Pulmonary embolism (PE) is form of embolism and thromboembolism in which a blockage of the pulmonary artery (or one of its branches), usually when a deep vein thrombosis (blood clot from a vein), becomes dislodged from its site of formation and embolizes to the arterial blood supply of one of the lungs. This process is termed thromboembolism.
The development of thrombosis is classically due to a group of causes named Virchow's triad (alterations in blood flow, factors in the vessel wall and factors affecting the properties of the blood). Often, more than one risk factor is present.
- Alterations in blood flow: immobilization (after surgery, injury or long-distance air travel), pregnancy (also procoagulant), obesity (also procoagulant)
- Factors in the vessel wall: of limited direct relevance in VTE
- Factors affecting the properties of the blood (procoagulant state):
- Estrogen-containing hormonal contraception
- Genetic thrombophilia (factor V Leiden, protein C deficiency, protein S deficiency, antithrombin deficiency, hyperhomocysteinemia and plasminogen/fibrinolysis disorders). The role of prothrombin mutation G20210A, is unclear.
- Acquired thrombophilia (malignancy, antiphospholipid syndrome, nephrotic syndrome, paroxysmal nocturnal hemoglobinuria)
The diagnosis of PE is based primarily on validated clinical criteria combined with selective testing because the typical clinical presentation (shortness of breath, chest pain) cannot be definitively differentiated from other causes of chest pain and shortness of breath. Patients can present with atypical syndromes such as unexplained exacerbations of chronic obstructive pulmonary disease.
Various clinical prediction rules exist to help diagnose PE, such as the Wells score and the Geneva rule. More importantly, the use of any rule may exclude PE when combined with a normal d-dimer and use of any rule might be associated with reduction in recurrent thromboembolism.
- History of the Wells score
The most commonly used method to predict clinical probability, the Wells score, is a clinical prediction rule, whose use is complicated by multiple versions being available. In 1995, Wells et al initially developed a prediction rule (based on a literature search) to predict the likelihood of PE, based on clinical criteria. The prediction rule was revised in 1998 This prediction rule was further revised when simplified during a validation by Wells et al in 2000. In the 2000 publication, Wells proposed two different scoring systems using cutoffs of 2 or 4 with the same prediction rule. In 2001, Wells published results using the more conservative cutoff of 2 to create three categories. An additional version, the "modified extended version", using the more recent cutoff of 2 but including findings from Wells's initial studies were proposed. Most recently, studies (including one by Wells) reverted to Wells's earlier use of a cutoff of ≤ 4 points to create only two categories.
- Wells score
The Wells score:
- clinically suspected DVT - 3.0 points
- alternative diagnosis is less likely than PE - 3.0 points
- tachycardia (>100 bpm) - 1.5 points
- immobilization/surgery for 3 days ore more in previous four weeks - 1.5 points
- history of DVT or PE - 1.5 points
- hemoptysis - 1.0 points
- malignancy (treatment for within 6 months, palliative) - 1.0 points
- Interpretation of the Wells score
- Score >6.0 - High (probability 59% based on pooled data)
- Score 2.0 to 6.0 - Moderate (probability 29% based on pooled data)
- Score <2.0 - Low (probability 4% to 15% based on pooled data)
- Score > 4 - PE likely. Consider diagnostic imaging.
- Score 4 or less - PE unlikely. Consider D-dimer to rule out PE.
The Geneva score also has several versions including the original version with 7 items that include blood gas and chest radiograph the 'revised' version with 8 items using only signs and symptoms:
|Age > 65||1|
|Previous PE or DVT||3|
|Surgery under general anesthesia or lower-limb fracture within 1 month||2|
|Malignancy (either active or considered cured within 1 year||2|
|Unilateral lower-limb pain||3|
|Heart rate 75-94||3|
|Heart rate > 94||5|
|Pain on lower-limb palpation and unilateral edema||4|
|Points||Clinical probability||Prevalence of PE|
|4 - 10||Intermediate||29%|
- age over 65
- history of deep venous thrombosis or pulmonary embolism
- surgery under general anesthesia or lower-limb fracture within 1 month
- active malignancy
- unilateral lower-limb pain
- heart rate between 75 and 94 (give additional point if > 95)
- pain on lower-limb palpation and unilateral edema
In this version, a patient with a score of 2 or less is unlikely to have a pulmonary embolism during the next three months.
The Pulmonary Embolism Rule-out Criteria (PERC) may identify patients who are at such low risk that d-dimer testing is not needed in low (<15% prevalence), but not medium (>20% prevalence), risk populations.
In low/moderate suspicion of PE, a normal D-dimer level (shown in a blood test) is enough to exclude the possibility of thrombotic PE. Unfortunately, many or even most doctors do not explicitly calculate pretest probability when interpreting the results of the d-dimer.
Immunologic tests for d-dimer are generally use immunoassays such as enzyme-linked immunosorbent assay or serologic tests such as agglutination tests. The immunoassays (more specifically, enzyme-linked immunosorbent assay) tend to be more sensitive.
|Elisa such as VIDAS™||95%
|Latex agglutination such as Tinaquant™||89%
|Whole blood hemagglutination test such as SimpliRED™||78%
Most patients with a pulmonary embolism have an abnormal alveolar-arterial oxygen gradient.
CT pulmonary angiography
Computed tomography with radiocontrast, also known as computed tomographic pulmonary angiography (CTPA), is increasingly used as the mainstay in diagnosis. Advantages are clinical equivalence, its non-invasive nature, its greater availability to patients, and the possibility of detecting alternative diagnoses from the differential diagnosis when there is no pulmonary embolism. CTPA has progressed to be available with 64 slices, each 0.625 mm thick. These machines take 3-4 seconds to scan and may be gated to the heart beat.
- Role in diagnosis
Assessing the accuracy of CT pulmonary angiography is hindered by the rapid changes in the number of rows of detectors available in multidetector CT (MDCT) machines. The PIOPED II study used a mixture of 4 slice and 16 slice scanners and reported a sensitivity of 83% and a specificity of 96%. This study noted that additional testing is necessary when the clinical probability is inconsistent with the imaging results.
|Location of embolism||Number of patients
with true positive CTA
|Total number of patients
with this finding on CTA
|Total number of patients
with embolism in this location
|Positive predictive value of CTA|
|Embolism in a main or lobar artery||116||120||Not reported||97%|
|Segmental vessel||32||47||Not reported||68%|
|Subsegmental branch||2||8||Not reported||25%|
- Role in Prognosis
Both systematic reviews concluded that is appears safe to withhold anticoagulation after a negative CTPA. However, there may be two limitations to these conclusions. First, only one study in the two reviews has a pretest probability over 40%. Thus, these conclusions may not generalize to patients who are high risk in the three level Wells score. Second, many of the patients in these studies had additional tests such as leg dopplers as part of their evaluation so the results may not address CTPA as an individual test.
A more recent randomized controlled trial used d-dimer along with a mixture of 16 to 64 row detectors and found that adding imaging of the legs was not needed. Among the patients included in this protocol, the prevalence of pulmonary embolism was 20.6%. All patients had either a d-dimer test or a leg ultrasonogram to help exclude pulmonary embolism.
A second randomized controlled trial was published after the two systematic reviews. This trial included patients with either patients with a Wells score of 4.5 or greater or a positive D-dimer assay result. The prevalence of pulmonary embolism during the initial evaluation was 14%. The trial found that CTPA, especially when multidector scans are used, increase the number of emboli found as compared to Ventilation/perfusion scan. The importance of the increased detection is uncertain, but may be partly overdiagnosis.
Ventilation/perfusion scan (or V/Q scan or lung scintigraphy), which shows that some areas of the lung are being ventilated but not perfused with blood (due to obstruction by a clot). This type of examination is used less often because of the more widespread availability of CT technology, however, it may be useful in patients who have an allergy to iodinated contrast or in pregnancy due to lower radiation exposure than CT.
Chest X-rays are often done on patients with shortness of breath to help rule-out other causes, such as congestive heart failure and rib fracture. Chest X-rays in PE are rarely normal, but usually lack signs that suggest the diagnosis of PE (e.g. Westermark sign, Hampton's hump).
Magnetic resonance imaging
Ultrasonography of the legs
Ultrasonography or Duplex Doppler ultrasonography of the legs may help by diagnosing deep venous thrombosis (DVT) of the legs that may have led to pulmonary embolism. The presence of DVT, as shown on ultrasonography of the legs usually warrants anticoagulation, because of the strong association between DVT and PE.
Examining the legs may be valid approach in pregnancy, in x-rays might cause birth defects in the unborn child. However, a negative scan does not rule out PE, and low-radiation dose scanning may be required if the mother is deemed at high risk of having pulmonary embolism.
An ECG may show signs of right heart strain or acute cor pulmonale in cases of large PEs - the classic signs are a large S wave in lead I, a large Q wave in lead III and an inverted T wave in lead III ("S1Q3T3"). This is occasionally (up to 20%) present, but may also occur in other acute lung conditions and has therefore limited diagnostic value; the most commonly seen sign in the ECG is sinus tachycardia.
In massive and submassive PE, dysfunction of the right side of the heart can be seen on echocardiography, an indication that the pulmonary artery is severely obstructed and the heart is unable to match the pressure. Some studies (see below) suggest that this finding may be an indication for thrombolysis. Not every patient with a (suspected) pulmonary embolism requires an echocardiogram, but elevations in cardiac troponins or brain natriuretic peptide may indicate heart strain and warrant an echocardiogram.
The specific appearance of the right ventricle on echocardiography is referred to as the McConnell sign. This is the finding of akinesia of the mid-free wall but normal motion of the apex. This phenomenon has a 77% sensitivity and a 94% specificity for the diagnosis of acute pulmonary embolism.
Combining tests into algorithms
Recent recommendations for a diagnostic algorithm have been published by the PIOPED II investigators; however, these recommendations do not reflect research using 64 slice MDCT. These investigators recommended:
- Low clinical probability. If negative D-dimer, PE is excluded. If positive D-dimer, obtain MDCT and based treatment on results.
- Moderate clinical probability. If negative D-dimer, PE is excluded. However, the authors were not concerned that a negative MDCT with negative D-dimer in this setting has an 5% probability of being false. Presumably, the 5% error rate will fall as 64 slice MDCT is more commonly used. If positive D-dimer, obtain MDCT and based treatment on results.
- High clinical probability. Proceed to MDCT. If positive, treat, if negative, addition tests are needed to exclude PE.
In most cases, anticoagulant therapy is the mainstay of treatment. Some patients at risk of bleeding and with low risk of recurrent embolism may have treatment safely withheld. Acutely, supportive treatments, such as oxygen or analgesia, are often required. See respiratory emergencies and critical care.
In most cases, anticoagulant therapy is the mainstay of treatment. Heparin, low molecular weight heparins (such as enoxaparin and dalteparin), or fondaparinux is administered initially, while warfarin therapy is commenced (this may take several days, usually while the patient is in hospital). Warfarin therapy often requires frequent dose adjustment and monitoring of the INR. In PE, INRs between 2.0 and 3.0 are generally considered ideal. If another episode of PE occurs under warfarin treatment, the INR window may be increased to e.g. 2.5-3.5 (unless there are contraindications) or anticoagulation may be changed to a different anticoagulant e.g. low molecular weight heparin. In patients with an underlying malignancy, therapy with a course of low molecular weight heparin may be favored over warfarin based on the results of the CLOT trial. Similarly, pregnant women are often maintained on low molecular weight heparin to avoid the known teratogenic effects of warfarin.
Duration of treatment
Regarding the duration of anticoagulation, see embolism and thrombosis: treatment.
Vena cava filter
Clinical practice guidelines address the management of severe forms of embolism and thrombosis which may require thrombolysis. An algorithm from the guidelines is online at http://circ.ahajournals.org/content/123/16/1788/F2.large.jpg. Massive PE causing hemodynamic instability (marked decreased oxygen saturation, tachycardia and/or hypotension) is an indication for thrombolysis, the enzymatic destruction of the clot with medication.
For submassive PE, some advocate thrombolysis if right ventricular dysfunction can be demonstrated on echocardiography. However, an uncontrolled study suggests that submassive saddle PEs may not require thrombolysis.
Thrombolysis can be given for severe PEs when surgery is not immediately available or possible (e.g. periarrest or during cardiac arrest). The only trial that addressed this issue had 8 patients; the four receiving thrombolysis survived, while the four who received only heparin died. The use of thrombolysis in moderate PEs is still debatable. The aim of the therapy is to dissolve the clot, but there is an attendant risk of bleeding or stroke.
Surgical management of PE
Surgical management of acute pulmonary embolism (pulmonary thrombectomy) is uncommon and has largely been abandoned because of poor long-term outcomes. However, recently, it has gone through a resurgence with the revision of the surgical technique and is thought to benefit selected patients.
Mortality from untreated PE is said to be 26% based on the outcome in patients who received placebo treatment. The rate of 26% in the placebo group is probably an overstatement, given that the technology of the day may have detected only severe PEs.
The PESI and Geneva prediction rules can estimate mortality and so may guide selection of patients who can be considered for outpatient therapy.
Evaluation for underlying causes for recurrence
After a first PE, the search for secondary causes is usually brief. Only when a second PE occurs, and especially when this happens while still under anticoagulant therapy, a further search for underlying conditions is undertaken. This will include testing ("thrombophilia screen") for Factor V Leiden mutation, antiphospholipid antibodies, protein C and S and antithrombin levels, and later prothrombin mutation, MTHFR mutation, Factor VIII concentration and rarer inherited coagulation abnormalities.
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