Prathap Sooriyakumaran and Jeffrey A. Tabas
Pulmonary embolism (PE) is a relatively common, life-threatening condition that presents a diagnostic dilemma for the emergency practitioner. The incidence in the United States is estimated at 650,000 to 900,000 patients per year, resulting in as many as 200,000 deaths per year (1). This makes PE the third leading cause of cardiovascular death. Correct diagnosis and treatment significantly decreases morbidity and mortality (2). Accurate diagnosis is essential, as a missed or delayed diagnosis is associated with increased rates of adverse outcomes (3), and over diagnosis subjects a patient to the risks of unnecessary anticoagulation as well as to the psychological and financial implications of carrying such a diagnostic label.
CLINICAL PRESENTATION
Pulmonary emboli may result from a myriad of causes. Most commonly, emboli arise from thrombi in the legs, but they may also originate from anywhere in the venous system proximal to the pulmonary arteries, such as pelvic veins, nonportal abdominal veins, upper-extremity veins, or right-sided heart valves. Other sources include fat emboli, usually in association with long-bone fractures, amniotic fluid emboli (in the setting of labor and delivery), air emboli, and septic emboli.
The signs and symptoms of pulmonary emboli result from the effects of obstructed pulmonary vasculature. This may result in local tissue ischemia or infarct, increased ventilation–perfusion mismatch that can cause increased alveolar dead space or increased alveolar–arterial oxygen gradient, and increased pulmonary vascular resistance that can cause right heart strain or failure. The spectrum of presentation varies from asymptomatic patients to those with mild subjective complaints to hemodynamically unstable patients with severe hypotension, respiratory failure, or pulseless electrical activity. The terms “submassive” and “massive” PE both describe symptomatic PE, with a systolic blood pressure less than 90 typically used to distinguish “massive” hemodynamically unstable PE, from “submassive” hemodynamically stable PE that nonetheless has some degree of right ventricular dysfunction and increased pulmonary hypertension. Differences in size, quantity, and location of emboli as well as underlying patient characteristics (such as cardiopulmonary reserve) contribute to the wide spectrum of presentation.
The most common signs and symptoms associated with the presence of PE are listed in Table 79.1 (4). A prospective cohort study of 7,940 patients with diagnosed PE found that patient history of PE or deep vein thrombosis (DVT), unilateral leg swelling, surgery within the previous 4 weeks, current estrogen use and hypoxemia (saturation <95%) were the strongest predictors of PE, with odd ratios (OR) between 2 and 3 (5). Common symptoms investigated include dyspnea (OR 1.26), pleuritic chest pain (OR 1.53), and symptoms of DVT such as unilateral leg swelling (OR 2.60). Although low-grade fever is not infrequent, temperatures >38.5°C are less common and suggest other causes (temperature >38.5°C had an OR of 1.13, but this was not statistically significant). Unfortunately, many of these signs and symptoms are manifestations of other conditions, and there is no combination of clinical findings that has been shown to be diagnostic for PE. In addition, the “classic” triad of hemoptysis, pleuritic chest pain, and tachypnea is uncommon.
TABLE 79.1
Relative Frequency of Presenting Symptoms and Signs in Patients with PE
Classic risk factors (Table 79.2) for thrombosis include Virchow’s triad of hypercoagulability, venous stasis, and endothelial injury. Commonly acquired hypercoagulable states include cancer, pregnancy, and estrogen therapy. There is increasing understanding and discovery of heritable thrombophilias, but these risk factors are often unknown at the time of presentation. Venous stasis may result from prolonged immobilization, recent surgery, extended travel, or medical conditions such as paraplegia or previous stroke. Damage to the vascular endothelium may result from fractures, surgery, catheter placement, or other forms of trauma. Demographic factors, such as advanced age, should also be taken into consideration. However, up to 30% of patients with a diagnosed PE have no known risk factors. In summary, although the presence of risk factors increases suspicion for PE, lack of known risk factors does not exclude the diagnosis.
TABLE 79.2
Risk Factors for PE
DIFFERENTIAL DIAGNOSIS
Given the wide spectrum of signs and symptoms associated with PE, the differential diagnosis in most presentations is extensive. Other causes of dyspnea or chest pain include pulmonary and cardiac causes such as chronic obstructive pulmonary disease (COPD) or asthma, congestive heart failure (CHF), pulmonary infections, pericarditis, acute coronary syndrome, aortic dissection, pneumothorax, trauma, or musculoskeletal pain. Abdominal sources such as biliary colic or pancreatitis may mimic a PE. The evaluation can be complicated by the fact that conditions such as CHF can both mimic signs and symptoms of PE as well as be a risk factor for PE. Musculoskeletal pain and anxiety are always diagnoses of exclusion and should be made only after more life-threatening causes have been confidently eliminated.
ED EVALUATION
Initial management of PE consists of rapid assessment and stabilization for immediate life-threatening conditions. When appropriate, intravenous access should be established, and cardiac and pulse oximetry monitors should be placed. Laboratory testing, electrocardiography, and chest radiography should be expedited. The probability of disease (see subsequent text) should be determined based on the patient’s signs, symptoms, identifiable risk factors, and the presence of an acceptable alternate diagnosis.
A complete blood count and serum chemistry panel are usually indicated in the general assessment of any patient with chest pain or shortness of breath. A creatinine level is helpful if contrast administration is planned. All patients suspected of having a PE should undergo an electrocardiogram (ECG). The ECG is a nonspecific test for PE, and the primary purpose is to detect other disease processes such as pericarditis or acute coronary syndromes. The most common ECG findings in patients with PE are nonspecific ST and T-wave abnormalities. Other common findings include tachycardia and T-wave inversion in the anterior precordial leads (V1 to V4). The classic ECG finding of S1Q3T3, consisting of an S wave in lead 1, and a Q wave with a flipped T wave in lead 3, is neither sensitive nor specific for PE. In a secondary analysis of a prospective, observational cohort of 6,049 ED patients who were tested for PE and had an ECG, both the findings of S1Q3T3 and T-wave inversions in V1 to V4 had positive likelihood ratios (LR+) of 3.7 and tachycardia had a LR+ of 1.8 (6). These findings were infrequent overall, but were observed more frequently in patients with the final diagnosis of PE compared to patients who did not have PE.
A chest radiograph should be obtained for patients with suspected PE. Given the lack of specific findings for PE, the primary purpose is again to detect other disease processes, such as a pneumothorax, pulmonary edema, malignancy, or pneumonia. In one large study of patients with proven PE, the most common chest radiographic interpretations were cardiac enlargement (27%), normal (24%), pleural effusion (23%), elevated hemidiaphragm (20%), pulmonary artery enlargement (19%), atelectasis (18%), and parenchymal pulmonary infiltrates (17%). Cardiomegaly is a common associated finding with PE, given that CHF is a risk factor. Classic radiographic findings, which occur infrequently, include Westermark sign (a prominent central pulmonary artery with decreased pulmonary vasculature distally) and Hampton’s hump (a wedge-shaped, pleural-based opacity representing pulmonary infarct) (7).
Arterial blood gases are rarely helpful in the evaluation of PE. One analysis of more than 100 patients with PE who lacked prior cardiopulmonary disease revealed that 38% had a normal alveolar–arterial (A–a) gradient. Patients with prior cardiopulmonary disease who proved not to have PE, had an elevated A–a gradient 24% of the time (8). One potentially useful scenario may occur when a patient is found to have a large, unexplained A–a gradient. However, these authors rarely obtain arterial blood gases for suspected PE alone.
Based upon the history, physical examination, and preliminary laboratory evaluation, the clinician should categorize a patient into very low (<2%), low (2% to 15%), moderate (15% to 40%), or high probability (>40%) suspicion for PE. Several clinical decision rules have been developed in an attempt to improve implicit clinician judgment, however, they appear to be no better than gestalt assessment by experienced providers in predicting probability of PE (9,10). These rules appear to be most effective at improving risk stratification for the clinically inexperienced practitioner and to provide some uniformity of approach within a department. The Wells Criteria (Table 79.3) is the most extensively tested decision rule. A modified approach, in which patients with a score less than or equal to 4 are considered safe for D-dimer testing and those greater than 4 are not, has been shown to be safe and effective (11).
TABLE 79.3
Criteria of Wells et al. for Assessment of Pretest Probability for PE
Evaluation for PE should be based on pretest probability. See Figure 79.1 for an algorithm summarizing our recommendations for how to proceed with the evaluation for PE. The results of diagnostic testing should be used to determine sequentially what further evaluation is needed to exclude or confirm the presence of PE. A posttest probability of 1% to 2% is a generally accepted risk level. This would presumably lead to a subsequent complication rate of <0.7%. Some patients and physicians may be willing to accept more or less risk.
FIGURE 79.1 Workup of PE in the ED.
For patients who are low to low-moderate probability (less than 15%) stratified either by clinical decision rule or gestalt, Kline et al. (12) have demonstrated that patients with a zero score on the Pulmonary Embolism Rule Out Criteria (PERC) do not need further evaluation for PE. PERC consists of 8 criteria (Table 79.4). When none of these are present in patients with low to low-moderate pretest probability, the risk of PE or death is similar to that of patients with negative V/Q or CT pulmonary angiography. In a meta-analysis of 11 studies investigating the diagnostic performance of PERC for PE, the pooled sensitivity and specificity was 0.97 (95% confidence interval 0.96 to 0.98) and 0.23 (95% confidence interval 0.22 to 0.24), respectively (13). For patients with less than 15% pretest probability who are PERC positive, the next step in evaluation is a D-dimer test. D-dimers are degradation products of cross-linked fibrin and are therefore elevated when there is activation of the coagulation pathway, as occurs in the setting of PE. Because of their nonspecific nature, D-dimers are also elevated in other conditions such as cancer, pregnancy, recent trauma, and even CHF. When used appropriately, a sensitive D-dimer assay is an effective screening test for PE, eliminating the need for further radiologic imaging. Most current assays show sensitivities as high as 90% to 95%. Bayesian analysis reveals that in a patient with 15% pretest probability (the upper limit of “low probability”), a negative likelihood ratio of 0.12 or less is required to provide a posttest probability of <2%. Most of the rapid, sensitive D-dimer tests demonstrate negative likelihood ratios within this range. Therefore, a negative result using currently available rapid, sensitive D-dimer assays is adequate to exclude PE in a patient with low to low-moderate pretest probability (14,15). Note that a positive D-dimer result has little impact on posttest probability.
TABLE 79.4
Pulmonary Embolism Rule-Out Criteria (PERC)
For low to low-moderate pretest probability patients (<15%) with positive PERC and D-dimer testing, and for moderate to high risk patients, imaging is required. When discussing the diagnostic accuracy of radiographic imaging of patients with suspected PE, it is important to remember that the goal of imaging is to detect the presence of any venous thromboembolism (VTE) to guide the initiation of treatment. Although patients with small or subsegmental pulmonary emboli may present with milder signs and symptoms, there is insufficient evidence to conclude that patients with “clinically insignificant” presentations are at a lower risk of recurrence than those with more clinically evident presentations (2).
Lower-extremity imaging for DVT in the assessment of suspected PE is most useful when there are clinical signs and symptoms in that extremity. Fifteen to twenty-five percent of patients with PE have clinically evident DVT (16). Bilateral lower-extremity imaging in a patient without clinical findings of DVT is probably of limited value except for unusual circumstances.
Ventilation/perfusion (V/Q) scanning involves low radiation exposure and displays high sensitivity. However, frequently indeterminate results and lack of information about other diagnoses have limited the use of the test in the evaluation of PE. Administration of an intravenous radioactive isotope is used to measure perfusion of the pulmonary vasculature, and administration of an inhaled radioactive isotope is used to measure pulmonary ventilation. A normal or near-normal result is 98% sensitive for the exclusion of PE. As with most tests, the V/Q scan should be interpreted within the context of pretest probability (Table 79.5). A low pretest probability with a low probability V/Q scan makes PE unlikely, and a high probability scan with a high pretest probability is considered diagnostic for PE. However, discordant results or intermediate probability scans, which account for a significant portion of results, mandate further studies. An indeterminate result is most common in patients with COPD, pre-existing cardiopulmonary disease, or markedly abnormal chest radiographs. V/Q scanning for assessment of suspected PE is appropriate when it is the only imaging modality available, in patients with a normal chest radiograph (and therefore likely to obtain a diagnostic result), or in patients who have contraindications to other imaging studies, such as contrast allergy or renal insufficiency. V/Q scanning is most likely to be diagnostic in patients with normal chest radiographs.
TABLE 79.5
Probability of Pulmonary Embolism Based on Clinical Suspicion and Results of Ventilation/Perfusion (V/Q) Scan
Computed tomography pulmonary angiography (CTPA) has high sensitivity and specificity for PE and, in about one-third of cases, demonstrates an alternative diagnosis, such as pneumonia, cancer, or aortic dissection. It is not particularly invasive and requires only a single breath-hold. Reported sensitivities for CTPA vary depending on scanner technology. A prospective multicenter study designed to assess the efficacy of multidetector CTPA (4, 8, and 16 row), reported a sensitivity of 83% and specificity of 96%. The addition of CT venography to CTPA increased sensitivity and specificity to 90% and 95%, respectively (17).
Pulmonary angiography, the traditional gold standard for the diagnosis of PE, is rarely performed. It has a false-negative rate of 1% to 2% and an indeterminate study rate of 3%. Significant complications include death in 0.5%, major nonfatal complications in 1%, and minor complications in up to 5%.
Transthoracic or transesophageal echocardiography may be helpful in the assessment of PE, especially in the unstable patient. Echocardiographic findings in patients with PE include right ventricular dilatation and hypokinesis, septal flattening and paradoxical motion, failure of the inferior vena cava to collapse during inspiration and, rarely, direct visualization of the thrombus.
Evaluation of the pregnant patient poses a particular challenge for the emergency department (ED) practitioner. Pregnancy increases risk of venous thrombosis up to fivefold. For women whose pregnancies result in a live birth, PE is the leading cause of death. Although exposure of the fetus to radiation is clearly undesirable, the safety of the mother takes priority. Evaluation of the stable pregnant patient with symptoms of PE may include a rapid sensitive D-dimer test in a low-suspicion patient (although specificity in pregnancy will be significantly decreased), ultrasonographic evaluation of the lower extremities (which if positive, will allow initiation of anticoagulation and deferral of further evaluation), and V/Q scanning or CTPA. Current literature suggests that radiation exposure from CTPA to the fetus, especially in the first or second trimester, is lower than radiation exposure from V/Q scanning (18).
ED MANAGEMENT
As with any critically ill patient, the emergency physician should start with the “ABCs.” Intravenous access, cardiopulmonary monitoring, and oxygen therapy should be initiated. The patient’s airway should be maintained and, if severely hypoxic, the patient should be emergently intubated. Hypotensive patients should be fluid resuscitated while more definitive treatments are being considered.
The goal of treatment in PE is primarily aimed at life-saving restoration of flow through occluded pulmonary arteries, or the prevention of potentially fatal early recurrences as well as long-standing damage from the initial insult (pulmonary hypertension and symptomatic right ventricular dysfunction). Anticoagulation remains the primary treatment for patients with PE. Anticoagulation should be initiated for high-risk patients while confirmatory studies are pursued. Typically patients are treated with 6 to 12 months of Coumadin, with initial treatment with heparin until a therapeutic INR is achieved. Intravenous unfractionated heparin or low-molecular-weight heparin (LMWH) has been shown to be equally effective in the treatment of pulmonary emboli. The advantages of LMWH are thought to include ease of use (subcutaneous instead of intravenous) and lack of need for laboratory monitoring, though the disadvantages include cost. However, a trial comparing fixed-dose unfractionated heparin, delivered subcutaneously without laboratory monitoring (333 U/kg SC initial dose, then 250 U/kg SC every 12 hours), to LMWH (100 IU/kg every 12 hours SC) found them to be of equivalent safety and effectiveness in patients with VTE (20% with PE) (19).
The FDA has approved the use of enoxaparin and tinzaparin: the dosing for enoxaparin is 1 mg/kg subcutaneously every 12 hours and for tinzaparin 175 anti-Xa IU/kg subcutaneously once daily. Contraindications include renal insufficiency, obesity, or weight <40 kg. If intravenous unfractionated heparin is used, weight-based dosing has been shown to be superior to standard dosing, with more rapid time to therapeutic levels and decreased rates of recurrence and complications. Patients should receive an initial bolus of 80 U/kg and then an infusion of 18 U/kg/hr. The activated partial thromboplastin time is measured every 4 to 6 hours and should be maintained at 1.5 to 2.3 times the control, with adjustment based on an established nomogram.
New anticoagulants being developed may ultimately show improvement over unfractionated heparin and LMWH. These new agents include direct thrombin inhibitors, direct and indirect factor Xa inhibitors, activated protein C, and tissue factor pathway inhibitors. Some of their superior properties include once-daily dosing without monitoring, oral administration, and improved pharmacodynamic profiles. The FDA has recently approved rivaroxaban, a factor Xa inhibitor, for VTE prophylaxis and treatment. EINSTEIN-PE, a randomized, open label study with 4,832 PE patients, showed noninferiority of rivaroxaban (15 mg twice daily for 3 weeks, followed by 20 mg once daily) compared to standard treatment with enoxaparin followed by an adjusted-dose vitamin K antagonist for 3, 6 or 12 months (20). The advantages of rivaroxaban compared to vitamin K antagonists such as warfarin, which patients who are started on unfractionated heparin or LMWH are transitioned to, include more stable pharmacokinetic and pharmacodynamic profiles which allows for it to be prescribed in a fixed dose without the requirement of frequent monitoring. A significant disadvantage is a lack of an antidote. Prothrombin complex concentrate (PCC) has been shown to reverse the effects of rivaroxaban on coagulation tests such as prothrombin time although the benefit in clinically reversing bleeding effects has not been studied (21).
For patients with hemodynamic instability resulting from PE, thrombolytic therapy is considered the treatment of choice. Despite this, in a modern cohort of ED patients with massive PE, analysis of the Emergency Medicine Pulmonary Embolism in the Real World Registry (EMPEROR) showed only 12% of these patients received thrombolytic therapy (22). Thrombolytics rapidly improve hemodynamic status by acutely reducing clot burden. The FDA has approved recombinant tissue plasminogen activator (r-TPA), streptokinase, and urokinase for the treatment of massive PE. The dosage used for r-TPA, which has been shown in several small studies to be associated with slightly better outcomes, is a 10-mg intravenous bolus and 90 mg over the next 2 hours. If streptokinase is used, the dosage is 250,000 IU over 30 minutes and then 100,000 IU an hour for 24 hours. Urokinase dosage is 4,400 IU/kg over 10 minutes followed by 4,400 IU/kg an hour for 12 to 24 hours. Before initiation of thrombolytic therapy, unfractionated heparin should be administered in full therapeutic doses (i.e., bolus followed by infusion). The heparin infusion should be suspended during delivery of thrombolytic therapy. The activated partial thromboplastin time should be checked immediately after completion of thrombolytic therapy and repeated until it is <80 seconds, at which point the heparin infusion should be restarted (without a bolus).
Current evidence is still insufficient to strongly support (or oppose) administration of thrombolytics to patients with acute right ventricular dysfunction or pulmonary hypertension from PE (i.e., patients with “submassive” PE). The Moderate Pulmonary Embolism Treated with Thrombolysis (MOPETT) trial tested the efficacy of half dose or “safe dose” thrombolysis in submassive PE. There is face validity that reducing the dose for PE would result in reduced complications while maintaining efficacy. Because the pulmonary vasculature receives the entire cardiac output, a given dose of drug would be expected to have greater effect than in the brain, which receives 15% of cardiac output, or coronary arteries, which receive 5%. This treatment resulted in statistically significant benefit for the composite outcome of recurrent PE and death (p = 0.0489) (23). The Pulmonary EmbolIsm THrOmbolysis (PEITHO) study (24) compared full dose thrombolytics versus heparin therapy in 1,006 randomized patients with submassive PE over a 10-year period. Preliminary data presented at the American College of Cardiology 2013 Summer Sessions, showed significant benefit (absolute risk reduction of 3% in death or hemodynamic collapse) which was balanced by significantly higher rates of major bleeding.
Pulmonary embolectomy (catheter-directed or surgical) is an uncommon procedure, but it may be used as treatment for hemodynamically unstable patients with contraindications to thrombolytics or when thrombolytics are not available.
CRITICAL INTERVENTIONS
• Risk-stratify patients into low, moderate, or high probability for PE based upon the history, physical examination, and preliminary laboratory evaluation.
• Anticoagulate patients with a high clinical suspicion for thromboembolism before definitive studies are performed. Significant delays in initiation of anticoagulation can negatively impact outcomes.
• Administer thrombolytic therapy for patients with hemodynamic instability caused by PE.
DISPOSITION
Patients diagnosed with PE are generally admitted to the hospital. An RCT of outpatient versus inpatient treatment in low-risk PE patients found no difference in safety (25). However, the exclusion criteria were so stringent, including patients with BP <100 or hypoxia, patients deemed unreliable (broadly defined), patients who were obese and patients who received IV pain medication, that very few patients meet these criteria. If admitted, patients who are hemodynamically stable may go to a nonmonitored setting. If unstable, they should be observed in the intensive care unit or a telemetry bed. Patients diagnosed with DVT who show no evidence of PE are routinely treated as outpatients, initially with LMWH and warfarin (see Chapter 96, “Deep Venous Thrombosis and Thrombophlebitis”). These patients transition off heparin in the outpatient setting.
Common Pitfalls
• Failing to consider PE in a patient presenting with pleuritic chest pain, dyspnea, or tachypnea in whom there is no convincing alternative diagnosis
• Failing to recognize that lack of risk factors does not exclude PE
• Failing to recognize atypical presentations, such as syncope, in the elderly
• Mistaking nonspecific radiographic findings of PE for an alternative diagnosis such as pneumonia in a patient with atelectasis on chest radiography
• Failing to apply PERC or D-dimer testing to avoid radiographic imaging in appropriate patients
• Failing to recognize that PE can recur in a patient who is adequately anticoagulated
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