Dr. Kabrhel will discuss the unlabeled use of 200 mg bolus of tPA in patients with unstable pulmonary embolism.

In this Cyberounds^®, we will discuss the diagnosis and treatment of acute pulmonary embolism (PE) in the emergency department. Acute PE represents the most dangerous end of the spectrum of venous thromboembolic disease, which also includes deep venous thrombosis. We will discuss the epidemiology and risk factors for PE and how they can be used to determine pretest probability. We will discuss modern testing, specifically the use of the plasma D-dimer and computed tomography. Finally, we will discuss treatment, with a focus on the use of low-molecular weight heparin and thrombolysis.

PE is both an important public health problem and a frequent diagnostic dilemma for emergency physicians. It is estimated that there are between 500,000 and 600,000 cases of acute PE and that PE causes an estimated 50,000 to 200,000 deaths in the United States every year.(1) PE represents about 1/400 of the 110 million emergency department visits each year.(2),(3)

The mortality of acute PE is extremely high. As many as 25% of patients with acute PE present with sudden death.(4) The mortality rate of acute PE has been estimated to be as high as 30%, though more recent studies have suggested that 5% may be a more accurate figure.(5) This makes PE the third most common cause of cardiovascular death in the United States, behind only myocardial infarction and stroke.

Moreover, in the past 20 years, the percentage of emergency department patients evaluated for PE who are ultimately diagnosed with PE has decreased markedly.(6),(7) Unfortunately, this is not because the incidence of PE has decreased but because testing has increased. Emergency physicians who rightly maintain a high index of suspicion for PE will typically test 10-20 patients for every PE they diagnose.(7)

Risk Assessment

The first step in the evaluation of possible PE is the assessment of the patient's risk for the diagnosis. In the late 19th century, Rudolph Virchow described the triad of venous stasis, hypercoagulability and endothelial injury as the major risk factors for the development of thromboembolic disease. Today, many factors have been independently associated with the development of acute PE, though they can still be thought of in terms of Virchow's three categories:

Of these, the most significant risk factors are: increasing age, a history of prior "idiopathic" PE or deep vein thrombosis, active malignancy, recent surgery (especially orthopedic surgery) and extremity trauma.(4) The inherited risk factor that confers the greatest risk is Factor V Leiden, which increases a patient's lifetime risk of venous thromboembolism by 7-50 times.(8) Protein C and Protein S deficiencies triple the lifetime risk of venous thromboembolism, for a risk of about 2-3% per year.(8) Long-haul travel increases the risk of PE but only by a small amount.(9),(10)

Diagnosis: Pretest Probability

Once the clinician has decided that a patient should be evaluated for possible PE, the next step is to determine the pretest probability of the diagnosis. Accurate pretest probability assessment is critical when deciding which diagnostic tests to use. For example, clinicians may want to measure the serum D-dimer, a breakdown product of cross-linked fibrin released into the bloodstream in the presence of acute thrombus. Or, clinicians may want to order a contrast enhanced CT scan of the pulmonary arteries. These tests are reasonably sensitive but may not be appropriate as stand-alone tests for patients with high pretest probability for PE. This topic will be discussed in more detail later. Finally, clinicians will also combine their pretest probability assessment with the results of these diagnostic tests in order to determine the post-test probability of PE. This Bayesian approach requires clinicians to have an accurate sense of the patient's pretest probability of PE and the test's characteristics (sensitivity and specificity).

Pretest probability can be estimated subjectively simply by considering the patient's symptoms and risk factors, then assigning a percentage estimate to the likelihood of the diagnosis.(11) This subjective approach has been shown to have similar accuracy as more standardized approaches described below,(11),(12) though experience does seem to improve subjective estimates omewhat.(13)

Clinicians who prefer a standardized approach can use one of a number of clinical scores to determine pretest probability. The most widely referenced score was developed by Wells et al. and is commonly referred to as the "Canadian Score" or the "Wells Score."(14) The score is comprised of seven questions:

The Wells score has been prospectively validated in several studies.(12),(15) A score of <2 is associated with a pretest probability of PE of about 4%. A score of <4 is associated with a pretest probability of PE of about 5-8%. A score of >6 is associated with a pretest probability of PE of about 33-60%. Generally speaking, patients with Wells score <4 are eligible to have PE ruled out with D-dimer testing alone, though this depends greatly on the D-dimer assay used.

Another helpful decision was developed by Kline et al. and is commonly referred to as the "Charlotte Rule."(16) The purpose of this rule is to determine which patients are eligible for D-dimer testing. It is designed primarily to identify patients whose pretest probability of PE is sufficiently high (greater than 40%) that a negative result with even the most sensitive D-dimer assay would not reduce the patient's post-test probability to below 2%.

The rule is outlined below:

Several other rules have been published. Some incorporate the results of arterial blood gas testing and are less commonly used in the United States, while others await external validation.(17),(18),(19)

Diagnostic Assays

The test characteristics (i.e., sensitivity and specificity) of D-dimer assays vary greatly depending on the assay. It is crucial that clinicians know which assay is used in their hospital laboratory prior to making clinical decisions based on the results.

Studies have shown that the ELISA has the highest sensitivity (about 96-100%) of any of the D-dimer tests.(20) Unfortunately, the specificity is relatively low at 45%, so many patients without PE will have positive ELISA D-dimer results and require radiological imaging. Initially, ELISA assays required batch processing, which usually required 1-2 days and made them impractical for emergency department use. However, rapid ELISA assays are now available which can return results in less than 2 hours. These tests can be reliably and safely used to rule out PE in patients with low or intermediate pretest probability(20),(21) (e.g., a Wells score <6 or a Charlotte rule "safe"). Unfortunately, a large proportion of patients will have positive results, even in the absence of PE, and will require further radiological testing.(7)

Assays such as erythrocyte agglutination assays are only moderately sensitive, though offer better specificity.(20),(22) These tests should only be used in patients with low pretest probability, such as a Wells score <2. Tests with low sensitivity, like traditional latex agglutination assays, are insufficiently sensitive to rule out PE even in patients with low pretest probability.(20),(22) These tests are not helpful in the diagnostic evaluation of PE.

The sensitivity and specificity of various assays are listed below.

Perhaps the most significant limitation of D-dimer testing is poor specificity. A large proportion of patients tested will have positive D-dimer results in the absence of PE. These patients all require further testing. A number of factors degrade the specificity of D-dimer assays even further - particularly advancing age and the presence of malignancy. Nearly 90% of patients 80 years or older will have a positive D-dimer.(23) The same is true for patients with active malignancy.(24) Other factors known to elevate the D-dimer are recent surgery, trauma, infection, pregnancy and autoimmune disease. Unfortunately, these are the same factors that predispose patients to PE, so radiological testing is frequently necessary.

Diagnostic Imaging

Computed tomography pulmonary angiography (CTPA) has effectively supplanted other modalities as the first imaging test for suspected PE. CTPA is generally performed by injecting IV contrast during a single breath hold and imaging with 1.25-3.0 mm collimation through the entire lung. Runoff venography can be added to image the large veins of the legs and pelvis.

Original technical studies of CTPA were very promising, though subsequent clinical studies demonstrated only moderate sensitivity and specificity. CTPA is readily available and frequently demonstrates alternative diagnoses (e.g., pneumonia) that might not be seen on V/Q scanning or pulmonary angiography.(25)

Single slice scanners were subsequently found to have sensitivity of only about 85% for large central PE and only 70% overall.(26) Multi-slice scanners have shown promise by decreasing scan time and improving resolution. However, the recently published PIOPED II study found that even multi-slice scanners have limited sensitivity of 83%.(27)

While studies have shown that using CTPA is safe,(28) CTPA should be used, as with ventilation/perfusion (V/Q) scanning, in conjunction with pretest probability assessment.(27) Concordant results (i.e., low pretest probability and a negative scan OR high pretest probability and a positive scan) can be considered diagnostic. However, patients with discordant results (i.e., high pretest probability and a negative scan OR vice versa) should be referred for confirmatory testing. To rule out PE, confirmatory testing may include a negative D-dimer, negative lower extremity venous ultrasound, normal or low probability V/Q scanning or negative pulmonary angiography. To diagnose PE, confirmatory testing may include positive lower extremity venous ultrasound, high probability V/Q scanning or positive pulmonary angiography.

Treatment Strategies

Patients diagnosed with PE require emergent treatment that is both supportive and directed. With adequate treatment and anticoagulation, the mortality of PE drops from as high as 25% to 5-10%.(5) Acute PE causes an increase in dead space ventilation, the release of inflammatory mediators, ventilation/perfusion mismatch, increased pulmonary artery pressure and may result in acute right heart failure. It is therefore important to augment both oxygenation and pre-load (with IV fluids) in patients with acute PE.

For decades, the standard treatment for acute PE has been anticoagulation with unfractionated (intravenous) heparin. Dosing should be based on the patient's weight: typically with a loading dose of 80 U/kg followed by an 18 U/kg/hour infusion. The infusion should be titrated to a goal partial thromboplastin time (PTT) of 60-80 seconds.

More recently, low-molecular-weight (fractionated) heparin has been shown to be a safe and effective alternative to unfractionated heparin. A well done meta-analysis and a Cochrane review suggested a lower rate of recurrent thromboembolism and major bleeding associated with low-molecular-weight heparin compared to unfractionated heparin.(29),(30) For patients with active malignancy and PE, low-molecular-weight heparin has been shown to decrease the frequency of recurrent thromboembolism and is preferred over unfractionated heparin.(31)

The dosing of low-molecular-weight heparin depends on the drug used. Examples of typical dosing regimens include: enoxaparin (1 mg/kg subcutaneously, twice daily), dalteparin (200 U/kg subcutaneously, once daily, or 125 U/kg subcutaneously, twice daily). Low-molecular-weight heparin has the advantage of a reliable dose-response and does not require PTT monitoring. However, low-molecular-weight heparin is renally cleared and should not be used in patients with renal failure.

For patients with documented reactions to heparin products, such as severe heparin induced thrombocytopenia (HIT), alternative anticoagulants exist. These include synthetic heparin analogues (e.g., fondaparinux) and direct thrombin inhibitors (e.g., hirudin, bivalirudin, argatroban). Fondaparinux is typically dosed at 7.5 mg subcutaneously, once daily, for patients with body weight between 50 kg-100 kg, 5 mg for patients with body weight <50 kg, and 10 mg for patients with body weight >100 kg. It has been shown to be an effective treatment of thromboembolism in multiple studies.(32),(33) Hirudin is a genetically engineered leech venom derivative that inhibits thrombin formation. It is dosed as a 0.4 mg/kg bolus, followed by 0.15 mg/kg/hr infusion to achieve a PTT of 1.5-2.5 times the control.

For patients with very large PE, or limited hemodynamic reserve, anticoagulation and supportive care may not be sufficient. Currently, thrombolysis is only indicated for patients with PE and hemodynamic instability.(34),(35) There are some data that suggest improved outcomes in hemodynamically stable patients with PE and right heart failure documented on echocardiogram, though support for this approach is incomplete.(36)

There are two approved thrombolytics for acute PE -- streptokinase and tissue plasminogen activator (tPA). Dosing of streptokinase is 250,000 IU bolus over 30 minutes followed by 100,000 IU/hour over 24 hours. The recommended dose of tPA for thrombolysis of a pulmonary embolism is 100 mg intravenously over 2 hours. Naturally, the treatment of unstable patients with a 2-24 hour dosing regimen may be impractical. In these cases, tPA may be given as a single 200 mg bolus, though this off-label dosing regimen is not FDA-approved.

Summary

PE is a common and potentially fatal disease that affects several hundred thousand Americans every year. The diagnosis of PE is complex and involves a combination of pretest probability assessment and diagnostic testing. Subjective and objective methods for pretest probability assessment are available. The most commonly used diagnostic tests for PE include D-dimer blood assays and CT scanning of the pulmonary arteries, though each modality has limitations. Once PE is diagnosed, acute treatment usually consists of anticoagulation with heparin, with recent studies supporting the use of low-molecular-weight heparin. Thrombolysis is effective for treating PE, but it has only been shown to clearly benefit hemodynamically unstable patients.