Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM
Review Date: 3/24/2013
Definition 
Pulmonary embolism (PE) is a potentially life-threatening condition due to obstruction of the pulmonary arteries due to thrombi dislodging and migrating from deep veins in the leg, arm, abdomen, pelvis or neck.
Description
- PE is a potentially life-threatening condition resulting from a deep vein thrombus migrating into central circulation and flowing through the right atrium, then onward to lodge in the pulmonary arteries
- This condition is characterized by chest pain, dyspnea, tachypnea, tachycardia, apprehension, and syncope in some cases. Some cases of massive PE will present as sudden death or profound shock
- The most established etiological model for PE is Virchow's triad of venous stasis, damage to blood vessel walls, and hypercoagulability
- If PE goes untreated, there is risk of death and long term sequelae such as pulmonary hypertension. Acutely, large PE can result in obstructive shock, with right ventricular failure and cardiac arrest
- The severity of PE can be classified as :
- Massive PE: Involves systemic arterial hypotension with thrombi obstructing a substantial amount of pulmonary artery circulation
- Moderate-to-large PE: Involves right ventricular (RV) stain, but systemic arterial pressure is not compromised
- Small-to-moderate PE: Right-heart function and systemic arterial pressure remain normal
Epidemiology
Incidence/Prevalence
- PE is the third most common cardiovascular condition in the U.S. with an incidence of 1 case per 1000 persons annually (1999 data)
- PE accounts for 200,000-300,000 hospitalizations yearly in the U.S.
- PE mortality rate depends upon multiple factors, but is approximately 10%
Age
- Mortality increases significantly with advanced age and co-morbidities
Gender
- Mortality rates are 20-30% higher in males
Race
- The incidence of PE is higher in African-Americans than Caucasians. African-Americans have a higher PE related mortality than any other races. Asians, Pacific Islanders, and American Indians have a significantly lower risk of thromboembolism
Risk Factors
- The major cause of PE is deep vein thrombosis (DVT). Thus, risks for PE mirror those of DVT:
- Active malignancy
- Advanced age
- Antithrombin III deficiency
- Antiphospholipid antibody syndrome
- Behcet's disease
- Central venous catheter/transvenous pacemaker
- Co-morbid conditions such as inflammation, infection, and immobility
- Elevated levels of coagulation factor VIIIc
- Factor V Leiden (Relative risk of venous thromboembolism 3-4 4 times greater in heterozygotes as compared to non-carriers)
- Fibrinogen abnormalities
- Hormone replacement (estrogens)
- Hospital or nursing home confinement
- Human Immunodeficiency Virus (HIV) infection
- Inflammatory bowel disease
- Limb immobilization
- Lower extremity trauma
- Major surgery within the last 3 months
- Male gender
- Myeloproliferative disorders
- Myocardial infarction
- Neurologic disease with extremity paresis
- Obesity
- Oral contraceptive (OCP) use
- Plasminogen/plasminogen activator abnormality
- Polycythemia
- Pregnancy
- Primary pulmonary hypertension
- Protein C or S deficiency
- Prothrombin gene mutation G20210A
- Recent long distance air travel
- Resistance to activated protein C
- Sickle cell anemia
- Superficial vein thrombosis (previous or current)
- Systemic Lupus Erythematosus (SLE)
- Varicose veins
- Other non-DVT specific risk factors include
- Cerebrovascular disease
- Heart failure
- Ischemic heart disease
Etiology
The most recognized etiological model for DVT and PE is Virchow's triad
- Blood vessel wall damage: Thrombus formation at venous valves is augmented by endothelial cell damage. Blood vessel injury can result from trauma, prior DVT, surgery, venous harvest and catheterization
- Blood stasis/venous stasis: Thrombus formation is promoted by poor blood flow and stasis. Venous stasis also causes valvular damage, which further augments thrombosis
- Hypercoagulability: Certain conditions such as malignancy, high-estrogen conditions (obesity, pregnancy, OCPs, and hormone replacement therapy), inflammatory bowel disease, nephrotic syndrome, sepsis, blood transfusion, and inherited thrombophilic disorders raises the risk for PE
[Outline]
History
- Anxiety or apprehension
- Chest pain (often pleuritic)
- Decreased exercise tolerance
- Dizziness, light-headed
- Dyspnea
- DVT symptoms/risk factors
- Fever (low grade)
- Hemoptysis
- Palpitations, rapid heart beat
- Presence of risk factors
- Prior DVT/PE/Thrombophilia
- Surgery
- Syncope or pre-syncope
- Tachypnea
- Trauma/Limb immobilization
Physical findings on examination
- Abdominal/flank tenderness (unusual)
- Accentuated pulmonic component of S2
- Atrial fibrillation (new onset)
- Altered level of consciousness (ALOC)-massive PE with ALOC due to hypotension and/or hypoxia
- Cough
- Cyanosis
- Diaphoresis
- Edema +/- erythema +/- tenderness of an extremity (signs of DVT)
- Elevated jugular venous pressure
- Fever (low grade)
- Gallop S3 or S4
- Hypotension
- Rales
- Signs suggesting thrombophlebitis
- Surgical or traumatic scar
- Tachycardia (common)
- Tachypnea
- There are three validated clinical prediction systems available for determining the probability of pulmonary embolism:
- Pulmonary Embolism Rule out Criteria (PERC): Pulmonary Embolism Rule out Criteria (PERC) is a list of items, which require all 8 to be present to designate the patient as having a low pre-test probability of PE. It is important to add an experienced doctor's ‘gestalt' of the likelihood of the patient's symptoms being due to PE into consideration. The combination of low ‘gestalt' and all 8 items being present generally indicates no further testing for PE is indicated (including no benefit to D-Dimer testing).
- Revised Geneva Scoring System
- Wells Prediction Rule Wells Criteria (PE)
- Despite the availability of scoring systems, clinical gestalt out performs both the Geneva and Wells scores in real life practice. Use of clinical gestalt versus these 2 scoring systems in 1038 patients in Europe who had a 31% prevalence of PE demonstrated superiority of clinical impression over such scores
[Outline]
- Signs and symptoms of PE are often non-specific. It is not unusual for a patient to have been evaluated for symptoms by several doctors before the correct diagnosis is made
- Routine laboratory testing often adds no value, except in excluding other diagnoses which might explain the patient's symptoms.
- Patients with symptoms suspicious for PE should undergo testing to determine the presence or absence of PE. D-dimer testing can be utilized in patients who are felt to be of low clinical suspicion of having a PE. In such patients, a negative D-dimer is generally felt to be sufficient indication of the absence of PE as the cause of the patient's symptoms
- Depending upon the clinical scenario, high and intermediate risk patients should undergo imaging to determine whether PE is present. In such patients, D-Dimer testing has little role. Such patients with symptoms suggesting PE should simply receive diagnostic imaging to determine presence or absence of PE
Blood test findings
- White blood cells
- May be elevated in PE, however such findings are non-specific and are present with almost any body stressor or infection
- Plasma D-dimer test (Quantitative)
- D-dimer is a breakdown product of thrombi. A negative test indicates a low probability (<1%) of PE being present. An elevated value (>500 ng/mL) however, is non-specific as many other conditions result in D-dimer positivity. Trauma, cancer, infection, inflammation, and pregnancy are common examples of conditions that will cause an elevated D-dimer
- D-dimer testing is highly sensitive but non-specific for PE. D-dimer testing is generally limited to those who are younger, don't have significant co-morbidities and are either low or intermediate risk for PE (some debate on including intermediate risk)
- D-dimer is not an appropriate test when the clinical probability of PE is high or intermediate, as it has a low negative predictive value in such cases
- Plasma lactate levels
- Plasma lactate levels using a cutoff of 18 mg/dL (2 mmol/L) were found to be highly predictive of mortality at 30 days in patients with PE
- In a 2013 study of 270 patients with PE, lactate levels of >18 mg/dL (2 mmol/L) had a 17% mortality by 30 days, whereas those with a level less than this cutoff had only a 1.6% mortality by 30 days
- Lactate levels were demonstrated to be more highly predictive of outcome than troponin levels
- Ischemia-Modified Albumin (IMA) level
- Is both more sensitive and specific for PE. One study examining use of IMA as compared to D-dimer testing concluded that use of IMA in combination with either Well's or Geneva PE scores improved both overall sensitivity and negative predictive value as compared to use of D-dimer in that setting
- Brain Natriuretic Peptide
- Although brain natriuretic peptide (BNP) tests are neither sensitive nor specific, patients with PE tend to have higher BNP levels
- Cardiac biomarkers
- Elevated serum troponin is present in approximately 50% of patients with moderate-to-large PE. Troponin levels have limited diagnostic value in PE, however it may be an important prognostic indicator of PE-related complications and mortality. High levels of serum troponin are also an indicator of significant cardiac strain
- Arterial blood-gas analysis
- Hypoxia and hypocapnea are present in many conditions that lead to clinical consideration of the diagnosis of PE. However, an ABG is of no value in diagnosing PE, as a normal or abnormal ABG in no way indicates a higher or lower probability of the patient's presentation being due to PE. Once PE is established as a diagnosis, ABG can be of value in assessing the A-a gradient in patients with a significant oxygen requirement
Radiographic findings
- Pulmonary angiography
- Pulmonary angiography has long been reported as the 'gold standard' for the diagnosis of PE. True pulmonary angiography is generally no longer performed. It is invasive and has been replaced by CT Pulmonary Angiography (CTPA), which is non-invasive. Angiography has a high negative predictive value (99%). Due to use of contrast media, standard angiography, and CTPA, is contraindicated in patients with significant renal insufficiency
- CT scan
- CTPA is the most commonly performed test for pulmonary embolism evaluation. It requires a proximal (antecubital) IV, preferably of at least 18 gauge in size. This test consists of a large, rapid infusion of contrast given in sequence with a timed rapid CT scan as the contrast flows through the pulmonary arteries
- The additional value of CTPA is that it allows evaluation of other conditions, such as aortic dissection, pneumonia, and most other structural conditions within the chest. It is not uncommon to find an unexpected non-PE cause of chest pain on CTPA
- Like pulmonary angiography, CTPA allows for direct visualization of a thrombus in a pulmonary artery. The test has a specificity of 96% and sensitivity of 86%
- The sensitivity of 86% of problematic, as many PE's may be missed; however, they tend to be smaller emboli at the subsegmental level and may not be as clinically significant. It is however important to be aware of this limitation. SPECT V/Q Scintigraphy is an option when a CTPA is negative and a high clinical suspicion remains (has 97% sensitivity)
- Contraindications are dye allergy, significant renal insufficiency, or inadequate IV access
- This test is generally acceptable for patients on hemodialysis as the dye is simply removed during their next dialysis
- Although radiation exposure in pregnancy is undesirable, the radiation involved is deemed acceptable by the American College of Obstetrics and Gynecology (ACOG)
- There is no evidence that V/Q scan is preferable in regard to radiation exposure during pregnancy. Varying opinions exist
- Ventilation-perfusion scan (V/Q scan)
- V/Q scan is an important diagnostic modality; however, it has now been relegated to occasional use. It is generally utilized only when CTPA is unavailable or the patient has significant renal insufficiency as a contraindication to IV dye
- This test establishes the probability of PE as negative, low, intermediate, or high probability. An area of ventilation without perfusion is an indicator of PE
- This test fails to examine the structures within the chest and other important diagnoses are often missed, which could be identified on CTPA
- It is important to note that V/Q SPECT scintigraphy, when available is substantially more sensitive than CTPA (97% vs. 86%) for presence of PE
- Chest x-ray
- Chest x-ray may help rule out other causes for dyspnea such as pneumonia, heart failure, or pneumothorax
- MRI
- MRI is suitable in patients with renal insufficiency or contrast-media allergy and gives results comparable to that of first-generation CTPA. MR pulmonary angiography efficiently detects proximal PE but may miss segmental and sub-segmental PE
- This test requires a completely stable patient and is rarely if ever used for this indication as it is more expensive and less sensitive than CTPA
- Ultrasonography
- For large or massive PE with shock the following are expected findings:
- Obstructed inferior vena cava (IVC) with larger than normal diameter and minimal caval index (IVC not collapsing with inspiration)
- No pneumothorax on ultrasound (and no clinical signs of tension pneumothorax clinically to explain an obstructed IVC)
- No evidence of pericardial tamponade on echocardiography
- Right ventricle larger than left ventricle consistent with cor-pulmonale
- These findings are typical for massive PE and in the patient who is too unstable to obtain a CTPA have been used to justify thrombolysis. This requires a clinician competent and credentialed in RUSH protocol ultrasonography
- Duplex Ultrasonography
- The diagnosis of PE can be supported when DVT is found at any site
- Lack of DVT found on the limbs is not helpful, as DVTs often occur in areas not routinely accessible by ultrasonography
- Two- thirds of PE patients do not have a DVT when all limbs undergo duplex ultrasonography. Given this, negative duplex ultrasound of the limbs does not markedly reduce the likelihood of PE; however a positive result is helpful
Other diagnostic test findings
- ECG
- ECG has a limited predictive value in diagnosis of PE
- The most common finding is sinus tachycardia
- The overly memorized ‘S1 Q3 T3' is not common, nor is it specific for PE. It is a finding seen with any cause of acute cor pulmonale (right heart strain)
- The ‘S1 Q3 T3' pattern consists of a deep ‘S' wave in lead I, deep ‘Q' wave in lead III, and an inverted ‘T' wave in lead III
- Acute Right Bundle Branch Block (RBBB) occurs in 80-85% of massive PE's
- Echocardiography
- Echocardiography is valuable in identifying right ventricular (RV) dysfunction, and thus has good prognostic value as the mortality rate is high in the presence of RV dysfunction. It may also help to rule out other conditions that mimic PE such as pericardial effusion
[Outline]
General treatment items
- Thrombolysis
- ACCP guidelines indicated that PE patients with evidence of hemodynamic compromise should undergo thrombolysis
- The 2013 MOPETT trial demonstrated that moderate pulmonary embolism can substantially benefit from thrombolysis. This protocol of alteplase (dosing in medication section below) yielded no additional bleeding complications, but resulted in shorter hospitalization (2.2 vs. 4.9), lower long term rates of pulmonary hypertension (16% vs. 57%), and lower rates of death (1.6% vs. 10%) as compared to usual care of providing only anticoagulation
- Patients with contraindications due to bleeding risks need to be considered on a case by case basis
- Additionally high-risk patients without hypotension who are at low risk for hemorrhage may be appropriate for thrombolysis
- Controlled studies have not shown superiority of thrombolytics over heparin in reduction of mortality rates or earlier resolution of symptoms
- Currently, thrombolytic therapy is accepted for patients with hemodynamic instability and acute RV dysfunction
- Agents used include recombinant tissue plasminogen activators, t-PA (alteplase, tenecteplase), u-PA (urokinase) and r-PA (reteplase), and streptokinase. FDA approval has only been obtained for streptokinase and alteplase
- Anticoagulation
- Anticoagulation along with supportive treatment is the mainstay of PE treatment. Unfractionated heparin (UFH) therapy is preferred for patients with massive PE, if concern for adequate SC absorption arises, severe renal failure is present or thrombolytic therapy is being considered or planned
- The vast majority of patients receive Low Molecular Weight Heparin (LMWH) for initial treatment of PE. LMWHs have the advantages of excellent bioavailability, the ability to administer as an outpatient, and no need to monitor aPTT
- LMWH and UFH are comparable in terms of safety. LMWHs include dalteparin, enoxaparin, and tinzaparin
- Factor Xa Inhibitors
- Fondaparinux is a synthetic polysaccharide derived from heparin; it catalyzes inactivation of factor Xa by antithrombin without inhibition of thrombin. Its administration does not require laboratory monitoring and has almost no risk of thrombocytopenia
- Rivaroxaban is an oral direct Xa inhibitor which can be used for treatment of PE. It can provide a safe and effective regimen of anticoagulation, and is cost-effective compared to other therapies. It has the advantage of being oral, and not requiring UFH or LMWH and is a complete long term treatment as warfarin is not required
- Warfarin therapy
- Warfarin acts by inhibition of vitamin K-dependent factors (II, VII, IX, and X). Warfarin requires approximately 5 days of therapy to reach a therapeutic level. INR monitoring is essential to assess the adequacy of warfarin therapy. The recommended target INR for thromboembolic patients is 2.0-3.0
- After stabilization of a dosing regimen, INR assessments should be performed every 1-2 weeks or at longer intervals on a case by case basis
- It is important to note that warfarin is initiated after UFH or LMWH is administered as it can cause a pro-thrombotic state until a therapeutic INR is achieved
- Duration of anticoagulant treatment: Therapy should be continued for 3 months, if there is a transient (reversible) cause for the PE. In the event no clear cause is identified, or an ongoing cause that increases risk for thrombosis is present (e.g. malignancy, thrombophilia), life-long therapy is typical
- Embolectomy
- American Heart Association (AHA) guidelines, indicate that catheter embolectomy and fragmentation, or surgical embolectomy may be suitable for patients with massive PE who have contraindications or failure of thrombolysis, or are deemed unstable for medical management
- Embolectomy is not recommended for low-risk patients
- Embolectomy avoids the hemorrhagic risks of fibrinolysis
- Inferior vena cava (IVC) filters
- IVC filters are filters which trap emboli without causing occlusion of the inferior vena cava
- IVC filters are rarely utilized and may not significantly decrease subsequent risk of thromboembolism
- Use of an IVC filter is recommended in patients who are unsuitable for initial anticoagulation. Although there is limited evidence to suggest the ideal time for placement of the filter, it should be done without delay if it is the only intervention suitable for the patient
- Such patients should subsequently receive post-filter anticoagulation after resolution of bleeding risks that contraindicated initial treatment with anticoagulants
- Supportive care
- Elastic compressive stockings are a safe and effective adjunctive therapy which can prevent extension of the thrombus
- In unstable patients, thrombolytics, IV fluids and inotropic agents (norepinephrine, dopamine or dobutamine) may be required
- Mechanical ventilation may be needed in cases where respiratory support is required
- Activity for most patients does not require any restriction, unless there is hemodynamic compromise
Medications indicated with specific doses
Thrombolytics
- Alteplase: Enhances conversion of plasminogen to plasmin to achieve fibrinolysis
- Adult Dosing
- Note that the 2013 MOPETT trial for moderate pulmonary embolism utilized a total dose of 50 mg (for weight
50 kg) with 10 mg as a bolus then 40 mg over 2 hours, along with heparin 70 U/kg bolus [Max 6000U] then infusion to keep APTT 1.5-2x control OR enoxaparin 1 mg/kg [Max 80 mg] given q12 hours - Pediatric Dosing
- Reteplase: Enhances conversion of plasminogen to plasmin to achieve fibrinolysis
- Tenecteplase: Enhances conversion of plasminogen to plasmin to achieve fibrinolysis [Not FDA approved-but widely used for massive PE]
Anticoagulants- Unfractionated heparin: Antithrombin activator that inhibits factors Xa and IIa
- Warfarin: Inhibits vitamin K-dependant coagulation factors II, VII, IX, X. Also inhibits biologic anticoagulant proteins C&S
Anticoagulants- Low molecular weight heparins- Dalteparin: Low molecular weight heparin, antithrombin activator that preferentially inhibits factor Xa and inhibits factor IIa
- Enoxaparin: Low molecular weight heparin, antithrombin activator that preferentially inhibits factor Xa and inhibits factor IIa
- Tinzaparin: Low molecular weight heparin, antithrombin activator that preferentially inhibits factor Xa and inhibits factor IIa
Anticoagulants- Factor Xa inhibitors- Fondaparinux: Synthetic pentasaccharide sequence of heparin that binds with antithrombin III to inactivate factor Xa
- Rivaroxaban: Direct Factor Xa inhibitor
Pressors/Inotropes: Important note on inotropes:
Before administering inotropes; make sure patient is sufficiently fluid resuscitated. Patients with massive PE are often extremely pre-load dependent. Addition of inotropes should be considered only after significant fluid resuscitation (which often works without the need for inotropes).
- Dopamine
- Dobutamine
- Norepinephrine
Dietary and activity restrictions
- Patients on anticoagulants like warfarin should avoid vitamin K-rich foods such as green leafy vegetables and drugs such as aspirin or acetaminophen
Disposition
Admission criteria
- Traditional approaches to PE include the recommendation that all patients with PE be admitted for anticoagulation and observation
- It is important to note, that outpatient treatment of PE can be reasonably undertaken, so long as the PE is small, the patient is hemodynamically stable, there is no contraindication to use of outpatient LWMH or other anticoagulation regimen, and close outpatient follow-up (often daily) is available
- Stable patients suspected of having PE, where this is a lack of availability of immediate diagnostic testing, should be anticoagulated, so long as they have no contraindications. Testing for PE can be undertaken thereafter
Discharge criteria
- Stable patients with an INR of 2-3 on warfarin. Some patients may go home on daily enoxaparin on other oral agents such as rivaroxaban, where there is otherwise no indication for admission or after observation in hospital with the patient being stable for outpatient continuation of therapy
Outpatient management of PE - Not all patients with pulmonary embolism require inpatient treatment. Nearly 50% of patients with symptomatic PE can be safely treated as outpatients
- Patients with normal vital signs and no recent history of bleeding may be considered for outpatient management in the absence of comorbid conditions such as ischemic heart disease, liver or renal failure, or thrombocytopenia
- Data from several non-randomized studies suggest that patients with non-massive PE, with low risk for adverse outcomes, can be safely treated in an outpatient setting with LMWH
- The Outpatient Treatment of Pulmonary Embolism (OTPE) trial was a breakthrough trial comparing outpatient vs inpatient treatment of PE. Some key findings of the trial were:
- Low risk patients for outpatient treatment can be easily identified using PESI (pulmonary embolism risk severity index) which is an 11 point scoring system that predicts 30 day mortality in PE patients. A score of 1 or 2 indicates low risk of mortality
- Outpatient treatment is significantly less expensive compared to inpatient treatment due to shorter length of stay; however, it is associated with increased home nursing visits
- Outpatient management should be initiated only after consideration of availability of adequate home nursing care, or the ability for close outpatient follow-up, and the patient's ability to follow instructions for self-injection of LMWHs
[Outline]
Prevention
- The occurrence of PE in hospitalized patients can be decreased with appropriate VTE prophylaxis, generally with administration of heparin, or LMWH
- Prevention of idiopathic outpatient PE remains a challenge
Prognosis
- When treatment is not instituted, this condition has a high mortality rate. Death occurs from cardiogenic shock secondary to right ventricular (RV) failure
- Unstable patients with a systolic BP <90 mmHg have significant mortality (31-58%)
- Patients with elevated troponin and ECG evidence of RV strain have a higher mortality
- Co-morbid diseases increase both long and short-term mortality
- Hemodynamically stable patients with a systolic BP >90 mmHg have a lower mortality rate
Pregnancy/Pediatric effects on the condition
- Pregnancy (all trimesters) and postpartum are associated with a higher risk of VTE and PE. PE is one of the leading causes of mortality during pregnancy
- PE may be safely treated with UFH/LMWH and/or fibrinolysis during pregnancy failing which, fetal death is imminent.Warfarin is strongly contraindicated during pregnancy due to risk of fetal teratogenecity
- Diagnostic procedures that expose the fetus to ionizing radiation are sometimes required (CTPA or V/Q); however; the risk to the fetus from such radiation exposures appears to be minimal
Abbreviations
ICD-9-CM
- 415.1 Pulmonary Embolism and infarction
- 415.11 Iatrogenic pulmonary embolism and infarction
- 415.19 Other pulmonary embolism and infarction (includes pulmonary embolism/thromboembolism, not otherwise specified)
ICD-10-CM
[Outline]
