Approach

Management of PE is based on an algorithmic diagnostic approach. History and physical examination are relatively insensitive and nonspecific, so must be combined with other diagnostic tests in the clinical decision-making process.

A high index of suspicion and prompt management are required as the highest risk of dying is within the first 2 hours of presentation.[8][86] However, PE is present in only a small minority of patients in whom it is suspected.

Clinical probability

Clinical probability, assessed by a validated prediction rule and/or clinical judgment, is the basis for all diagnostic strategies for PE.[4]​​[87]​​​​ In hemodynamically stable patients with non-high (low or intermediate) clinical probability of PE, D-dimer measurement is recommended to assess the need for imaging.[87] In patients with very low clinical probability of PE, D-dimer testing is reserved for those who do not meet all of the Pulmonary Embolism Rule-Out Criteria (PERC).[87]

Those with a high clinical probability of PE, or with an abnormal D-dimer, should proceed immediately to computed tomographic pulmonary angiography (CTPA; or ventilation-perfusion [V/Q] lung scan if CTPA is contraindicated), as should any patient with suspected PE with shock or hypotension. In patients with high pretest probability of PE, anticoagulation should be initiated while awaiting imaging results.[21][22]

Confirmation of PE

Confirmation of the diagnosis requires documentation of a blood clot in a pulmonary artery by an imaging study (such as CTPA). Confirmation of PE with a definitive test is essential because treatment is associated with significant bleeding risk.

[Figure caption and citation for the preceding image starts]: Summary: pulmonary embolism diagnostic pathwayCreated by BMJ Knowledge Centre [Citation ends].com.bmj.content.model.Caption@7ebbb038

History

History can vary greatly between individuals. Many will report an acute onset of either chest discomfort or dyspnea, but PE may present with more unusual symptoms, or even be asymptomatic.[88]

Pleuritic chest pain and dyspnea are the common presenting features.[88][89]​ A sense of apprehension is often reported.[5][90]​ Hemoptysis and syncope are less common; the latter suggests a larger clot burden, more significant right ventricular dysfunction, and poorer prognosis.[4]​​​[88][89]

Risk factors for venous thromboembolism (VTE) should be ascertained.

Signs and physical examination

Signs of PE include tachycardia, tachypnea, increased respiratory effort, fever (usually low-grade), and, in more severe cases, hypotension and signs of hypoperfusion (shock).

Physical examination is often nonspecific.[88] In severe cases, findings of right ventricular overload may be present, such as elevated jugular venous pulsation, loss of palpability of the left ventricular apex (due to posterior displacement of the left ventricle by enlargement of the right ventricle), and a right-sided third heart sound.

PE which has progressed over a period of time may present with physical findings of pulmonary hypertension, such as a right ventricular heave, holosystolic murmur of tricuspid regurgitation, loud pulmonic component of the second heart sound, elevated jugular venous pressure, and pitting edema of the extremities.[91][92][93] As PE most often originates from lower extremity deep vein thrombosis (DVT), physical findings of this condition may be present.

Patients with suspected PE with shock or hypotension

Shock (end-organ hypoperfusion and a systolic BP <90 mmHg or vasopressor requirement to maintain systolic BP >90 mmHg) or hypotension (systolic BP <90 mmHg or >40mmHg from known baseline for at least 15 minutes) occurs in a minority of cases but portends a high risk of mortality.[4]​​

More than 95% of patients who present with acute PE are hemodynamically stable.[94]

Ideally, PE should be confirmed by CTPA before thrombolytic therapy is administered.[4]​​​[95] However, a negative V/Q lung scan effectively excludes PE, and is a radiation- and medium-sparing procedure.[4]​​ If the patient is at risk of imminent cardiac arrest, treatment may be commenced on clinical grounds alone.[96]

Patients with suspected PE without shock or hypotension

When history and physical exam fail to rule out PE, the pretest probability of PE should be determined using a validated prediction rule and/or clinical judgment.[4]​​[87]​​​​ A prediction rule may be preferable, particularly for clinicians who rarely evaluate patients for PE, because clinical judgment lacks standardization.[4]​​[87]​​​​[97]

Assessing clinical probability of PE

Patients with suspected PE can be classified into distinct categories of clinical (pretest) probability that correspond to confirmed PE prevalence, using the original Wells criteria (modified), simplified Wells criteria (modified), original Geneva score (revised), or the simplified Geneva score (revised).[4]​​​[98][99] Each of these clinical decision tools assigns a value (a single point, or points) to a series of historic and physical examination features, the sum of which determines whether PE is likely or unlikely.

[ Pulmonary Embolism Wells Score Opens in new window ]

[ Revised Geneva Score for Estimation of the Clinical Probability of Pulmonary Embolism in Adults Opens in new window ]

[Figure caption and citation for the preceding image starts]: Original and simplified Wells criteria (modified)Created by the BMJ Knowledge Centre [Citation ends].com.bmj.content.model.Caption@74971d07

[Figure caption and citation for the preceding image starts]: Original and simplified Geneva score (revised)Created by the BMJ Knowledge Centre [Citation ends].com.bmj.content.model.Caption@1aaf930e

The simplified versions of the modified Wells criteria or revised Geneva score may be preferred in clinical practice because of their ease of use.[100] Both simplified versions have been validated; neither has been shown to be superior to the other.[87][101] However, the Geneva score is based entirely on objective clinical items and may be more reproducible (the Wells criteria [original and simplified] include the subjective clinical item "alternative diagnosis less likely than PE").[102]

The Wells criteria and revised Geneva score categorize patients dichotomously (PE unlikely or PE likely). However, earlier iterations of each tool attributed low, intermediate, or high clinical probabilities of PE. If the two-level classification is used, PE is confirmed in 50% of patients in the PE-likely category compared with 12% in the PE-unlikely category. If the three-level classification is employed, the proportion of patients with confirmed PE will be around 10% in the low probability category, 30% in the intermediate probability category, and 65% in the high probability category.[103]

PE likely (high clinical probability)

Multiple-detector CTPA should be ordered for patients with a PE likely clinical (pretest) probability.[4]​​​[87]​​​​ V/Q lung scan effectively excludes PE, and is a radiation- and medium-sparing procedure.[4]​​ D-dimer testing should not be performed: a normal plasma D-dimer level does not obviate the need for imaging in this patient population.[87]

PE unlikely (intermediate or low clinical probability)

Guidelines from the American College of Physicians recommend the application of the PERC to exclude PE in patients initially assessed to have a very low pretest probability of PE.[87]

In patients who meet all PERC criteria (age <50 years; initial heart rate <100 bpm; initial oxygen saturation >94% on room air; no unilateral leg swelling; no hemoptysis; no surgery or trauma within the last 4 weeks; no history of VTE; no estrogen use), the risk for PE is considered to be lower than the risk of testing, and no further testing is indicated. Patients who do not meet all of the PERC criteria can be stratified using D-dimer testing.[87] 

One meta-analysis of studies that assessed the accuracy of PERC to rule out PE reported a sensitivity of 97%.[104]

D-dimer test

D-dimer testing is highly sensitive (>95%) but nonspecific.

A normal plasma D-dimer level below threshold safely excludes PE in patients with an unlikely (intermediate or low) pretest probability of PE, and no further testing is required.[87][95] The risk of PE within 3 months is <1% in these patients.[105][106] 

D-dimer may be adjusted to age (normal is <age × 10 micrograms/L in patients aged ≥50 years) or pre-test probability of disease (1000 nanograms/mL cutoff in low-probability patients, or 500 nanograms/mL in intermediate-probability patients) to increase the specificity, and thus the percentage of patients who can avoid an imaging study.[4]​​[107][108] In patients with cancer, using an age-adjusted D-dimer cut-off doubled the proportion of patients in whom PE could be excluded by clinical decision rule and D-dimer, without imaging.[109] The YEARS algorithm with risk-adapted D-dimer thresholds has been studied in pregnant patients suspected of PE.[110]

Patients with an abnormal D-dimer level should undergo multiple-detector CTPA (or V/Q lung scan if CTPA is contraindicated) to confirm or exclude a diagnosis of PE.[4]​​[87]​​​​[95] 

Initial imaging studies

CTPA confirms the diagnosis by direct visualization of thrombus in a pulmonary artery, where it appears as a partial or complete intraluminal filling defect. The likelihood ratio to rule in a PE with a filling defect in the segmental or subsegmental branches is 24.1 (range of 12.4 to 46.7), whereas the likelihood to rule it out is 0.11 (range of 0.06 to 0.19), which means that CTPA has the best diagnostic accuracy of all advanced noninvasive imaging methods.[111][Figure caption and citation for the preceding image starts]: Contrasted CTPA scan showing subsegmental right pulmonary artery emboli (see arrows)From the collection of Seth W. Clemens; used with permission [Citation ends].com.bmj.content.model.Caption@218923f5 

V/Q lung scan, preferably using single photon emission computed tomography (SPECT, which may reduce the number of inconclusive scans), is an alternative to CTPA.[112] A negative V/Q scan effectively excludes PE. V/Q scan is a radiation- and medium-sparing procedure and may be appropriate for patients with contraindications or relative contraindications to CT (e.g., contrast allergy, moderate to severe renal failure, pregnancy, young patients).[4]​​​

Subsegmental PE

CTPA appears to increase the proportion of patients diagnosed with subsegmental PE without lowering the 3-month risk of thromboembolism, leading to potential over-diagnosis (because subsegmental PE may not warrant anticoagulant treatment in select patients).[113]

The risk of over-diagnosis may be mitigated by adherence to diagnostic algorithms that limit imaging in patients at lower probability of disease.[114]

Other imaging studies

A normal chest x-ray does not eliminate PE as a diagnosis.[115] However, a chest-ray may rule out other causes of a patient’s symptoms such as pneumothorax or pneumonia.[115]

Magnetic resonance angiography can be used to evaluate the central and segmental arteries.[115] Three different techniques are available: gadolinium-contrast enhanced angiography (Gd-MRA), real-time angiography (RT-MRA), and MR-perfusion images.[116]

Transthoracic echocardiography is generally not indicated in the diagnosis of acute PE, but it is useful in identifying right ventricular strain and assisting with severity classification and determining prognosis.[4]​​[115] Echocardiographic evidence of right heart thrombi is significantly associated with increased 30-day mortality in patients diagnosed with acute PE.[117][Figure caption and citation for the preceding image starts]: Gd-MRA showing a right main pulmonary artery pulmonary embolism (see arrow)From the collection of Seth W. Clemens; used with permission [Citation ends].com.bmj.content.model.Caption@331ddfbc

Despite its diagnostic accuracy, pulmonary angiography is rarely used for the diagnosis or exclusion of PE.[4]​​​[118] It is associated with risk of morbidity/mortality, and (less invasive) CTPA affords comparable diagnostic precision.[4]​​​[119]

Laboratory investigations

Baseline laboratory tests including prothrombin time (PT), activated partial thromboplastin time (aPTT), and international normalized ratio (INR) are important to aid decisions about the safety and type of initial anticoagulation selected. Renal and hepatic function panels also help determine the appropriate choice of anticoagulant therapy, as different agents carry precautions or are contraindicated in renal or hepatic dysfunction.[120] Complete blood count may detect hematologic abnormalities.

Troponin can be used to assist in determining the severity category of acute PE, which impacts management decisions. It is suggested in patients who have either an elevated Pulmonary Embolism Severity Index (PESI) category, or abnormalities of the right ventricle on imaging.[4]​​

Thrombophilia screen

Thrombophilia commonly refers to five hereditary conditions (Factor V Leiden, prothrombin gene 20210A, deficiencies in antithrombin, protein C deficiency, and protein S deficiency) and antiphospholipid syndrome (an acquired condition). However, many gene variants and acquired conditions modify thrombosis risk.[121]

Indications for screening are controversial.[121][122] Hereditary thrombophilia does not sufficiently modify the predicted risk of recurrent thrombosis to affect treatment decisions, and a conservative approach to testing is reasonable.[21] If a thrombophilia screen is indicated, it should be deferred until a minimum of 3 months of anticoagulant therapy has been completed because some thrombophilia tests are influenced by the presence of acute thrombosis or anticoagulant therapy.[121]  Some guidelines suggest testing only in situations where the result is likely to change a clinical decision (such as in patients with unprovoked DVT or PE who are considering stopping anticoagulants).[22] If a hereditary thrombophilia screen is considered, it should be deferred until a minimum of 3 months of anticoagulant therapy has been completed because some thrombophilia tests are influenced by the presence of acute thrombosis or anticoagulant therapy.[121]

The presence of a hereditary thrombophilia does not significantly increase the predicted risk of recurrent VTE after a provoked DVT, and guidelines discourage testing in this setting.[123]

Antiphospholipid syndrome

Antiphospholipid antibodies may predict a higher risk of future thrombosis following an initial VTE event and may impact selection of therapy.[59] Controversy exists regarding whether broad screening for antiphospholipid antibodies or screening only on the basis of clinical suspicion should be preferred.[124][125] Some guidelines suggest testing only in situations where the result is likely to change a clinical decision (such as in patients with unprovoked DVT or PE who are considering stopping anticoagulants, however these guidelines recommend seeking specialist advice as these tests may be affected by anticoagulants).[22]

For antiphospholipid antibody screening, cardiolipin and beta-2 glycoprotein-I antibodies can be performed without regard to the presence of anticoagulants; however, most anticoagulants interfere with assays for lupus anticoagulant.[59]

Arterial blood gas analysis is of limited utility

Hypoxemia is considered to be a typical finding in acute PE, but arterial blood gas analysis is of very limited diagnostic utility, alone or in combination with other clinical variables, in suspected PE.[4]​​​[126]

A PaO₂ <80 mmHg, a PaCO₂ <36 mmHg, or an abnormal alveolar-arterial gradient (A–aO₂) are not predictive of PE in patients suspected of having PE.[126] In patients with suspected acute PE with normal arterial blood gas results, PE could not be excluded in 38% of those without cardiopulmonary disease and 14% with pre-existing cardiopulmonary disease, respectively.[127]

Other investigations

Electrocardiography (ECG) cannot definitively establish or eliminate PE as a diagnosis, and specific findings may only be suggestive of PE.[89][128][129] ECG can, however, be used to assess right ventricular function in patients with confirmed PE without shock or hypotension.[4]​​[21]​​​ Right ventricular dysfunction is predictive of adverse outcome and enables risk stratification in these patients.[130][131][132]

If a definitive imaging modality is unavailable, echocardiography may be considered for patients with suspected PE presenting with shock or hypotension.[4]​​​[95]

Special patient populations

Symptoms and signs of VTE may be less specific in pregnant women than in nonpregnant patients.[95]

D-dimer levels increase through normal pregnancy, complicating its use as a test to exclude suspected PE.[4]​ However, increasing evidence supports the use of pre-test probability algorithms adapted to pregnant patients with D-dimer.[110][133] Guidelines support use of multi-step algorithms over universal imaging in pregnant patients with suspected PE.[4]​​

When an algorithm indicates that imaging is indicated in a pregnant patient suspected of PE, exposure to radiation-associated imaging should be minimized. Bilateral venous compression ultrasound to establish the presence of thrombosis suggestive of PE is recommended in pregnant patients with suspected PE.[4]​​[134] Chest x-ray is the first radiation-associated procedure if PE is suspected.[134]  In the setting of a normal chest x-ray, American Thoracic Society consensus guidelines recommend lung scintigraphy (with V/Q scan).[134] Pregnant women with a nondiagnostic V/Q scan, in whom further investigation is deemed appropriate, may undergo CTPA.[134] European Society of Cardiology guidelines suggest that CTPA in patients with abnormal chest x-ray and either V/Q scan or CTPA if chest x-ray is normal.[4]​ The administered dose of radiopharmaceutical should be reduced by a factor of 2 when lung scans are indicated in pregnant women; longer acquisition times should be used to achieve adequate imaging.[112] 

Adolescents and young adults

CTPA should be used with discretion, especially if PE can be ruled out by other noninvasive methods with less radiation exposure.[135]

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