Epidemiology

The annual incidence of diagnosed pulmonary embolism (PE) is approximately 1.5 new cases per 1000 persons and is relatively similar among western populations.¹ Dyspnea and chest discomfort are the most typical symptoms of PE, and these chief complaints are responsible for between 9 and 10 million annual patient visits to U.S. emergency departments (EDs).² Physicians evaluate large numbers of patients for PE because the symptoms can be vague and severity may range from asymptomatic to shock and subsequent cardiac arrest.³

The widespread availability of D-dimer and computed tomography (CT) testing for PE, as well as medical-legal concerns of missing the diagnosis, continues to result in dramatic increases in testing relative to the last decade. In some settings it is not uncommon for 1% to 3% of all adult ED patients to undergo some testing for PE. Physicians have become aware that patients without what was previously thought to be “classic” risk factors (hypercoagulability, trauma, and immobility) may still have PE. In addition, the aging demographics of the U.S. population will continue to drive the need to evaluate for PE in the ED because increased age is a strong independent risk factor for PE. To deal with these challenges, the practicing physician has three aims:

Pathophysiology

PE is part of the continuum of venous thromboembolism (VTE), which most often starts with deep vein thrombosis (DVT) in the leg. Patients with DVT often have concurrent PE when evaluated with imaging tests, and many patients with PE have concurrent DVT. Treatment is similar for both. Risk factors for VTE include the triad described by Virchow: injury, venous stasis, and hypercoagulability. These conditions are most commonly thought of as occurring at the level of the venous endothelium, but it is helpful to also think of them as occurring at the level of the patient. For instance, overall injury to the patient (trauma), stasis of the patient (immobility), and hypercoagulability of the patient (malignancy and known thrombophilic conditions) all result in elevated risk. Table 70.1 lists several risk factors for VTE. Understanding risk factors is critical to recognizing the potential for PE to exist.

Table 70.1 Risk Factors for Pulmonary Embolism

CVA, Cerebrovascular accident; DVT, deep vein thrombosis; MI, myocardial infarction; PE, pulmonary embolism; VTE, venous thromboembolism.

An embolus in the pulmonary vasculature may result in a large bilateral central clot with severe obstruction of flow (so-called saddle embolism), a medium clot in the lobar or segmental branches, or a small clot in the peripheral vasculature. Embolism involving the pulmonary vasculature activates the process of local inflammation and thereby leads to vasoconstriction and some degree of pulmonary hypertension with resultant symptoms of dyspnea and possibly chest pain.

Presenting Signs and Symptoms

Dyspnea and chest pain are the most common findings in patients with PE. Brief, resolved chest pain in the absence of any shortness of breath or any respiratory signs or symptoms is not a typical manifestation. Other symptoms that can be associated with PE include syncope, cough, flank pain, abdominal pain, and even fever (Box 70.1). The severity of symptoms in a given patient is a function of two factors: the baseline cardiopulmonary status of the patient and the size of the clot⁴ (Fig. 70.1). This is why large clots are occasionally tolerated fairly well in young patients with no cardiopulmonary disease whereas a much smaller clot burden may result in hypotension, hypoxemia, and deterioration in patients with preexisting cardiopulmonary disease. Older patients often have a worse clinical course and outcome with PE, largely as a consequence of having worse cardiopulmonary status at baseline rather than simply being elderly.

Fig. 70.1 The degree of severity of symptoms in a given patient is a function of two factors: (1) the baseline cardiopulmonary status of the patient and (2) the size of the clot. PE, pulmonary embolism; R, right.

(Adapted from Wood KE. Major pulmonary embolism: review of a pathophysiologic approach to the golden hour of hemodynamically significant pulmonary embolism. Chest 2002;121:877-905.)

Shock may be a primary sign of PE. Patients may not be able to provide a history of symptoms or risk factors for PE and may not be sufficiently stable to allow imaging outside the ED, yet consideration of empiric treatment of PE with anticoagulation may be warranted. A rapid bedside evaluation to search for clues to non-PE diagnoses can be done promptly and is described in Figure 70.2. A potential pitfall is to attribute shock to a primary cardiac etiology despite an electrocardiogram (ECG) with no significant ischemic changes and no significant dysrhythmia and a chest radiograph with no evidence of pulmonary vascular congestion or cardiomegaly. If patients can be stabilized, imaging with CT should be done. If not, emergency bedside echocardiography to look for signs of massive PE (right ventricular dilation and hypokinesis, septal shift to the left, tricuspid regurgitation) should be done as an alternative means of heightening certainty of the diagnosis of PE.

Fig. 70.2 Stepwise approach to undifferentiated shock with consideration of pulmonary embolism (PE) as a possible cause.

CXR, Chest x-ray; ECG, electrocardiogram; GI, gastrointestinal.

The other end of the spectrum is the diagnosis of PE in patients with relatively mild symptoms. Despite the fact that patients may have PE with normal oxygen saturation, no known risk factors, and no pulmonary symptoms, this combination is uncommon. Strict attention to details such as oxygen saturation after walking, physician-obtained respiratory rate, examination of the legs, and serial assessment may help either reassure physicians that patients have such a low probability of PE that testing is unwarranted or provide evidence to justify an evaluation for PE.

Differential Diagnosis and Medical Decision Making

Because of the vague yet common nature of dyspnea and chest pain, the differential diagnosis is broad. However, a targeted diagnostic approach should be used rather than a “chest pain work-up” in an attempt to test for every diagnosis possible without regard to the pretest probability or negative consequences of overtesting. This is particularly important for PE because tests are not 100% sensitive or specific and the consequences of a false-positive diagnosis may include 6 months of oral anticoagulation with high direct and indirect costs to the patient and society. This is especially true in young patients with limitations in activity, as well as in older patients at risk for falls, medication interaction, and bleeding. Table 70.2 lists potential alternative diagnoses in ED patients evaluated for PE and clues to assist in rapid decision making. It is not surprising that many of these conditions are common entities such as pneumonia, bronchitis, asthma, musculoskeletal pain, gastroesophageal reflux or spasm, and anxiety or panic attack. Many of the most threatening alternative diagnoses can initially be evaluated with a chest radiograph, an ECG, bedside cardiac ultrasound, and cardiac enzyme testing during the first hour in the ED.

Table 70.2 Other Diagnoses That Should Be Considered Along with Pulmonary Embolism

CXR, Chest x-ray; ECG, electrocardiogram; GERD, gastroesophageal reflux disease.

It is most helpful to think of PE as a continuum of cardiopulmonary stress as shown in Figure 70.1. Even in normotensive patients, in-hospital or 30-day mortality in those with diagnosed PE is approximately 8% to 13%.^5–9 This mortality in PE patients without shock is greater than that for acute myocardial infarction.¹⁰ When early signs of right heart dysfunction occur, mortality begins to curve upward. This is followed by compensated shock, which may initially respond to intravenous fluid. Later, as left-sided filling is decreased because of septal shift into the left ventricle, as well as decreased filling of the left atrium, overt shock is present and mortality is in excess of 30%. If untreated, cardiac arrest ensues, with pulseless electrical activity being the most likely first rhythm.^11,12

Diagnostic Testing

Pretest probability is the probability that the physician believes to be present before any test results are obtained. It is typically calculated by either a scoring system or the physician’s own “gestalt” estimation. Despite the fact that debate exists over the relative accuracy of using gestalt versus a structured means of assessing pretest probability, the American College of Emergency Physicians practice guideline of 2003 recommended pretest probability assessment in patients being evaluated for PE.¹³

The main structured pretest probability system with the longest track record of use and investigation is the Canadian score derived by Wells et al., which results in a score for an individual patient that can be used to estimate ranges of pretest probability¹⁴ (Table 70.3 and Fig. 70.3). Widespread clinical application of this scoring system can be challenging because of difficulty in physician recall¹⁵ and the fact that it provides a range of probability rather than an exact estimate. An alternative to these structured pretest probability systems is unstructured or implicit estimation systems whereby physicians arrive at their own pretest probability based on their experience and overall integration of clinical information for a unique patient. This is commonplace but imprecise and subject to wide variability.¹⁶ Recent data from a large multicenter study of ED patients in the United States found that several variables not in the Wells score may be significantly associated with the outcome of PE in ED patients who are tested. These variables are noted in Figure 70.3 and may be important in addition to the Wells score in formulating overall pretest probability.¹⁷

Table 70.3 Components of the Wells Score

Other factors to consider include estrogen use (oral contraceptive pill or hormone replacement therapy), thrombophilic condition, pleuritic nature of the chest pain if present, family history of PE or DVT, and oxygen saturation lower than 95%.

DVT, Deep vein thrombosis; PE, pulmonary embolism.

Fig. 70.3 Typical algorithmic approach to ruling out pulmonary embolism (PE).

BNP, B-type natriuretic peptide; CT, computed tomography; DVT, deep vein thrombosis; ECG, electrocardiogram; , ventilation-perfusion.

The most typical approach to testing for PE is to determine whether the pretest probability is sufficiently low (Wells score ≤ 4 or physician’s gestalt of “low risk”) and then to use a sensitive D-dimer blood test that detects the presence of fibrin breakdown products (see Fig. 70.3). If D-dimer is normal in these low-risk patients, the posttest probability of PE is below a sufficient test threshold (<1% to 2%), and PE can be considered to be sufficiently excluded in these patients.^18,19 Typically, two types of D-dimer tests are available for ED testing: (1) quantitative tests, including enzyme-linked immunosorbent assay or immunoturbidimetric tests, which are considered to be abnormal at a particular cutoff, typically ≥500 ng/mL, and (2) qualitative whole blood agglutination or immunofiltration tests, which yield a binary result of positive or negative. Benefits of the quantitative tests include higher sensitivity. Benefits of the qualitative tests include rapid results because of bedside testing. Table 70.4 describes how the two different types of D-dimer tests may be used to rule out PE. These are estimates of diagnostic test performance, and individual tests will vary in their actual sensitivity, specificity, and likelihood ratio, thus emphasizing the importance of clinician knowledge of the specific test at their institution.

Table 70.4 Comparison of Two Different Types of D-Dimer Tests

ELISA, Enzyme-linked immunosorbent assay; PE, pulmonary embolism.

^* low sensitivity makes this test unfavorable.

Unfortunately with these tests, 20% to 40% of positive results may be falsely positive because of the low specificity of these blood tests. These patients require confirmation of the presence or absence of PE with an imaging test, usually a CT scan of the pulmonary arteries or a ventilation-perfusion scan. If imaging tests are negative in these low-risk patients, PE can be considered to be sufficiently excluded.

The decision to test for PE should always assume that if D-dimer is positive, more definitive tests would be undertaken. It is therefore important to consider the possible consequences of radiation exposure, contrast reaction, and volume overload from the osmotic effects of contrast agents; concerns in pregnant patients; and the overall safety of leaving the ED when initiating testing for PE.

For these reasons, as well as the significant negative impact that a false-positive diagnosis may have for the patient because of months of anticoagulation, attempts to reduce testing in very low-risk settings have been proposed. One such method is the PE rule-out criteria shown in Box 70.2.^18,20 It was derived from a multicenter U.S. sample and provides simple, easy-to-apply clinical criteria that when satisfied, indicate that the baseline probability of PE is below a test threshold (<1.8%) and testing in this setting may be more likely to lead to patient harm than benefit. This is only an attempt to support clinician judgment when the probability of PE is already very low and it is not intended to replace or dictate individual patient-based decision making. Patients who meet the PE rule-out criteria but for other reasons are thought to need testing for PE should undergo the standard evaluation.

CT has largely supplanted the use of scans because of the perception that they produce a binary positive/negative result, as well as the fact that other chest pathology may be seen with CT.²¹ The sensitivity and specificity of chest CT angiography have improved with the advent of multidetector CT with higher spatial resolution and lower image acquisition time. Overall, well-accepted sensitivity and specificity data are lacking because of diverse differences in the equipment used, image acquisition technique, and image interpretation, but spiral CT is generally regarded to have greater than 90% sensitivity and specificity. One systematic review based on 3500 patients in 15 studies reported a pooled negative predictive value of 99.1% and a likelihood ratio for a negative result of 0.07. Newer CT scan machines with 128 detector systems and sophisticated image postprocessing will become more commonplace and improve the diagnostic accuracy of current imaging. Even with these newer machines, motion artifact, inadequate contrast bolus timing, and varied experience of readers may result in a surprising level of indeterminate or nondiagnostic results.²² Pretest probability assessment and D-dimer testing will still be important to avoid unnecessary radiation exposure and possible false-positive CT results in a large number of patients who have a very low likelihood of PE.

scanning is an alternative to CT for patients with contrast allergy or renal insufficiency and for pregnant patients. It is important to remember that patients who are found to be at high risk by pretest probability assessment and have low or indeterminate scans cannot be assumed to have PE ruled out. These patients need anticoagulation and further testing—typically, duplex Doppler ultrasound of the lower extremities.

Controversy exists regarding the optimal approach in pregnant patients. The estimated radiation dose from CT of the chest is low (7 to 14 millisieverts), and with shielding of the abdomen and pelvis, only a small fraction of this dose would be expected to be received by the fetus. It would be expected to be significantly lower than the threshold of teratogenicity. However, no prospective longitudinal data exist to clearly know what the optimal strategy should be or what the long-term risk is. scans have been used over a long period in pregnant patients and are thought to provide minimal to no risk to the fetus. However, the need for experienced technicians and experienced nuclear medicine physicians may limit the availability of scans. Regardless of what imaging method is available or chosen, it is important to minimize the amount of potential radiation received by the fetus. Discussion with the patient, obstetrician, radiologist, and family needs to occur at the outset even before tests are ordered and should include comment on the probability of disease, extremely low probability of radiation-associated negative effects, and potential morbidity with undiagnosed PE. Tests should be performed if appropriate concern exists for PE. The use of D-dimer is problematic in pregnant patients because the likelihood of a false-positive D-dimer result increases with progression of the pregnancy. It has been advocated that an elevated cutoff for quantitative D-dimer in a low-risk patient may be adequate to rule out PE. However, no prospective management trials exist to clarify a potential role of D-dimer in pregnancy. If used in early pregnancy, when the likelihood of a false-positive result is at its lowest, it may be adequate to rule out PE if the patient is low risk and the result is normal. Patients who are otherwise low risk should not be automatically assumed to have a high pretest probability just because they are pregnant.

Treatment

The defining characteristic of the emergency medicine physician is simultaneous treatment and evaluation. Oxygen should be given to patients suspected of having PE. Correction of local hypoxemia assists in decreasing reflexive vasoconstriction in the pulmonary vasculature. Patients who are thought to be at high risk for PE and have a high pretest probability should be considered candidates for empiric treatment with anticoagulation while awaiting the results of tests, provided that they have no contraindications. Low-molecular-weight heparin (LMWH) has become standard therapy despite being more costly than unfractionated heparin. It has benefit in achieving appropriate anticoagulation rapidly without the need to monitor coagulation levels, and it is also associated with a less likelihood of heparin-induced thrombocytopenia with thrombosis. Some studies have suggested that LMWH may have somewhat higher efficacy in terms of time to thrombus resolution and recurrence in patients with DVT.²³ Unfractionated heparin is still a safe and effective treatment and may be especially useful if a shorter term of anticoagulation with the ability to rapidly cease anticoagulation is desired. Unfractionated heparin and LMHW do not act to break down existing thrombus but rather act to decrease thrombus propagation and extension. Endogenous mechanisms of antithrombin and plasmin activation are responsible for gradually effecting thrombus breakdown. The dose of enoxaparin, the most commonly used LMHW, is 1 mg/kg subcutaneously every 12 hours. The dose of unfractionated heparin is typically a 80-U/kg bolus intravenously and then an 18-U/kg/hr intravenous infusion.

Risk Stratification

It is critical to assess the likelihood for further deterioration. Figure 70.1 demonstrates the increase in mortality that occurs gradually with right heart strain and then more steeply with shock. It is possible to gather data in the ED to estimate the likelihood of right heart strain and early shock. The ECG is the starting point, and the presence of T-wave inversion in leads V₁ to V₄, incomplete or complete right bundle branch block, an S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III may all be evidence of right heart strain. Pulse oximetry is an important predictor of 30-day mortality in normotensive ED patients with PE when less than 95% on room air.⁷ Other means of risk stratification include brain natriuretic peptide (BNP) and troponin blood testing. Though not specific for PE and not helpful in establishing the diagnosis, these factors are being seen in emerging studies to predict a more complicated course both in the hospital and several months later. The most accepted means of risk stratification is the echocardiogram. Though often not available on an emergency basis in many EDs, it is a rapid means of identifying right heart strain (Box 70.3).

Treatment of Patients With Confirmed Pulmonary Embolism and Shock

In a practice guideline statement the American College of Emergency Physicians recommended fibrinolytic therapy for hemodynamically unstable patients with confirmed PE as a class B recommendation.¹³ (Class B represents a moderate level of certainty.) Despite controversy over the use of thrombolytics and mortality in patients with PE and shock, in selected samples it seems clear that fibrinolytic therapy has been associated with improved perfusion and better right heart function. Catheter-based techniques of thrombus fragmentation, as well as surgical embolectomy, are alternatives to pharmacologic fibrinolysis. These techniques are unlikely to be available outside dedicated interventional radiology and cardiovascular surgery centers and are highly operator dependent. No evidence has shown that they are superior to pharmacologic approaches.

When the use of fibrinolytics has been studied in patients without overt shock but with right ventricular dysfunction, they have been associated with decreased need to escalate therapy with vasopressors, as well as reduced rates of intubation or additional thrombolytic treatment.²⁴ The Food and Drug Administration–approved on-label use of fibrinolytic therapy for PE is alteplase, 15 mg as an intravenous bolus and then 85 mg intravenously over a 2-hour period (heparin infusion should be stopped during alteplase administration). Other off-label dosing regimens have been described, including a 15-mg bolus with an 85-mg infusion over a 90-minute period, which has been used in the near-arrest setting.²⁵ In conclusion, it is accepted that fibrinolytic therapy is appropriate in patients with confirmed PE and shock. Identification of PE as a cause of shock can be aided by a stepwise approach to diagnosis with consideration of other causes of shock (see Fig. 70.2). If shock is present and no right heart abnormalities are seen on echocardiography, PE is a very unlikely explanation for the shock.

Follow-Up, Next Steps In Care, and Patient Education

Most patients with a new diagnosis of acute PE will be admitted to the hospital for initiation of anticoagulation and serial evaluation of oxygen saturation, blood pressure, and overall functional capacity. Patients with minimal cardiopulmonary comorbidity, normal oxygen saturation, and no evidence of hypotension are typically discharged shortly after warfarin anticoagulation is initiated, and trends outside the United States have included outpatient treatment of low-risk PE patients. In either case, patients continue home self-treatment with LMWH for several days until the outpatient international normalized ratio is above 2.0, at which point they may stop taking LMHW and continue warfarin.

Patients with low oxygen saturation (less than 95%), right heart strain on an echocardiogram or ECG, elevated BNP, or elevated troponin should be observed closely for deterioration. The decision for intensive care unit management should be based on the level of specialized care that patients need (Box 70.4).

Patients with a history of previous PE present several challenges. Recurrent PE, defined as an acute clot in a new or different anatomic location, should be treated as acute PE, and if patients are no longer taking anticoagulation agents, they need treatment as stated earlier. In contrast, a persistent or chronic clot is not uncommonly seen in the same areas as previous PE and may look radiographically distinct from acute PE on CT. If patients are appropriately anticoagulated and do not have other indications for admission, they may be discharged from the ED, provided that no other inpatient evaluation for the symptoms is warranted. However, patients with no new clot visualized on CT may be suffering from chronic venous thromboembolic syndrome, a condition in which pulmonary hypertension and chronic vascular changes in the lung can lead to chronic disabling dyspnea and other symptoms that may prompt ED evaluation. Depending on oxygenation and functional status, these patients should be admitted or, if discharged, referred for outpatient echocardiography and pulmonary consultation, but no specific therapy as yet exists for this condition, which may affect 1% to 3% of all patients with PE (Box 70.5).