AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
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INTRODUCTION

Section 2 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Pulmonary embolism (PE) is a common and potentially lethal disease; unfortunately, the diagnosis is often missed because patients with PE present with nonspecific signs and symptoms. If left untreated, approximately one third of patients who survive an initial PE subsequently die from a future embolic episode. Most patients succumb to PE within the first few hours of the event. In patients who survive, recurrent embolism and death can be prevented with prompt diagnosis and therapy.

The mortality and morbidity rates from venous thromboembolism are best described by Ken Moser in 2 words: substantial and unacceptable. In the 1940s, Bauer performed fundamental studies that led to the current understanding of the pathogenesis of deep vein thrombosis (DVT). Subsequently, Savitt and Gallagher performed autopsy-based studies of the prevalence of venous thromboembolism in patients who had lower extremity fractures and other risk factors for PE. The most important conceptual advance that occurred over the last several decades is that PE is not a disease; rather, it is a complication of DVT.

Virtually every physician who is involved in patient care (eg, internist, generalist, orthopedic surgeon, gynecologic surgeon, urologic surgeon, pulmonary subspecialist, cardiologist) encounters patients who are at risk of venous thromboembolism.

Pathophysiology

The pathophysiology of PE encompasses several aspects, as described below.

Natural history of venous thrombosis

In the 19th century, Verchow identified a triad of factors that lead to the pathogenesis of venous thrombosis: venous stasis, injury to the intima, and changes in the coagulation properties of the blood. Thrombosis usually originates as a platelet nidus in the region of venous valves located in the veins of the lower extremities. Further growth occurs by accretion of platelets and fibrin and progression to red fibrin thrombus, which may either break off and embolize or result in total occlusion of the vein. The endogenous thrombolytic system leads to partial dissolution; then, the thrombus becomes organized and is incorporated into the venous wall.

Natural history of pulmonary embolism

Pulmonary emboli usually arise from the thrombi originating in the deep venous system of the lower extremities; however, rarely they may originate in the pelvic, renal, or upper extremity veins and the right heart chambers. After traveling to the lung, large thrombi lodge at the bifurcation of the main pulmonary artery or the lobar branches and cause hemodynamic compromise. Smaller thrombi continue traveling distally, occluding a smaller vessel in the lung periphery. These are more likely to produce pleuritic chest pain by initiating an inflammatory response adjacent to the parietal pleura. Most pulmonary emboli are multiple, and the lower lobes are involved more commonly than the upper lobes.

Respiratory consequences

Acute respiratory consequences of PE include increased alveolar dead space, pneumoconstriction, hypoxemia, and hyperventilation. Later, 2 additional consequences may occur: regional loss of surfactant and pulmonary infarction. Arterial hypoxemia is a frequent but not universal finding in patients with acute embolism. The mechanisms of hypoxemia include ventilation-perfusion mismatch, intrapulmonary shunts, reduced cardiac output, and intracardiac shunt via patent foramen ovale. Pulmonary infarction is an uncommon consequence because of the bronchial arterial collateral circulation.

Hemodynamic consequences

PE reduces the cross-sectional area of the pulmonary vascular bed, resulting in an increment in pulmonary vascular resistance, which, in turn, increases the right ventricular afterload. If the afterload is increased severely, right ventricular failure may ensue. In addition, the humoral and reflex mechanisms contribute to the pulmonary arterial constriction. Prior poor cardiopulmonary status of the patient is an important factor leading to hemodynamic collapse. Following the initiation of anticoagulant therapy, the resolution of emboli occurs rapidly during the first 2 weeks of therapy. Significant long-term nonresolution of emboli causing pulmonary hypertension or cardiopulmonary symptoms is uncommon.

Frequency

United States

PE is present in 60-80% of patients with DVT, even though more than half the patients are asymptomatic. PE is the third most common cause of death in hospitalized patients, with at least 650,000 cases occurring annually. Autopsy studies have shown that approximately 60% of patients who died in the hospital had PE, and the diagnosis was missed in up to 70% of the cases. Prospective studies have demonstrated DVT in 10-13% of all medical patients placed on bed rest for 1 week, 29-33% of all patients in medical intensive care units, 20-26% of patients with pulmonary diseases who are given bed rest for 3 or more days, 27-33% of those admitted to a critical care unit after a myocardial infarction, and 48% of patients who are asymptomatic after a coronary artery bypass graft.

A 30-year, population-based study collated the cases of DVT or PE in women during pregnancy or during the postpartum period. The relative risk was 4.29, and the overall incidence of venous thromboembolism (absolute risk) was 199.7 per 100,000 woman-years. Among postpartum women, the annual incidence was 5 times higher than the pregnant women (511.2 vs 95.8 per 100,000 women). The incidence of DVT was 3 times higher than that of PE (151.8 vs 47.9 per 100,000 women). PE was relatively less common during pregnancy versus the postpartum period (10.6 vs 159.7 per 100,000 women) (Heit, 2005).

International

The incidence of PE may differ substantially from country to country; observed variation is likely due to differences in the accuracy of diagnosis rather than the disease incidence.

Mortality/Morbidity

• Unexpected death from a massive PE is second only to the sudden cardiac death. Autopsy studies of hospitalized patients have shown approximately 80% of these patients died from massive PE.
• Approximately 10% of patients who develop PE die within the first hour, and 30% die subsequently from recurrent embolism. Anticoagulant treatment decreases the mortality rate to less than 5%.
• The diagnosis of PE is missed in approximately 400,000 patients in the United States per year, approximately 100,000 deaths could be prevented with proper diagnosis and treatment.

Sex

• The risk of PE is increased in pregnancy and during the postpartum period; otherwise, sex is not a significant risk factor for PE.

Age

• In hospitalized elderly patients, PE is commonly missed and often is the cause of death.

CLINICAL

Section 3 of 11  

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History

The presentation of pulmonary embolism (PE) may vary from a sudden onset of catastrophic hemodynamic collapse to gradually progressive dyspnea. The diagnosis of PE should be sought actively in patients with respiratory symptoms unexplained by an alternate diagnosis. The symptoms of PE are nonspecific; therefore, a high index of suspicion is required, particularly when a patient has risk factors, which include recent surgery, immobility, or a hypercoagulable state.

The presentation of patients with PE can be categorized into 4 classes based on the acuity and severity of pulmonary arterial occlusion. These categories are (1) massive PE, (2) acute pulmonary infarction, (3) acute embolism without infarction, and (4) multiple pulmonary emboli.

• Massive pulmonary embolism
• • Large emboli compromise sufficient pulmonary circulation to produce circulatory collapse and shock.
  • The patient has hypotension; appears weak, pale, sweaty, and oliguric; and develops impaired mentation.
• Acute pulmonary infarction
• • Approximately 10% of patients have peripheral occlusion of a pulmonary artery causing parenchymal infarction.
  • These patients present with acute onset of pleuritic chest pain, breathlessness, and hemoptysis.
  • Although the chest pain may be indistinguishable from ischemic myocardial pain, normal electrocardiogram findings and no response to nitroglycerine rules it out.
• Acute embolism without infarction: Patients have nonspecific symptoms of unexplained dyspnea and/or substernal discomfort.
• Multiple pulmonary emboli
• • This group consists of 2 subsets of patients.
  • The first subset has repeated documented episodes of pulmonary emboli over years, eventually presenting with signs and symptoms of pulmonary hypertension and cor pulmonale.
  • The second subset has no previously documented pulmonary emboli but have widespread obstruction of the pulmonary circulation with clot. They present with gradually progressive dyspnea, intermittent exertional chest pain, and, eventually, features of pulmonary hypertension and cor pulmonale.
• Most patients with PE have no obvious symptoms at presentation. In contrast, patients with symptomatic deep vein thrombosis (DVT) commonly have PE confirmed on diagnostic studies in the absence of pulmonary symptoms.
• The most common symptoms of PE in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study were dyspnea (73%), pleuritic chest pain (66%), cough (37%), and hemoptysis (13%).
• Patients with PE may present with atypical symptoms, where strong suspicion in a high-risk patient often leads to consideration of PE in the differential diagnosis. These symptoms include the following:
• • Seizures
  • Syncope
  • Abdominal pain
  • Fever
  • Productive cough
  • Wheezing
  • Decreasing level of consciousness
  • New onset of atrial fibrillation
• Pleuritic chest pain without other symptoms or risk factors may be a presentation of PE.

Physical

The physical examination is quite variable in PE and, for convenience, may be grouped into 4 categories as follows:

• Massive pulmonary embolism
• • These patients are in shock. They have systemic hypotension, poor perfusion to the extremities, tachycardia, and tachypnea.
  • Additionally, signs of pulmonary hypertension such as palpable impulse over second left interspace, loud P2, right ventricular S3 gallop, and a systolic murmur louder on inspiration at left sternal border (tricuspid regurgitation) may be present.
• Acute pulmonary infarction
• • These patients have decreased excursion of involved hemithorax, palpable or audible pleural friction rub, and even localized tenderness.
  • Signs of pleural effusion, such as dullness upon percussion and diminished breath sounds, may be present.
• Acute embolism without infarction
• • These patients have nonspecific physical signs that may easily be secondary to another disease process.
  • Tachypnea and tachycardia frequently are detected, pleuritic pain sometimes may be present, crackles may be heard in the area of embolization, and local wheeze may be heard rarely.
• Multiple pulmonary emboli or thrombi
• • Patients belonging to both the subsets in this category have physical signs of pulmonary hypertension and cor pulmonale.
  • Patients may have elevated jugular venous pressure, right ventricular heave, palpable impulse in the left second intercostal space, right ventricular S3 gallop, systolic murmur over the left sternal border that is louder during inspiration, hepatomegaly, ascites, and dependent pitting edema.
  • These findings are not specific for PE and require a high index of suspicion for pursuing appropriate diagnostic studies.
• The most common physical signs in the PIOPED study were as follows:
• • Tachypnea (70%)
  • Rales (51%)
  • Tachycardia (30%)
  • Fourth heart sound (24%)
  • Accentuated pulmonic component of the second heart sound (23%)
• Fever of less than 39°C may be present in 14% of patients; however, temperature higher than 39.5°C is not from PE.
• Chest wall tenderness upon palpation, without a history of trauma, may be the sole physical finding in rare cases.

Causes

The causes for PE are multifactorial and are not readily apparent in many cases. The following causes have been described in the literature:

• Venous stasis
• • Venous stasis leads to accumulation of platelets and thrombin in veins.
  • Increased viscosity may occur due to polycythemia and dehydration, immobility, raised venous pressure in cardiac failure, or compression of a vein by a tumor.
• Hypercoagulable states
• • The complex and delicate balance between coagulation and anticoagulation is altered by many diseases, by obesity, after surgery, or by trauma.
  • Concomitant hypercoagulability may be present in disease states where prolonged venous stasis or injury to veins occurs.
  • Hypercoagulable states may be acquired or congenital. Factor V Leiden mutation causing resistance to activated protein C is the most common risk factor. Factor V Leiden mutation is present in up to 5% of the normal population and is the most common cause of familial thromboembolism.
  • Primary or acquired deficiencies in protein C, protein S, and antithrombin III are other risk factors. The deficiency of these natural anticoagulants is responsible for 10% of venous thrombosis in younger people
• Immobilization
• • Immobilization leads to local venous stasis by accumulation of clotting factors and fibrin, and a thrombus is synthesized.
  • The risk of PE increases with prolonged bed rest or immobilization of a limb with plaster.
  • Paralysis increases the risk.
• Surgery and trauma
• • Both surgical and accidental trauma predispose patients to venous thromboembolism by activating clotting factors and causing immobility.
  • Fractures of the femur and tibia are associated with the highest risk, followed by pelvic, spinal, and other fractures.
  • Severe burns carry a high risk of DVT or PE.
  • A recent study by Greets in 1994 indicated that major trauma was associated with a 58% incidence rate of DVT, 18% of these were in proximal veins.
  • PE may account for 15% of all postoperative deaths. Leg amputations and hip, pelvic, and spinal surgery are associated with the highest risk.
• Pregnancy
• • The incidence of thromboembolic disease in pregnancy has been reported to range from 1 case in 200 deliveries to 1 case in 1400 deliveries.
  • Fatal events may occur rarely, 1-2 cases per 100,000 pregnancies.
  • The mechanism of DVT is venous stasis, decreasing fibrinolytic activity, and increased procoagulant factors.
• Oral contraceptives and estrogen replacement
• • Estrogen-containing birth control pills have increased the occurrence of venous thromboembolism in healthy women.
  • The risk is proportional to the estrogen content and is increased in postmenopausal women on hormonal replacement therapy.
  • The relative risk is 3-fold, but the absolute risk is 20-30 cases per 100,000 persons per year.
• Malignancy
• • Malignancy has been identified in 17% of patients with venous thromboembolism.
  • The neoplasms most commonly associated with PE, in descending order of frequency, are pancreatic carcinoma; bronchogenic carcinoma; and carcinoma of the genitourinary tract, colon, stomach, and breast.
• Other recognized risk factors include the following:
• • Stroke
  • Indwelling venous catheters
  • Previous history of venous thromboembolism
  • Congestive heart failure
  • Fractures of the long bone
  • Obesity
  • Pregnancy
  • Varicose veins
  • Inflammatory bowel disease

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Differential diagnoses are extensive, and they should be considered carefully with any patient thought to have pulmonary embolism (PE). These patients also should have an alternate diagnosis confirmed, or PE should be excluded, before discontinuing the workup. The additional problems to be considered include the following:

Musculoskeletal pain
Pleuritis
Costochondritis
Rib fracture
Pericarditis
Angina pectoris
Salicylate intoxication
Hyperventilation

WORKUP

Section 5 of 11  

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Lab Studies

• Clinical signs and symptoms are nonspecific; therefore, patients suspected to have pulmonary embolism (PE) must undergo diagnostic tests until the diagnosis is ascertained or eliminated or an alternative diagnosis is confirmed. Routine laboratory findings are nonspecific and are not helpful in PE, although they may direct towards another diagnosis.
• PE should be suspected in any patient with unexplained dyspnea, tachypnea, or chest pain. All patients suspected of PE must be risk stratified, ideally with a criteria-validated clinical decision rule. Review of the current evidence for new diagnostic modalities suggests that in patients with low-risk normal D-dimer assays, PE is reliably excluded; no further testing is required. Computed tomography angiography (CTA) angiogram is the initial imaging modality of choice for stable patients. Ventilation-perfusion (V/Q) scans should be used only when CT is not available or if the patient has a contraindication to CT scans or intravenous contrast. For suspected massive PE, either bedside echocardiography or initial stabilization of the patient and then CT angiogram should be the initial tests.
• Arterial blood gases
• • Arterial blood gases (ABGs) characteristically reveal hypoxemia, hypocapnia, and respiratory alkalosis; however, the predictive value of hypoxemia is quite low.
  • Both the PaO₂ and the calculation of alveolar-arterial oxygen gradient contribute to the diagnosis in a general population thought to have PE.
  • Nonetheless, in high-risk settings such as patients in postoperative states where other respiratory conditions can be ruled out, a low PaO₂ in conjunction with dyspnea may have a strong positive predictive value.
• D-dimer
• • D-dimer, a degradation product produced by plasmin-mediated proteases of cross-linked fibrin, is measured by performing a latex agglutination test or by performing an enzyme-linked immunosorbent assay (ELISA). The latex agglutination test is unreliable and has a sensitivity of 50-60%. The ELISA is more sensitive but does not carry a highly negative predictive value.
  • The D-dimer test misses 10% of patients with PE, while only 30% of patients with positive D-dimer findings have a confirmatory diagnosis of PE. Therefore, the D-dimer test alone is not routinely recommended at present for aiding in a definitive diagnosis or in guiding the initiation of treatment in patients suspected to have PE.
  • Although extensive literature exists for D-dimer test in deep venous thrombosis (DVT) or PE, its role still remains unclear. Multiple D-dimer assays are currently available and concerns persist about their sensitivities and variability. A systematic review of prospective studies of high methodologic quality was recently performed. For DVT, the ELISA showed a sensitivity of 0.96 and negative likelihood ratio 0.12, and the quantitative rapid ELISA had a sensitivity of 0.96 and negative likelihood ratio of 0.09. For PE, the ELISA had a sensitivity of 0.95 and negative likelihood ratio of 0.13, and the quantitative rapid ELISA had a sensitivity of 0.95 and negative likelihood ratio of 0.13. In summary, these results showed that both the ELISA and quantitative rapid ELISA have negative likelihood ratios that yield a high certainty for excluding DVT or PE and are as diagnostically useful as a normal lung scan or negative duplex ultrasonography. However, the positive likelihood values failedtoincreasethecertainty of such a diagnosis (Stein, 2004).

Imaging Studies

• Chest radiograph
• • Initially, the chest radiography findings commonly are normal. However, in later stages, the x-ray film may show radiographic signs that include a Westermark sign (dilatation of pulmonary vessels and a sharp cutoff), atelectasis, a small pleural effusion, and an elevated diaphragm.
  • Although chest radiograph findings may indicate an alternate diagnosis, this study alone is not sufficient to confirm the diagnosis of PE.
• Ventilation-perfusion (V/Q) scanning of the lungs is an important diagnostic modality for establishing the diagnosis of PE. The PIOPED classification scheme allows the interpretation of the V/Q scan more meaningfully, in order to treat patients with anticoagulation. The scans should be interpreted primarily as a diagnostic or nondiagnostic pattern, indicating whether the patient has a high likelihood or does not have a high likelihood of having PE.
• • Diagnostic pattern - Normal V/Q scan findings or findings indicating a high probability
    • Normal V/Q scan findings indicate an absence of any perfusion defects. Four percent of these patients still may have PE. Unless the patient has features indicating very high clinical suspicion, these findings may be considered negative for PE.
    • High-probability scan findings are 2 or more segmental or 1 larger perfusion defect in the presence of normal chest radiography findings and ventilation scan findings. Approximately 87% of these patients were found to have PE. If accompanied by high pretest probability, the likelihood of pulmonary emboli increases to 95%.
  • Diagnostic pattern - Nondiagnostic scans interpreted as low or intermediate probability
    • Low-probability scan findings consist of small perfusion defects associated with corresponding abnormalities upon chest radiograph or ventilation scan. A single segmental perfusion defect with normal chest x-ray findings and nonsegmental perfusion defects are common nondiagnostic patterns. Twelve percent of the patients with this pattern have PE, unless the patient has a very low pretest probability or clinical suspicion. Further diagnostic studies must be carried out to confirm or exclude the diagnosis of PE.
    • Intermediate probability is indicated by those patients with any V/Q abnormality that is not classified as high or low probability. Approximately 30% have PE; therefore, the finding of this scan pattern must be followed by further investigation to definitely exclude the diagnosis of PE.
• Noninvasive tests for lower extremity DVT
• • These may be helpful in the evaluation of patients who have nondiagnostic V/Q scan patterns of further intermediate and low probability.
  • Compression ultrasonography: Color-flow Doppler imaging and compression ultrasonography have a high sensitivity (89-100%) and specificity (89-100%) for detection of proximal DVT in symptomatic patients. However, compression ultrasonography has a low sensitivity (38%) and a low positive predictive value (26%) in patients without symptoms of DVT. Patients with positive findings for DVT can be anticoagulated irrespective of their V/Q scan results; other patients must have more invasive investigations performed to definitely rule out PE.
• Spiral CT scanning (helical CT scan)
• • The role of a spiral CT scan for the diagnosis of PE has evolved over the last decade. Spiral CT can visualize main, lobar, and segmental pulmonary emboli with a reported sensitivity of greater than 90%. The spiral CT scan can detect emboli as small as 2 mm that are affecting up to the seventh border division of the pulmonary artery. The only problem with spiral CT is that small subsegmental emboli may not be detected. The CT scan has another benefit, an alternate diagnosis may be suggested in up to 57% of the patients.
  • Technique is described as follows:
    • Spiral CT examination is performed immediately after infusion of 150-200 mL of 30% contrast material.
    • The scan is performed from the level of the aortic arch to approximately 2 cm below the level of the inferior pulmonary vein while the patient is holding his breath at full inspiration.
    • If the patient is not able to hold his breath for 20-30 seconds, the scan may be performed during gentle breathing.
  • Sensitivity and specificity are discussed as follows:
    • The spiral CT scan has sensitivities for PE reported to be 53-100%.
    • The specificity has been reported to be 78-96%.
    • The negative predicted value is 81-100%, and the positive predictive value is 60-100% for detecting emboli in segmental or larger arteries.
    • When one evaluates the clinical outcome following a negative result from a spiral CT scan, the outcome is favorable and the likelihood for subsequent thromboembolic events is extremely small.
    • Upon CT scan imaging, positive features include a central intravascular filling defect within the vessel lumen, eccentric tracking of contrast material around a filling defect, and complete vascular occlusion. Smooth filling defects making an obtuse angle with a vessel wall may represent chronic thrombi or recent recanalization. The parenchymal findings of oligemia, pulmonary hemorrhage (ground-glass attenuation), and pulmonary infarction (peripheral wedge-shaped pleural-based opacification) may be seen.
  • Pitfalls include the following:
    • The problems in CT imaging for PE are technically inadequate examinations due to patients' dyspnea, interobserver disagreement, and obliquely/horizontally oriented vessels within the right middle lobe and left lingula.
    • Breathing artifact cardiac motion may produce false filling defects, and unilateral extensive air space consolidation also may produce pseudo filling defects because of significant decrease in blood flow through pulmonary arteries in these areas.
  • Future research will determine whether the role of spiral CT scanning is as a screening examination or as a criterion-standard test. Spiral CT scans are extremely useful in the workup of suspected PE. Their role in an individual patient and institution is variable and needs to be assessed in view of the available scientific data.
  • Spiral computed tomographic pulmonary angiography (CTPA) is increasingly being used to confirm diagnosis of suspected PE. However, CTPA has limitation of inadequate sensitivity, particularly when subsegmental emboli are present. A meta-analysis published in 2004 reviewed 23 studies reporting on 4657 patients with negative CTPA results for PE who did not receive anticoagulation. The rate of venous thromboembolism was 1.4% and the rate of fatal PE was 0.51% at 3 months. These results are similar to negative results on conventional pulmonary angiography. Therefore, it appears to be safe withholding anticoagulation after negative CTPA results (Moores, 2004).
• Combined spiral CT scan for detection of pulmonary embolism and deep venous thrombosis
• • A combined CT scan for PE/DVT enhances the utility of spiral CT scans by further identifying emboli in the deep venous system of the lower extremities or the pelvic veins.
  • Good venous enhancement of the lower extremity veins occurs 2 minutes following lung CT scan as 5-mm scans are performed at 5-cm intervals from the upper calves to the diaphragm.
  • Alternatively, 1-cm images are performed from the iliac bones to the tibial plateau. The additional radiation dose needs to be considered in the formulation of this protocol. With this technique, up to 4% of patients with negative results upon CT scan examination for PE have been identified to have DVT.
• Pulmonary angiography
• • Pulmonary angiography remains the criterion standard for the diagnosis of PE.
  • Following injection of iodinated contrast, anteroposterior, lateral, and oblique studies are performed on each lung.
  • Positive results consist of a filling defect or sharp cutoff of the affected artery. Nonocclusive emboli are described to have a tram-track appearance.
  • Abnormal findings on V/Q scans performed prior to angiography guide the operator to focus on abnormal areas.
  • Angiography generally is a safe procedure. The mortality rate for patients undergoing this procedure is less than 0.5%, and the morbidity rate is less than 5%.
  • Patients who have long-standing pulmonary arterial hypertension and right ventricular failure are considered high-risk patients.
  • Negative pulmonary angiogram findings, even if false-negative, exclude clinically relevant PE.
• Magnetic resonance imaging
  • Upon an MRI, evidence of pulmonary emboli may be detected by using standard or gated spin-echo techniques.
  • Pulmonary emboli demonstrate increased signal intensity within the pulmonary artery. By obtaining a sequence of images, this signal that is originating from slow blood flow may be distinguished from PE. However, this remains a problem in pulmonary hypertension.
  • Presently, magnetic resonance angiography is performed following intravenous administration of gadolinium.
  • MRI has a sensitivity of 85% and specificity of 96% for central, lobar, and segmental emboli; MRI is inadequate for the diagnosis of subsegmental emboli.
• Echocardiography
• • This modality generally has limited accuracy in the diagnosis of PE.
  • Transesophageal echocardiography may identify central PE, and the sensitivity for central PE is reported to be 82%.
  • Overall sensitivity and specificity for central and peripheral PE is 59% and 77%.
  • Echocardiography may demonstrate right ventricular dysfunction in acute PE, predicting a higher mortality and possible benefit from thrombolytic therapy.

Other Tests

• Electrocardiogram
• • The most common ECG abnormalities of PE are tachycardia and nonspecific ST-T wave abnormalities. These findings are not sensitive or specific enough to aid in the diagnosis of PE.
  • The classic finding of right-heart strain demonstrated by an S1-Q3-T3 pattern is observed in only 20% of patients with proven PE.

TREATMENT

Section 6 of 11  

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Medical Care

Immediate full anticoagulation is mandatory for all patients suspected to have deep vein thrombosis (DVT) or pulmonary embolism (PE). Diagnostic investigations should not delay empirical anticoagulant therapy. Initial anticoagulation is performed with intravenous heparin, which activates antithrombin III to slow or prevent the progression of DVT and reduces pulmonary emboli. Heparin does not dissolve the existing clot. The patient should be started simultaneously on oral anticoagulation with warfarin. After a therapeutic dose of warfarin is established, heparin is discontinued and warfarin therapy is maintained.

• Thrombolytic therapy
• • Thrombolytic therapy should be considered for patients who are hemodynamically unstable, patients who have right-heart strain, and high-risk patients with underlying poor cardiopulmonary reserve.
  • Although most studies demonstrate superiority of thrombolytic therapy with respect to resolution of radiographic and hemodynamic abnormalities within the first 24 hours, this advantage disappears 7 days after treatment. Controlled clinical trials have not demonstrated benefit in terms of reduced mortality rates or earlier resolution of symptoms when currently compared to heparin.
  • Until randomized clinical trials demonstrate a clear morbidity or mortality benefit, the role of thrombolytic therapy in the management of acute PE remains controversial. The currently accepted indications for thrombolytic therapy include hemodynamic instability or right ventricular dysfunction demonstrated on echocardiography.
• Goals of anticoagulation therapy
  • The efficacy of heparin therapy depends on achieving a critical therapeutic level of heparin within the first 24 hours of treatment. The critical therapeutic level of heparin is 1.5 times the baseline control value or the upper limit of normal range of the activated partial thromboplastin time (aPTT).
  • This level of anticoagulation is expected to correspond to a heparin blood level of 0.2-0.4 U/mL by the protamine sulfate titration assay and 0.3-0.6 by the antifactor X assay.
  • Each laboratory should establish the minimal therapeutic level for heparin, as measured by the aPTT, to coincide with a heparin blood level of at least 0.2 U/mL for each batch of thromboplastin reagent being used.
  • Heparin therapy generally is overlapped with warfarin for a minimum of 4-5 days.
  • A weight-based heparin dosing nomogram is an effective approach for achieving adequate anticoagulation. An initial bolus of 80 U/kg is followed by an infusion of 18 U/kg/h. The heparin dose is further adjusted to maintain an aPTT in the therapeutic range.
• Low molecular weight heparin
• • Low molecular weight heparins (LMWHs) have many advantages over unfractionated heparin. These agents have a greater bioavailability, can be administered by subcutaneous injections, and have a longer duration of anticoagulant effect.
  • A fixed dose of LMWH can be used, and laboratory monitoring of aPTT is not necessary.
  • Trials comparing LMWH to unfractionated heparin have shown that LMWH is at least as effective and as safe as unfractionated heparin.
  • The studies have not pointed to any significant differences in recurrent thromboembolic events, major bleeding, or mortality between the 2 types of heparin.
  • LMWH can be administered safely in an outpatient setting. This has lead to the development of programs in which clinically stable patients with PE are treated at home at substantial cost savings.
• Oral anticoagulant therapy
  • The anticoagulant effect of warfarin is mediated by the inhibition of vitamin K–dependent factors, which are II, VII, IX, and X. The peak effect does not occur until 36-72 hours after drug administration, and the dosage is difficult to titrate.
  • A prothrombin time ratio is expressed as an International Normalized Ratio (INR) and is monitored to assess the adequacy of warfarin therapy. The recommended therapeutic range for venous thromboembolism is an INR of 2-3. This level of anticoagulation markedly reduces the risk of bleeding without the loss of effectiveness. Initially, INR measurements are performed on a daily basis; once the patient is stabilized on a specific dose of warfarin, the INR determinations may be performed every 1-2 weeks or at longer intervals.
• Duration of anticoagulation
• • A patient with a first thromboembolic event occurring in the setting of reversible risk factors such as immobilization, surgery, or trauma, should receive warfarin therapy for 3-6 months. In the absence of an identifiable risk factor, the first idiopathic thromboembolic event should be treated for a minimum of 6 months, and 3 months of anticoagulation is insufficient in this setting.
  • Warfarin treatment for longer than 6 months is indicated in patients with recurrent venous thromboembolism or in those in whom a continuing risk factor for venous thromboembolism exists, including malignancy, immobilization, or morbid obesity.
  • Patients who have PE and preexisting irreversible risk factors, such as deficiency of antithrombin III, protein S and C, factor V Leiden mutation, or the presence of antiphospholipid antibodies, should be placed on long-term anticoagulation.

Surgical Care

• Inferior vena cava (IVC) interruption by the insertion of an IVC filter (Greenfield filter) is indicated in the following settings:
• • Patients with acute venous thromboembolism who have an absolute contraindication to anticoagulant therapy, eg, recent surgery, hemorrhagic stroke, or significant active or recent bleeding
  • Patients with massive PE who survived but in whom recurrent embolism will be invariably fatal
  • Patients who have objectively documented recurrent venous thromboembolism, adequate anticoagulant therapy notwithstanding
• An ideal IVC filter should have the following characteristics:
• • Easy and safe placement by percutaneous technique
  • Biocompatible and mechanically stable
  • Ability to trap emboli without causing occlusion of the vena cava
• One large trial has shown that during the first 12 days after insertion of IVC filters, significantly fewer patients had recurrent PE. However, following a 2-year follow-up, no significant differences in survival rates existed between the 2 groups. Furthermore, significantly higher rates of recurrent DVT occurred among patients who received an IVC filter. Other complications of IVC filters include proximal migration of the filter into the right heart chambers and perforation of the IVC.

Activity

• Activity is recommended as tolerated.

MEDICATION

Section 7 of 11  

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• Workup
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• Medication
• Follow-up
• Miscellaneous
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Immediate therapeutic anticoagulation is initiated for patients with suspected DVT or PE. Anticoagulation therapy with heparin reduces mortality rates from 30% to less than 10%. Thrombolytic therapy is recommended for 3 groups of patients: (1) those patients who are hemodynamically unstable, (2) those who have right-heart strain, and (3) those who have limited cardiopulmonary reserve.

Chronic anticoagulation is critical to prevent relapse of DVT or PE following initial heparinization. The optimum duration of anticoagulation has not been well-studied and is controversial. The general consensus is that a significant reduction in recurrence is associated with 3-6 months of anticoagulation.

Drug Category: Thrombolytics

Thrombolysis is indicated for hemodynamically unstable patients with PE. Thrombolysis dramatically improves acute cor pulmonale. Thrombolytic therapy has replaced surgical embolectomy as the treatment for hemodynamically unstable patients with massive PE.

Thrombolytic regimens currently in use for PE include 2 forms of recombinant tissue-plasminogen activators, alteplase (t-PA) and reteplase (r-PA), along with urokinase and streptokinase. The comparative clinical trials have shown that administration of a 1-h infusion of alteplase is more rapidly effective than urokinase or streptokinase over a 12-h period. The safety and efficacy of different thrombolytic agents is comparable. Streptokinase may cause anaphylaxis, hypotension, and other adverse reactions, leading to the cessation of therapy in many cases.

Rarely, empiric thrombolysis may be indicated in selected patients who are hemodynamically unstable, eg, the clinical likelihood of PE is overwhelming and the patient's condition is rapidly deteriorating (with the possibility of imminent death). In such patients, the possible risk of severe complications from thrombolysis should be carefully evaluated against the potential benefits.

Drug Category: Anticoagulants

Heparin augments activity of the natural anticoagulant antithrombin III and prevents conversion of fibrinogen to fibrin. Full-dose LMWH or unfractionated IV heparin should be initiated at the first suspicion of DVT or PE. Heparin does not dissolve an existing clot, but it does prevent clot propagation and embolization. Recurrence or extension of DVT and PE may occur despite therapeutic anticoagulation with heparin.

With proper dosing, several LMWH products have been found to be safer and more effective than unfractionated heparin for prophylaxis and treatment of patients with DVT and PE. Not necessary or useful to monitor aPTT while using LMWH. Drug is most active in tissue phase, and, as opposed to unfractionated heparin, LMWH does not exert most of its effects on coagulation factor IIa.

Many different LMWH products are currently available. Because of the pharmacokinetic differences, dosing and interval of administration is highly product-specific. Presently, 3 LMWH products are available in the US (enoxaparin, dalteparin, ardeparin). Enoxaparin is the only one that is approved by the FDA for treatment of patients with DVT. The FDA has approved all 3 for DVT prophylaxis at a lower dose. LMWH administered via subcutaneous route is preferred for commencing anticoagulation therapy. Maintenance therapy with warfarin usually is initiated simultaneously. The weight-adjusted heparin dosing regimens have proven to be efficacious for treatment of patients with DVT and PE and are endorsed by the experts.

FOLLOW-UP

Section 8 of 11  

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• Follow-up
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Deterrence/Prevention

Heparin prophylaxis: The incidence of venous thrombosis, pulmonary embolism (PE), and death can be significantly reduced by embracing a prophylactic strategy in high-risk patients. Prevention of deep vein thrombosis (DVT) in lower extremities inevitably reduces the frequency of PE; therefore, populations at risk must be identified, and safe and efficacious prophylactic modalities should be used. The risk groups identified in clinical practice and the prophylaxis recommended by the Sixth Consensus Conference on Antithrombotic Therapy are described in the Table.

Prophylaxis Against Venous Thromboembolism

*Approximate risk without prophylaxis for all and/or proximal DVT or symptomatic PE

Sequential compression devices

• Compression stockings provide a compression of 30-40 mm Hg gradient and are a safe and effective therapy to prevent venous thromboembolism in patients who are at high risk when heparin therapy is not desirable or is contraindicated. These devices provide a gradient of compression that is highest at the toes and gradually decreases to the level of the thigh. This mechanism reduces the capacitative venous volume by approximately 70% and increases the measured velocity of blood flow by a factor of 5 or more in lower extremity veins.
• A 1994 meta-analysis calculated a DVT risk ratio of 0.28 for gradient compression stockings (compared to no prophylaxis) in patients undergoing abdominal surgery, gynecologic surgery, or neurosurgery. Other studies have reported that gradient compression stockings and LMWH were the most effective modalities in reducing the incidence of DVT after hip surgery.
• The universal white stockings, known as antiembolic stockings or Ted stockings, produce a maximum compression of only 18 mm Hg. Ted stockings rarely are fitted in such a way as to provide adequate gradient compression to the deep venous system. Therefore, Ted stockings have no proven efficacy in the prevention of DVT and PE.
• Gradient compression pantyhose (30-40 mmHg) are available in pregnant sizes. They are recommended by many specialists for all women who are pregnant because they not only prevent DVT but also reduce or prevent the development of varicose veins.
• Although strict bed rest was recommended in the past for acute DVT to reduce the risk of PE, a study has shown no benefit from prescribing bed rest. Therefore, strict bed rest for 5 days is not justified if adequate therapy with low molecular weight heparin and adequate compression is assured.

Complications

• Sudden cardiac death
• Obstructive shock
• Pulseless electrical activity
• Atrial or ventricular arrhythmias
• Secondary pulmonary arterial hypertension
• Cor pulmonale
• Severe hypoxemia
• Right to left intracardiac shunt
• Lung infarction
• Pleural effusion
• Paradoxical embolism

Prognosis

• The prognosis of patients with PE depends on 2 factors: (1) the underlying disease state and (2) appropriate diagnosis and treatment.
• Most patients treated with anticoagulants do not develop long-term sequelae upon follow-up evaluation.
• At 5 days of anticoagulant therapy, 36% of lung scan defects are resolved; at 2 weeks, 52% are resolved; at 3 months, 73% are resolved.
• The mortality rate in patients with undiagnosed PE is 30%.
• In the PIOPED study, the 1-year mortality rate was 24%. The deaths occurred due to cardiac disease, recurrent PE, infection, and cancer.
• The risk of recurrent PE is due to the recurrence of proximal venous thrombosis; approximately 17% of patients with recurrent PE were found to have proximal DVT.
• In a small proportion of patients, PE does not resolve; hence, chronic thromboembolic pulmonary arterial hypertension results.

Patient Education

For excellent patient education resources, visit eMedicine's Lung and Airway Center and Circulatory Problems Center. Also, see eMedicine's patient education articles Pulmonary Embolism and Blood Clot in the Legs.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia