PE is a common and sometimes fatal disease. It is due to obstruction of a pulmonary artery or one of its branches by material (e.g., thrombus, tumor, air, or fat) that originated elsewhere in the body.
PE can be classified according to the presence or absence of hemodynamic stability (hemodynamically unstable or stable), the temporal pattern of presentation (acute, subacute, or chronic), the anatomic location (saddle, lobar, segmental, subsegmental), and the presence or absence of symptoms (symptomatic or asymptomatic).
Patients with hemodynamically unstable PE, defined as a systolic blood pressure <90 mmHg or a drop in systolic blood pressure of ≥40 mmHg from baseline for >15 minutes, should be distinguished from patients with hemodynamically stable PE because the hemodynamically unstable PE patient are more likely to die from obstructive shock in the first two hours of presentation and may, therefore, benefit from more aggressive treatment.
The overall incidence of PE is approximately 112 cases per 100,000. PE is slightly more common in males than females, and the incidence increases with age. Deaths from PE account for approximately 100,000 deaths per year in the United States.
The pathogenesis of PE is similar to that of DVT. Most emboli arise from lower extremity proximal veins (iliac, femoral, and popliteal). However, they may also originate in the right heart, inferior vena cava or the pelvic veins, and in the renal and upper extremity veins.
There is often more than one risk factor at play in any given patient, which may include both hereditary and acquired factors. The most frequent hereditary causes of VTE are the factor V Leiden and prothrombin gene mutations, which account for 50% to 60% of cases. The major acquired risk factors for VTE include prior thromboembolism, recent major surgery, trauma, immobilization, antiphospholipid antibodies, malignancy, pregnancy, oral contraceptives, and myeloproliferative disorders.
PE has a wide variety of presenting features, ranging from no symptoms to shock or sudden death. The most common presenting symptom is dyspnea, followed by CP (classically but not always pleuritic) and cough and symptoms of DVT. However, many patients, including those with large PE, have mild symptoms or are asymptomatic.
For most patients with suspected PE, an approach is suggested which combines clinical and PTP assessment and tests, including ECG, CXR, BNP and troponin levels, ABGs, and D-dimer testing. However, these tests are neither sensitive nor specific for the diagnosis of PE and are most useful for confirming the presence of alternative diagnoses or providing prognostic information in the event that PE is diagnosed. Definitive diagnostic imaging, usually CTPA and, less commonly, V/Q scanning should be performed.
The initial approach to patients with suspected PE should focus upon stabilizing the patient while clinical evaluation and definitive diagnostic testing are ongoing. Supplemental oxygen should be administered to target an oxygen saturation of ≥90%. Severe hypoxemia, hemodynamic collapse, or respiratory failure should prompt consideration of mechanical ventilation. When mechanical ventilation is necessary, an expert in cardiovascular anesthesia should be consulted, when feasible, to avoid catastrophic hypotension due to sedation and positive pressure ventilation. For those who require hemodynamic support, cautious infusions of IVF (500 to 1000 mL of normal saline) is suggested rather than larger volumes. Vasopressor therapy should be initiated if perfusion fails to respond to IVF.
Once the diagnosis is made, the mainstay of therapy for patients with confirmed PE is anticoagulation, depending upon the risk of bleeding. Alternative treatments include thrombolysis, IVC filters, and embolectomy.
For patients with a high clinical suspicion for PE who are hemodynamically unstable and successfully resuscitated, immediate anticoagulation and definitive diagnostic imaging are preferred. For patients with a low or moderate suspicion of PE who are successfully resuscitated, the same approach to diagnosis and empiric anticoagulation should be used for patients who are hemodynamically stable. For patients who remain unstable despite resuscitation, bedside echocardiography and lower extremity US with Doppler of the leg veins can be used to obtain a rapid or presumptive diagnosis of PE (visualization of thrombus or new right heart strain) to justify the administration of potentially life-saving therapies, including thrombolytic agents.
For patients with suspected PE who are hemodynamically stable, an approach that selectively integrates clinical evaluation, three-tiered PTP testing, Wells criteria, PERC, D-dimer, and imaging is advocated. CTPA, also called chest CT angiogram with contrast, is the preferred imaging exam.
Thrombolytic therapy for acute PE accelerates clot lysis and leads to early hemodynamic improvement (e.g., improved pulmonary arterial blood pressure, RV function, and pulmonary perfusion). However, it also increases major bleeding and has not been convincingly shown to improve mortality or reduce the frequency of recurrent thromboembolism.
In most cases, thrombolytic therapy should be considered only after acute PE has been confirmed because the adverse effects of thrombolytic therapy can be severe. Patient values and preferences should be taken into consideration when discussing the risk and benefits of thrombolytic therapy.
In hemodynamically unstable patients, the following applies:
- For patients with confirmed acute PE who are persistently hypotensive due to PE (systolic blood pressure <90 mmHg or a drop in systolic blood pressure of ≥40 mmHg from baseline) and do not have an increased risk of bleeding, systemic thrombolytic therapy is suggested followed by anticoagulation, rather than anticoagulation alone. A similar approach is also appropriate in those whose course is complicated by hypotension assessed to be due to recurrent PE despite anticoagulation.
- Once it is decided that thrombolytic therapy is warranted, it is suggested that the thrombolytic agent be administered by a peripheral venous catheter rather than a pulmonary arterial catheter. A thrombolytic regimen with a short infusion time (i.e., ≤2 hours) is suggested, rather than a regimen with a more prolonged infusion time.
- For patients who have failed systemic thrombolysis, or patients at high risk of bleeding, catheter-directed thrombus removal with or without thrombolysis is suggested rather than no intervention, provided local expertise is available. Although guidelines suggest CDT in patients at risk of death before systemic therapy can manifest effectiveness (e.g., within hours), this is often impractical. As such, systemic thrombolysis is clearly a more rapid approach.
In hemodynamically stable patients, the following applies:
- For most patients with acute PE who do not have hemodynamic compromise, thrombolytic therapy is not suggested.
- Acute PE with RV dysfunction constitutes a spectrum of severity, and more data are needed before thrombolytics can be routinely administered in this population of patients. However, thrombolysis may be considered on a case-by-case basis when the benefits are assessed by the clinician to outweigh the risk of hemorrhage. The optimal method of administering thrombolytic therapy in this population is unknown. If thrombolytic therapy is to be administered in acute PE with RV dysfunction, CDT rather than systemic therapy may be preferred, provided the expertise is available. Systemic therapy is an alternative if expertise is not available.
- Surgical embolectomy may be warranted when there are contraindications to thrombolysis, thrombolysis fails to induce clinical improvement, or catheter-based thrombolysis is not available.
Initial anticoagulation refers to anticoagulant therapy that is administered immediately following a diagnosis of acute VTE. It is often given over the first few days (typically from 0 to 10 days) while planning for long term anticoagulation. Anticoagulation should be started immediately as a delay increases the risk of embolization and death.
Every patient with acute VTE should be assessed for the risk of bleeding prior to anticoagulation. Most clinicians agree that anticoagulation should be administered to patients with a low risk of bleeding and avoided in those at high risk. For patients with a moderate risk of bleeding, the decision to anticoagulate must be individualized according to the values and preferences of the patient, as well as, the risk-benefit ratio as assessed by the clinician.
For most patients with acute VTE, LMW heparin SQ, fondaparinux SQ, or the factor Xa inhibitors, rivaroxaban PO or apixaban PO are preferred rather than UFH IV. A decision between these agents is usually made based upon clinician experience, as well as the risks of bleeding, patient comorbidities, preferences, cost, and convenience. Dosing for each agent is individualized.
Other populations require special consideration:
- For most patients with acute VTE who have severe renal failure (e.g., creatinine clearance <30 mL/minute), hemodynamic instability, or massive iliofemoral DVT, or for patients in whom there is a high likelihood of needing to discontinue or reverse anticoagulation acutely, IV UFH is preferred rather than LMW heparin. IV UFH may also be an alternative to LMW heparin when SQ absorption is potentially poor (e.g., massive edema, anasarca). A weight-based protocol is preferably used to administer UFH at a dose sufficient to prolong the aPTT, with a target aPTT ratio of 1.5 to 2.5 over the control.
- For patients with malignancy and pregnant women, LMW heparin is the preferred initial anticoagulant.
- For patients with HIT, heparin is contraindicated, and immediate anticoagulation with a non-heparin anticoagulant (e.g., argatroban, danaparoid, fondaparinux, bivalirudin) is indicated.
- Outpatient rather than inpatient anticoagulation can be considered in select patients.
The decision to empirically anticoagulate while waiting for diagnostic test results depends upon the clinical suspicion for VTE, the expected timing of diagnostic tests, and the bleeding risk.
Full anticoagulation should be ensured during the transition from initial to long-term (maintenance) therapy when switching agents.
In patients with a low clinical probability of PE (e.g., <15%, Wells score <2), the PERC criteria should be applied. Patients who fulfill all eight criteria do not need additional testing. For patients who do not meet PERC criteria or in whom PERC cannot be applied (e.g., critically-ill patients), further testing with sensitive D-dimer measurement is indicated. No imaging is required when the D-dimer level is normal (<500 ng/mL), while imaging is indicated in those with a positive D-dimer (≥500 ng/mL).
In patients with an intermediate clinical probability of PE (e.g., Wells score 2 to 6), sensitive D-dimer testing is preferred to determine whether or not diagnostic imaging is indicated. Patients with a negative D-dimer do not need imaging, while those with a positive D-dimer should have chest imaging. However, some experts proceed directly to diagnostic imaging in select patients (e.g., those with limited cardiopulmonary reserve or those in the upper zone of the intermediate range such as a Wells score of 4 to 6).
In patients with a high clinical probability of PE (e.g., Wells score >6), diagnostic imaging with CTPA is preferred. A positive result confirms the diagnosis of PE, while a negative result excludes it in nearly all cases.
CTPA acquires thin (≤2.5 mm) section volumetric images of the chest after a bolus administration of IV contrast that is timed precisely for maximal enhancement of the pulmonary arteries. A multidetector row (≥16 detectors rows) CT scanner is required to achieve sufficient diagnostic performance. A chest CT with contrast not performed as a CTPA but for other indications is not an adequate exam to exclude suspected PE.
For patients with suspected PE in whom CTPA is contraindicated, unavailable, or inconclusive, V/Q scanning is the alternative imaging exam. V/Q scan results reported as high-, intermediate- or low-probability for PE, or normal, should be interpreted in conjunction with clinical suspicion. A high-probability V/Q scan and high clinical probability is sufficient to confirm PE. A normal scan or a low-probability scan in the setting of low clinical probability of PE can also be used to rule out PE. All other combinations of V/Q results and clinical probability are nondiagnostic.
For patients in whom both CTPA and V/Q scanning are contraindicated, unavailable, or inconclusive, noninvasive testing with lower extremity compression ultrasonography with Doppler is preferred (although not diagnostic of PE).
A diagnosis of PE is made radiographically based upon CTPA, MRPA, or catheter-based pulmonary angiography by the demonstration of a filling defect in any branch of the pulmonary artery.
The differential diagnosis of PE includes many other entities that present similarly with dyspnea, CP, hypoxemia, leg pain and swelling, tachycardia, syncope, and shock. Other competing diagnoses including heart failure, myocardial ischemia, pneumothorax, pneumonia, and pericarditis, which may be distinguished on ECG, echocardiographic, laboratory, and CXR testing. However, PE can coexist with these conditions and, therefore, the presence of an alternate diagnosis does not entirely exclude the diagnosis of PE.
For patients with suspected PE who are hemodynamically stable or hemodynamically unstable and successfully resuscitated, the administration of empiric anticoagulation depends upon the risk of bleeding, the clinical suspicion for PE, and the expected timing of diagnostic tests.
For patients with a low risk of bleeding and a high clinical suspicion for PE, empiric anticoagulation is suggested rather than waiting until definitive diagnostic tests are completed. A similar approach is used in those with moderate or low clinical suspicion for PE in whom the diagnostic evaluation is expected to take longer than four hours and 24 hours, respectively.
It is not suggested that anticoagulation therapy be initiated in patients with absolute contraindications to anticoagulant therapy or those who have an unacceptably high risk of bleeding.
For patients with a moderate risk of bleeding, empiric anticoagulant therapy may be administered on a case-by-case basis according to the assessed risk-benefit ratio.
The optimal agent for empiric anticoagulation depends upon hemodynamic instability, the anticipated need for procedures or thrombolysis, and the presence of risk factors and comorbidities.
In patients with a high clinical suspicion for PE who are hemodynamically unstable and who have a definitive diagnosis by portable perfusion scanning or a presumptive diagnosis of PE by bedside echocardiography (because definitive diagnostic testing is unsafe or not feasible), systemic thrombolytic therapy is suggested rather than empiric anticoagulation or no therapy. If bedside testing is delayed or unavailable, the use of thrombolytic therapy as a life-saving measure should be individualized. If not used, the patient should receive empiric anticoagulation.
For patients who are hemodynamically unstable and the clinical suspicion is low or moderate, empiric anticoagulation similar to that suggested for patients who are hemodynamically stable is indicated. Empiric thrombolysis is not justified in this population.
For patients in whom definitive diagnostic testing excludes PE, anticoagulant therapy should be discontinued if it was initiated empirically, and alternative causes of the patient’s signs and symptoms should be sought.
For patients in whom the diagnostic evaluation confirms PE, an approach that is stratified according to whether or not the patient is hemodynamically stable or unstable is suggested. At any time, the strategy may need to be redirected as complications of PE or therapy arise.
For most hemodynamically stable patients with PE (i.e., low risk/nonmassive), the following applies:
- For those in whom the risk of bleeding is low, it is recommended that anticoagulant therapy be initiated or continued. Outpatient anticoagulation is safe and effective in select patients at low risk of death, provided that they do not have respiratory distress, serious comorbidities, or requirements for oxygen or narcotics and that they also have a good understanding of the risks and benefits of such an approach. Most patients with SSPE should be anticoagulated. However, in a small select population, observation with serial lower extremity ultrasonography may be appropriate.
- For those who have contraindications to anticoagulation or have an unacceptably high bleeding risk, an IVC filter should be placed rather than observation.
- For those in whom the risk of bleeding is moderate, therapy should be individualized according to the risk-benefit ratio and preferences of the patient.
- In most hemodynamically stable patients, thrombolytic therapy is not recommended.
- For hemodynamically stable (i.e., normotensive) patients with intermediate-risk/submassive PE, anticoagulation should be administered and patients monitored closely for deterioration. Examples of such patients include those who subsequently deteriorate due to recurrent PE, have a large clot burden, severe RV enlargement/dysfunction, have high oxygen requirements, and/or are severely tachycardic. Thrombolysis and/or catheter-based therapies may be considered on a case-by-case basis when the benefits are assessed by the clinician to outweigh the risk of hemorrhage (e.g., deterioration due to PE).
For most patients with hemodynamically unstable PE, the following applies:
- For patients with refractory hypotension and without contraindications to thrombolysis, systemic thrombolytic therapy is suggested followed by anticoagulation rather than anticoagulation alone. A similar approach is suggested for select patients whose course becomes complicated by hypotension during anticoagulation in whom the suspicion for recurrent PE despite anticoagulation is high.
- For those in whom thrombolysis is contraindicated, catheter or surgical embolectomy is suggested rather than observation. The choice between these options depends upon a variety of factors.
- For those in whom systemic thrombolysis is unsuccessful, the optimal therapy is unknown. Options include repeat systemic thrombolysis, CDT, or catheter or surgical embolectomy. The preference is for CDT. However, in many cases, the choice is dependent upon available resources and local expertise.
In patients with PE who are fully anticoagulated, early ambulation is suggested rather than bed rest, when feasible. Although IVC filters are not routinely used adjunctively in patients who are therapeutically anticoagulated, they are used in rare circumstances by some experts (e.g., those with poor cardiorespiratory reserve), although this strategy is largely unproven.
PE, left untreated, has a mortality of up to 30%, which is significantly reduced with anticoagulation. The highest risk occurs within the first seven days, with death most commonly due to shock. Prognostic models that incorporate clinical findings (e.g., Pulmonary Embolism Severity Index [PESI] and the simplified PESI [sPESI] and/or biochemical markers that indicate right ventricle strain (natriuretic peptides, troponin) can predict early death and/or, recurrence.
Patients treated with UFH and/or warfarin should be monitored for laboratory evidence of therapeutic efficacy. Patients should also be monitored for early (e.g., recurrence) and late (e.g., CTEPH) complications of PE, as well as, for the complications of anticoagulation and other definitive therapies. In addition, patients should be investigated for the underlying cause of PE.
Inadequate anticoagulation is the most common reason for recurrent VTE while on therapy. The clinician should test for therapeutic levels of anticoagulants when relevant, as well as considering additional etiologies of recurrence (e.g., suboptimal therapy, ongoing prothrombotic stimuli, and alternate diagnoses).
PE can be complicated by recurrent thrombosis, CTEPH, and death.