Pulmonary Embolism: Presentation, Natural History, and Treatment

Introduction

Acute pulmonary embolism (PE) is a partial or complete occlusion of the pulmonary arteries, with hemodynamic consequences determined by the size and location of the embolus, preexisting cardiopulmonary disease, and the severity of ventilation and oxygenation compromise. Acute PE is the third leading cause of cardiovascular mortality, with well over 100,000 deaths per year in the United States. Recent registries and cohort studies suggest that approximately 10% of all patients with diagnosed acute PE will die within 3 months after diagnosis. ^, Despite being the most preventable cause of hospital mortality and despite advances in diagnosis and management, it accounts for 5% to 10% of in-hospital deaths.

In the majority of patients with PE, the cause is lower extremity or pelvic venous thrombosis. The physical obstruction of the pulmonary arteries is accompanied by hypoxemic vasoconstriction and release of potent pulmonary arterial vasoconstrictors, which further increase pulmonary vascular resistance and right ventricular (RV) afterload. The increasing RV afterload can cause RV hypokinesis and dilation, tricuspid regurgitation, and ultimately RV failure with subsequent life-threatening reduction in coronary perfusion and cardiac output. Although in the majority of the survivors pulmonary thromboemboli will gradually resolve, in some patients, it may organize into fibrotic deposits permanently occluding the pulmonary arteries, leading to chronic pulmonary hypertension and RV dysfunction.

Clinical Presentation

The clinical presentation varies from asymptomatic (incidentally diagnosed) to fatal. Development of symptoms depends on the embolic burden and the severity of any underlying cardiopulmonary disease. The diagnosis of PE is never made in approximately 70% of those who survive the initial event. Thus, it is critical that a high level of suspicion is maintained.

In most patients, PE is suspected on the basis of dyspnea, chest pain, presyncope or syncope, and/or hemoptysis. The onset of dyspnea may be acute and severe usually representing a PE in the main or lobar vessels; in small peripheral PE, it is often mild and may be transient. Chest pain is a frequent symptom and is usually caused by pleural irritation due to distal emboli causing pulmonary infarction. In central PE, chest pain may have a typical angina character, possibly reflecting RV ischemia and requiring differential diagnosis with acute coronary syndrome or aortic dissection. Hemoptysis can occur with pulmonary infarction.

Common clinical signs include tachypnea, tachycardia, rales or decreased breath sounds, jugular venous distension, and rarely fever mimicking pneumonia. Half of the patients will also present with symptoms of leg deep venous thrombosis (DVT) or rarely with symptoms of upper extremity DVT. Arterial hypotension and shock are rare (<10%) but critical clinical presentations because they indicate central PE and/or a severely reduced hemodynamic reserve. Syncope is infrequent but may occur regardless of the presence of hemodynamic instability.

Diagnosis

A high index of suspicion is required for the diagnosis of PE because symptomatology is nonspecific and overlaps with other pathologies, such as acute coronary syndromes, aortic dissection, pericardial tamponade, new onset arrhythmia, pneumonia, and pneumothorax. ^, Clinical impression alone has a sensitivity and specificity of 85% and 51%, respectively. For this reason, clinical prediction algorithms have been developed. Various laboratory and imaging tests are complimentary of the clinical suspicion.

Laboratory Tests

Routine blood tests in patients with PE are nonspecific and may include leukocytosis, elevated LDH and AST, CRP, and ESR. Plasma D-dimer levels, preferably using a high-sensitivity assay, are useful in patients who are unlikely to have PE or the clinical probability is low or intermediate to reduce unnecessary computed tomography pulmonary arteriography (CTPA) or lung scans. In these cases, a normal D-dimer level (<500 μg/L or <10 μg/L × age when >50 years old) practically excludes PE. On the contrary, a positive D-dimer test is associated with a notoriously low specificity and should prompt further testing.

Biomarkers of RV dysfunction include troponin and brain natriuretic peptide (BNP). Their diagnostic value is limited because they are neither sensitive nor specific. However, in patients with confirmed PE, cardiac troponin (TnT or TnI) and BNP (or its precursor NT-proBNP) tests are recommended for further stratification of patients at intermediate risk (see below). ^, The standard cutoff values for TnT, TnI, and BNP are 0.1 ng/mL, 0.4 ng/mL, and 90 pg/mL, respectively, although they may vary depending on the assay and the lab. Similar to D-dimers, age-adjusted and not standard values are better predictors of adverse outcomes for troponin (e.g., high sensitivity TnT is prognostic at 45 pg/mL instead of 14 pg/mL for patients older than 75 years). NT-proBNP has its optimal prognostic value when it exceeds 600 pg/mL instead of the previously proposed 300, 500, or 1000 pg/mL. An alternative novel marker of myocardial injury is the heart-type fatty acid–binding protein emerging as a significant predictor of mortality in patients with intermediate risk PE.

Arterial blood gases are also nonspecific and do not assist in the diagnosis of PE. However, hypoxemia may have a prognostic value for confirmed PE as an indicator of anticipated complications, respiratory failure, or death. Pulse oximetry is a more reasonable noninvasive alternative, at least for the low- or intermediate-risk patients.

Electrocardiogram

Electrocardiographic changes associated with acute PE are neither sensitive nor specific. They are similar to all other causes of pulmonary hypertension (e.g., acute bronchospasm, pneumothorax). The S1Q3T3 (prominent S wave in lead I, Q wave and inverted T wave in lead III) pattern is a sign of acute RV overload (acute cor pulmonale) and reflects strain; it is seen in less than 20% of diagnosed PEs. The greatest utility of the ECG in a suspected PE is to rule out acute myocardial infarction.

Chest X-Ray

Chest radiographs are not sensitive or specific for PE but can rule out alternative diagnoses (e.g., pneumothorax). Frequently, patients with PE have a normal chest X-ray. Atelectasis or parenchymal density and pleural effusion are probably the most frequent findings. Radiographic signs such as the Fleischner sign (enlarged pulmonary artery), Hampton hump (peripheral wedge of airspace opacity – lung infarction), Westermarck sign (regional oligemia), and knuckle sign (abrupt tapering or cutoff of a pulmonary artery) are rare but should raise the suspicion of PE.

Computed Tomographic Arteriography

Computed tomographic pulmonary arteriography (CTPA) is the method of choice for imaging the pulmonary vasculature in patients with suspected PE ( Fig. 152.1A ). It allows adequate visualization of the pulmonary arteries down to at least the segmental level and has a high predictive value, particularly when combined with clinical probability. Based on the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II trial, CTPA has a sensitivity of 83% and a specificity of 96% and several studies have demonstrated its efficiency as a stand-alone imaging test for confirming or excluding PE.

Figure 152.1, Pulmonary Embolism (PE) and Right Ventricular Imaging.

CTPA, particularly if it is electrocardiogram gated, can further serve as a prognostic tool for the severity and outcomes of PE. Heart chamber dimension measurements may detect RV enlargement as an indicator of RV dysfunction, typically defined as a right-to-left ventricular end-diastolic dimensional ratio ≥0.9 ( Fig. 152.1B ).

Echocardiogram

Transthoracic echocardiography (TTE) is the most common first-line examination to diagnose the signs of RV dysfunction but cannot definitely diagnose PE because an elevated RV pressure may be the result of other conditions such as pulmonary hypertension and RV infarction. Echocardiography is most useful in patients with diagnosed PE, for prognostic purposes. Confirmation of RV dysfunction is a key determinant of PE prognosis because it seems to increase the risk of death by at least twofold.

RV/LV end-diastolic diameter ratio has been commonly used as an indicator of RV dysfunction, defined as RV/LV end-diastolic ratio greater than 1, but its reproducibility is only fair because the ventricular walls cannot always be well defined ( Fig. 152.1C ). ^, Tricuspid annular plane systolic excursion (TAPSE) is a quantitative echocardiographic parameter that is the least user dependent and most reproducible. Another sign of RV dysfunction is the depressed contractility of the RV free wall compared with the RV apex (McConnell sign), reported to retain a high positive predictive value for PE, even in the presence of preexisting cardiorespiratory disease. Finally a relatively rare finding suggestive of PE is thrombus in the RV, also known as thrombus in transit. Thrombus in the pulmonary arteries can be seen with transesophageal echocardiography.

Overall, echocardiography is not recommended as part of the routine diagnostic workup in patients with suspected PE, unless they are hemodynamically unstable. On the other hand, confirmation of RV dysfunction may justify emergency reperfusion treatment for PE if immediate CTPA is not feasible.

Other Imaging Modalities

Ventilation/perfusion (V/Q) scans are rarely used currently unless the patient with a suspected PE is pregnant or has renal insufficiency that prohibits CTPA. V/Q scanning is a highly sensitive but poorly specific study for the diagnosis of PE. When the V/Q scan is inconclusive (and CTPA contraindicated), magnetic resonance pulmonary angiography can be a reasonable alternative, acknowledging the complexity of the protocol, suboptimal resolution, and low sensitivity. Finally, invasive pulmonary angiography is a historical “gold standard,” that currently would be justified for diagnostic purposes only provided that some kind of catheter-directed intervention (CDI) is planned (e.g., catheter thrombolysis or aspiration thrombectomy) upon confirmation of PE ( Fig. 152.1D ).

Lower extremity venous duplex will show a DVT in 30% to 50% of patients with PE, and finding a proximal DVT in patients suspected of having PE is considered sufficient to warrant anticoagulant treatment without further testing. Among patients who have symptoms or clinical signs of DVT, only half will have it confirmed by ultrasound (see Ch. 148 , Acute Lower Extremity Deep Venous Thrombosis: Presentation, Diagnosis, and Medical Treatment). Patients with acute symptomatic PE and confirmed DVT have an almost twofold higher risk of short-term death when compared with those without a DVT. ^,

Diagnostic Strategies

Several explicit clinical prediction rules have been developed to improve stratification and care. These rules apply to nonpregnant hemodynamically stable patients. Hemodynamically unstable patients with suspected PE are expected to receive an expeditious life-saving reperfusion therapy (e.g., systemic thrombolysis), skipping a potentially time-consuming probability assessment. For these hemodynamically stable patients in whom PE is suspected, following clinical and laboratory assessment, the pretest probability is most frequently assessed using the Wells or modified Geneva scores, both of which have been simplified and validated ( Table 152.1 ).

TABLE 152.1

Probability Scores for Pulmonary Embolism

Wells Score	Probability Score
Wells Score	Original	Simplified
Previous PE or DVT	1.5	1
Heart rate ≥100 bpm	1.5	1
Surgery of immobilization within the past 4 weeks	1.5	1
Hemoptysis	1	1
Active cancer	1	1
Clinical signs of DVT	3	1
Alternative diagnosis less likely than PE	3	1
Clinical Probability
Three-level Score
Low	0–1	n/a
Intermediate	2–6	n/a
High	≥7
Two-level Score
PE unlikely	0–4	0–1
PE likely	≥5	≥2
Revised Geneva Score	Original	Simplified
Previous PE or DVT	3	1
Heart rate 75–95 bpm ≥95 bpm	3 5	1 2
Surgery or fracture within the past month	2	1
Hemoptysis	2	1
Active cancer	2	1
Unilateral lower limb pain	3	1
Pain on lower limb deep venous palpation and unilateral edema	4	1
Age >65 years	1	1
Clinical Probability
Three-level Score
Low	0–3	0–1
Intermediate	4–10	2–4
High	≥11	≥5
Two-level Score
PE unlikely	0–5	0–2
PE likely	≥6	≥3

DVT , deep venous thrombosis; PE , pulmonary embolism.

Among patients who are likely to have PE based on these scores or unlikely but with a D-dimer level ≥500 ng/mL, CTPA is the imaging modality of choice. If negative, no further testing is required; if positive, treatment (anticoagulation) should be initiated. While awaiting the CTPA, initiation of empiric anticoagulation can be individualized based on the clinical scenario. Patients who are unlikely to have PE do not require a CTPA but a sensitive D-dimer test. If the levels are less than 500 ng/mL, no further testing is required (see Chapter Algorithms).

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