Managing patients with suspected pulmonary embolism
Two thirds of patients with PE die within an hour of symptom onset. This article reviews how to diagnose PE and treat the patient within this golden hour—the best way to avoid a fatality.
Andrea M. Forgione, MHS, PA-C
The author works in a cardiology practice in New Haven, Conn. She has indicated no relationships to disclose relating to the content of this article.
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 Detecting and accurately diagnosing a suspected pulmonary embolism (PE) has been the focus of considerable research over the past few decades.1 The diagnosis of PE poses one of the greatest clinical dilemmas to health care practitioners.2 If undetected, a PE can be fatal.1-4 An overwhelming majority of PE deaths result from failure to diagnose rather than from treatment failure.5 The major reasons for this are that the clinical signs and symptoms of PE—such as the classic trio of dyspnea, chest pain, and hemoptysis—are not specific to the condition and that the presentation is variable. Clinical prediction models and a variety of tests are now available to aid in diagnosis, but their combined efficacy has been hard to establish.3
Epidemiology
The incidence of PE in the general population and the associated morbidity and mortality risks have been difficult to determine.6 There are more than 650,000 known cases of PE per year and 50,000 to 200,000 fatalities annually, making PE the third leading cause of death in the United States.6-8 Additionally, estimates are that more than 400,000 PE diagnoses are missed in the United States annually.8 Two thirds of patients die within 1 hour of symptom onset; this first hour is known as the golden hour.7 If PE is diagnosed and treated within this first hour, the mortality rate drops to 3% to 8%.6
The overall mortality from PE in the United States has decreased from 1979 to 1998.9 When the patient does not present early for evaluation and treatment, the mortality rate in the first 3 months after diagnosis is more than 15%.10 In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study in 1990, 10% of patients in whom PE was missed had a recurrence during 3 months of follow-up.11 Unfortunately, most studies have shown that fewer than one third of patients who die from PE receive a correct diagnosis before death. The objective of one postmortem study was to determine if clinical signs and symptoms are accurate indications in diagnosing PE. The researchers discovered that only 45% of patients received a correct diagnosis—possibly because only 55% of the patients had the textbook symptoms of dyspnea, chest pain, and hemoptysis.12
 Etiology, pathophysiology, and risk factors
Thrombophleblitis, deep vein thrombosis (DVT), and PE can be collectively categorized as disease caused by venous thromboembolism (VTE).13 PE itself can be divided into massive PE, in which a patient can present with hemodynamic instability and shock, or submassive PE, which is characterized by its sudden onset with normal systemic pressure.14 Etiology Most pulmonary emboli arise from a thrombus located in the calf, iliac, deep femoral, or popliteal vein, although a few PEs originate from upper extremity sources.6 Rudolf Virchow was the first to identify the pathophysiology of PE. The triad of hypercoagulability, venous stasis, and endothelial injury, described as Virchow’s triad, is still used today to explain the development of a thrombus.6,15 Postmortem studies have revealed that 60% to 90% of PEs originate from DVT.16 As a thrombus breaks free, it travels to the heart and obstructs branches of the pulmonary arterial tree.17 Large clots may remain lodged in the central pulmonary artery as saddle emboli, while small emboli may travel to peripheral subsegmental arteries.1 The clinical signs, symptoms, and outcome depend on
the size of the emboli and any underlying cardiopulmonary disease.7,18
Risk factors Risk factors for VTE may be inherited or acquired;6 all have their basis in one or more components of Virchow’s triad1,8,15 (see Table 1). Reversible risk factors for PE include obesity, smoking, and hypertension.10 PIOPED identified the most common risk factors as immobilization, stroke, history of VTE, recent surgery, and malignancy.11 An absence of risk factors does not exclude the diagnosis of PE, as many patients have no identifiable risk factors.1
Clinical presentation and differential diagnosis
The range of the differential diagnosis for PE is extensive8 (see Table 2). The combination of dyspnea, chest pain, and hemoptysis is neither sensitive nor specific for a diagnosis of PE, as other diseases and conditions may manifest similarly.6,8,19 Table 3 lists signs and symptoms associated with PE, with the most common symptom being sudden-onset dyspnea.1 The International Cooperative Pulmonary Embolism Registry (ICOPER) found that hemoptysis occurred in only 7% of patients with diagnosed PE.20
Clinical signs may raise suspicion of PE and guide a practitioner toward further workup, although their absence cannot exclude the diagnosis.2 A 2001 study demonstrated that in 67 patients who died of PE, the condition was suspected clinically in only 44.8% before death. Of note is that PE was suspected less often in patients with preexisting chronic obstructive pulmonary disease (COPD) or coronary artery disease, perhaps because these patients do not present with the characteristic symptoms of PE.12 Although DVT predisposes a patient to developing PE, edema and calf tenderness, which are not always present when a patient has DVT, are unreliable diagnostic aids.1
Clinical pretest probability
Clinical scoring systems help clinicians to determine the pretest probability (PTP) of PE and to decide what further diagnostic testing is necessary.1,5 The PIOPED study used no standardized clinical scoring system, and the ensuing criticism encouraged the development of clinical prediction criteria.21 Now such prediction rules can be applied in the inpatient, outpatient, or emergency department (ED) setting.3 One of the most popular scoring systems uses the Wells’ criteria for PTP of PE6,22 (see Table 4).
The Wells’ criteria score is based on data derived from inpatient and outpatient populations. Points are assigned to each positive response to any of six clinical variables. The remaining criterion is a subjective statement of whether the clinician believes that an alternative diagnosis is less likely than PE. This single subjective component is the main reason that the Wells’ score has been criticized.1,6,21 Based on the total number of points, patients are classified as being at a low, moderate, or high risk for having a PE.5 Results from ventilation-perfusion (V/Q) scanning, pulmonary angiography, or spiral CT are then interpreted in light of the PTP score.4
D-Dimer
The main cross-linked component of a thrombus, known as fibrin, is broken down by plasmin causing the fibrin to lyse, producing the primary degradation product known as the D-dimer.1,2,4,8,10,23,24 In the diagnosis of PE,
D-dimer has the greatest predictive value for patients with low PTP scores. However, D-dimer values are not relevant only to PE and may be elevated in pregnancy, trauma, surgery, or malignancy.1,2,5,6,8,16,24 Also, several different assays are available, each varying in sensitivity and specificity. The enzyme-linked immunosorbent assay (ELISA) and whole blood assays are the most widely used.3 Recommendations by the 2003 American College of Emergency Physicians (ACEP) Clinical Policy Committee suggest that a negative quantitative D-dimer (turbidimetric or ELISA) value in conjunction with a low PTP score or a negative whole blood D-dimer value paired with a Wells’ score of 2 or less can safely be used to exclude PE.25 Even so, there is no consensus on the use of D-dimer values in the evaluation of a patient with suspected PE.2,5
 V/Q lung scanning
In nuclear scintigraphic V/Q lung scanning, the patient inhales a radiopharmaceutical agent that makes it possible to identify areas of ventilation, and a radioisotope is injected to determine perfusion. If areas lacking adequate perfusion are identified during the scan, it is likely that there is an obstruction caused by a PE.6
PIOPED, which compared the value of the V/Q scan to that of pulmonary angiography, determined that the diagnosis or exclusion of PE by V/Q scan combined with clinical assessment could be made for only a minority of patients. Therefore, a vast majority of patients will require further diagnostic procedures after V/Q scanning.7 The algorithm shows the application of each of the available diagnostic modalities.5 Pulmonary angiography is not preferred for patients unable to tolerate contrast because of allergies, for pregnant women, or for those with a history of PE previously diagnosed by V/Q scan.10
Evaluation of extremities
Confirming or excluding DVT in the extremities is of critical significance in the diagnosis of PE, especially when a patient has a high PTP score.26 When used before other modalities, Doppler ultrasonography (US) indicates proximal DVT in approximately 10% of patients with suspected PE.27 About half of patients with confirmed PE have asymptomatic lower extremity thrombosis, showing no warmth, tenderness, or swelling. Therefore, much research has been devoted to the value of utilizing US of lower extremities to confirm or exclude DVT, especially in patients with nondiagnostic V/Q scans.1 Even if there is no evidence of PE when lower-extremity Doppler imaging is positive for a DVT, meaning that the veins do not become occluded with pressure from the instrument, this in itself justifies immediate anticoagulation.26 In 2003, a 21-year trend analysis revealed a decline in the use of V/Q scans between 1986 and 1999, coinciding with the use of US of the lower extremities.28
Pulmonary angiography and spiral CT
Pulmonary angiography has long been considered the gold standard in the diagnosis of PE. However, this procedure is costly and invasive, performance and accurate interpretation of the test require trained personnel, and the test is associated with many complications, such as bleeding and contrast intolerance.1,5,6,15 Alternative approaches are quickly becoming mainstream.7,27
Although the PIOPED study recommended using pulmonary angiography for definitive diagnosis,11 spiral CT, which can provide alternative diagnoses, is being used more and more29 (see Figure 1). This shift is crucial because in the past, PE could not be confirmed in two thirds of patients suspected to have it.1 Newer, third-generation multidetector spiral CT scanners are able to provide 1-mm resolution with shorter imaging times1,10 and can be used instead of V/Q scanning, as recommended by ACEP.25 Unfortunately, smaller institutions may not have these third-generation scanners.30
As these scanners have become more widely available and more frequently used, PE has been diagnosed more quickly.28 Unlike V/Q scans or angiograms, CT scans can be interpreted quickly, even during off hours. Older, single-slice helical CT scanners produce false-negative rates nearly 30% of the time.31 However, the newer-generation scanners are beginning to have a higher negative predictive value to rule out PE. Numerous studies have proven that spiral CT scans have excellent positive predictive value as well.28 Thus, anticoagulation can be safely withheld from a patient with no evidence of PE on a spiral CT scan of good diagnostic quality.31
Research into the ultimate value of spiral CT for diagnosing PE is ongoing and extensive. Recruitment began in 2001 for subjects for the long-awaited PIOPED II investigation. As the original PIOPED focused on determining the usefulness of the V/Q scan, the main objective of PIOPED II is to determine the overall diagnostic efficacy of spiral CT in patients suspected of having PE. Experts hope that the results of this investigation will eliminate the need for pulmonary angiography.32
Other tests
 ECG, chest radiographs, and arterial blood gas (ABG) analysis have limited value in diagnosing PE because they are nonspecific.1,6 It was once proposed that most patients with PE had the classic S1Q3T3 finding on ECG,1,15 but other signs indicative of right ventricular strain are more common, such as T-wave inversion in leads V1 through V4 or new right bundle branch block.33 A retrospective review of patients with PE diagnosed in the ED did not find ECG features that could help to confirm or exclude thromboembolic disease.34
Chest radiography is useful for ruling out diseases such as pneumonia, pneumothorax, and congestive heart failure.1,6 Signs such as Hampton’s hump and Westermark’s sign, which historically have existed on radiographs in patients with PE, have proven to be rare.8
Similarly, a normal PaO2 value on ABG analysis does not rule out PE, and a PaO2 value is more likely to be abnormal in patients presenting with massive PE, not acute PE.1,15 A retrospective study of PIOPED proved that in patients with PE diagnosed via pulmonary angiography, 35% of those with no prior COPD and 14% of those with prior COPD had normal ABG values.35
Transthoracic echocardiography (TTE) and transesophageal echocardiography may be useful in characterizing the extent of heart remodeling or in diagnosing entities such as valvular insufficiency.1,29,33,36 Direct visualization of emboli is rare, but TTE may be utilized by the bedside in the ED to guide and monitor treatment choices.14,18
Treatment
The chance of a PE’s recurring is greatest immediately following its onset. Therefore, aside from basic resuscitation, rapid anticoagulation is the preferred treatment in patients with VTE, provided that active bleeding and hypersensitivity to the drugs used for treatment are absent and the patient is stable.1,33 The accepted treatment of PE is unfractionated IV heparin using a weight-based nomogram. Howver, the use of a low molecular weight heparin, such as enoxaparin, has proven to be just as effective and may be associated with greater length of effect and reduced likelihood of thrombocytopenia, but the effects are more difficult to reverse.1,7 The goal is to achieve an activated partial thromboplastin time of 60 to 80 seconds.33 Oral anticoagulation with warfarin, begun at the same time as heparin, is strongly suggested. Continue to administer heparin and warfarin concurrently for at least 5 days; a therapeutic international normalized ratio must be achieved for at least 2 days.1 Based on current evidence, a 6-month course of oral anticoagulation in patients with PE due to trauma or surgery is recommended; therapy should go on indefinitely if the cause of PE is unknown.
Thrombolytics, such as recombinant tissue plasminogen activator, should be used only in hemodynamically unstable patients with massive PE since data are lacking on their long-term morbidity and mortality.1,7,8,33 Researchers who conducted a meta-analysis of 748 patients in 2004 concluded that there is currently no substantial evidence regarding the benefit of thrombolytic therapy compared to heparin.37 Thrombolytics may produce a worse outcome because of side effects such as bleeding and hemorrhage. For a massive PE, catheter-based embolectomy, a surgical alternative treatment, may be considered in patients for whom anticoagulant therapy is contraindicated.
 Inferior vena cava filters, used to prevent the propagation of emboli from a DVT, can be used when anticoagulant therapy has failed or the patient will be unable to tolerate a repeat PE.1,7 The filters, however, do not stop the thrombotic process and may serve as a site for future DVT formation.33
Conclusion
Clinicians should consider PE in patients presenting with risk factors or a clinical presentation suggestive of DVT.1 Clinical suspicion, based on a thorough history and physical examination, can determine PTP, which will, in turn, guide the selection of the initial diagnostic procedure. The V/Q lung scan and spiral CT are first-line choices.5 Diagnostic strategy, however, should depend on the protocol at the practitioner’s institution and the available resources.3 Given the continually innovative developments regarding spiral CT, pulmonary angiography is becoming a notion of the past. Experts hope that with more research into standardized algorithms and further technological advances, the rate at which PE goes undiagnosed will be significantly reduced.1
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