynamics. Some reports suggest improved outcomes in massive pulmonary embolism cases. Astudy of 256 pulmonary embolism patients with RV dysfunction showed a 15% mortality reduction with heparin plus alteplase (Activase) compared with heparin plus placebo.²² We limit our use of thrombolytic therapy to hemodynamically unstable patients without a major contraindication to thrombolytics (eg, active GI bleeding, intracranial hemorrhage, very recent surgery).

Pulmonary embolectomy

Unstable patients and those with severe RV dysfunction who have contraindications to thrombolysis may be candidates for surgical or catheter-based embolectomy. In a series of 29 patients who underwent surgical embolectomy from October 1999 through October 2001, 26 (89%) survived more than 1 month postoperatively.²³ The high success rate was attributed to improved surgical techniques, rapid diagnosis and triage, and selection of patients who had moderate-to-severe RV dysfunction but were not in circulatory shock.²³ Implementing early risk-stratification techniques may result in continued improvement on the historically poor survival rates after this procedure.

Conclusion

Pulmonary embolism remains a common and dangerous clinical entity. Though great strides have been made in recent years in diagnosis, risk stratification, and treatment, it remains underdiagnosed and inappropriately treated. In the medical community, there has been a lag in integrating the newly acquired knowledge into mainstream clinical pathways. This review underscores the need for astute clinicians practicing current concepts in the community.

SELF-ASSESSMENT TEST

1. All the following are risk factors for VTE, except:

• Osteoporosis
• Lower-extremity trauma

2. Which of these are the most common signs and symptoms of acute pulmonary embolism?

• Cough and tachycardia
• Rales and hemoptysis

3. Which finding is NOT common in patients with pulmonary embolism?

• Normal ECG
• Abnormal chest x-ray

4. Which of the following statements about risk stratification is true?

• Elevated BNP level is best for identifying low-risk patients
• ECG is best for identifying patients who may need more aggressive treatment

5. Which of these is NOT an appropriate treatment recommendation?

• Begin warfarin therapy while the patient is still being treated with heparin
• Use thrombolytic therapy for hemodynamically unstable patients with massive pulmonary embolism

(Answers at end of reference list)

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Answers:

1. B; 2. A; 3. B; 4. A; 5. C