PULMONARY EMBOLISM

TOPIC № 13. PULMONARY EMBOLISM

 

 

Introduction

 

Background

Pulmonary embolism (PE) is as well recognized a thromboembolic disease, as are cerebral infarction and myocardial infarction in Western countries. However, the number of the patients with PE is still much lower in Japan than in the West. The Ministry of Health, Labor and Welfare in Japan reported in a patient survey that there were 1,220,000 patients with cerebral infarction, 82,000 with myocardial infarction, and only 4,000 with PE in 1999 . Vital statistics in the same year found 51,688 deaths from cerebral infarction, 48,806 from myocardial infarction, and only 1,738 from pulmonary embolism. In this chapter,we show the epidemiological results on PE in Japan, and consider the reasons for the difference in the incidence of PE between Japan and Western countries.

From the point of view of vital statistics, crude deaths from PE rapidly increased, and female deaths exceeded male deaths in the 1990s.

Age-specific mortality was higher in the elderly and, in recent years, lower in females than in males. The results of crude deaths reflect the fact that many more elderly people are female than male. The adjusted mortality in 1996 was 0.71 per 100,000 persons in males and 0.83 in females, which is comparable to the mortality of non-Blacks and non-Whites in the United States. The reduced mortality in the United States was achieved by widespread prevention of venous thromboembolism.

Pulmonary embolism (PE) is a relatively common cardiovascular emergency. By occluding the pulmonary arterial bed it may lead to acute life-threatening but potentially reversible right ventricular failure. PE is a difficult diagnosis that may be missed because of non-specific clinical presentation. However, early diagnosis is fundamental, since immediate treatment is highly effective. Depending on the clinical presentation, initial therapy is primarily aimed either at life-saving restoration of flow through occluded pulmonary arteries (PA) or at the prevention of potentially fatal early recurrences.

Both initial treatment and the long-term anticoagulation  that is required for secondary prevention must be justified in each patient by the results of an appropriately validated diagnostic strategy.

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

 

The most important conceptual advance regarding pulmonary embolism over the last several decades has been the realization that pulmonary embolism is not a disease; rather, pulmonary embolism is a complication of venous thromboembolism, most commonly deep venous thrombosis (DVT). Virtually every physician who is involved in patient care (eg, internist, family physician, orthopedic surgeon, gynecologic surgeon, urologic surgeon, pulmonary subspecialist, cardiologist) encounters patients who are at risk for venous thromboembolism, and therefore at risk for pulmonary embolism.

 

 

Fig. 1. A large pulmonary artery thrombus in a hospitalized patient who died suddenly.

 

 

 

Fig. 2. Pulmonary embolism was identified as the cause of death in a patient who developed shortness of breath while hospitalized for hip joint surgery

 

Pathophysiology

 

The pathophysiology of pulmonary embolism encompasses several aspects, as described below.

 

Natural history of venous thrombosis

 

In the 19th century, Virchow identified a triad of factors that lead to venous thrombosis: venous stasis, injury to the intima, and enhanced coagulation properties of the blood. Thrombosis usually originates as a platelet nidus on valves 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 or the right heart chambers. After traveling to the lung, large thrombi can lodge at the bifurcation of the main pulmonary artery or the lobar branches and cause hemodynamic compromise. Smaller thrombi typically travel more distally, occluding smaller vessels 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 pulmonary embolism include increased alveolar dead space, pneumoconstriction, hypoxemia, and hyperventilation. Later, 2 additional consequences may occur: regional loss of surfactant and pulmonary infarction (see the image below). 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 a patent foramen ovale. Pulmonary infarction is an uncommon consequence because of the bronchial arterial collateral circulation.

 

 

Fig. 3. Lung infarction secondary to pulmonary embolism occurs rarely.

 

 

Hemodynamic consequences

 

Pulmonary embolism 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

 

The incidence of pulmonary embolism in the United States is estimated at 1 case per 1000 persons per year.1 Studies from 2008 suggest that the increasing use of computed tomography (CT) for assessing patients with possible pulmonary embolism has led to an increase in the reported incidence of pulmonary embolism.2,3

 

Pulmonary embolism is present in 60-80% of patients with DVT, even though more than half these patients are asymptomatic. Pulmonary embolism 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 pulmonary embolism, 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 population-based study covering the years 1966-1995 collated the cases of DVT or pulmonary embolism in women during pregnancy or postpartum. The relative risk was 4.29, and the overall incidence of venous thromboembolism (absolute risk) was 199.7 incidents per 100,000 woman-years. Among postpartum women, the annual incidence was 5 times higher than in pregnant women (511.2 vs 95.8 incidents per 100,000 women).

 

The incidence of DVT was 3 times higher than that of pulmonary embolism (151.8 vs 47.9 incidents per 100,000 women). Pulmonary embolism was relatively less common during pregnancy versus the postpartum period (10.6 vs 159.7 incidents per 100,000 women).4 A national review of severe obstetric complications from 1998-2005 found a significant increase in the rate of pulmonary embolism associated with the increasing rate of cesarean delivery.

 

International

 

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

 

Mortality/Morbidity

 

From 1979-1998, the age-adjusted death rate for pulmonary embolism in the United States decreased from 191 deaths per million population to 94 deaths per million population.1  Regional studies covering more recent years have found either a slight decrease or no change in mortality.2,3

As a cause of sudden death, massive pulmonary embolism is second only to sudden cardiac death. Autopsy studies of patients who died unexpectedly in a hospital setting have shown approximately 80% of these patients died from massive pulmonary embolism.

Approximately 10% of patients who develop pulmonary embolism 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 pulmonary embolism 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.

 

Race

The incidence of pulmonary embolism appears to be significantly higher in blacks than in whites.6 Mortality rates from pulmonary embolism for blacks have been 50% higher than those for whites, and those for whites have been 50% higher than those for people of other races (eg, Asians, Native Americans).1

 

Sex

The risk of pulmonary embolism is increased in pregnancy and during the postpartum period.

Data are conflicting regarding male sex as a risk factor for pulmonary embolism; however, an analysis of national mortality data found that death rates from pulmonary embolism were 20-30% higher among men than among women.1

 

Age

In hospitalized elderly patients, pulmonary embolism is commonly missed and often is the cause of death.

 

Clinical

Predisposing factors for venous thromboembolism

 

 

 

 

 

Clinical prediction rules for PE: the Wells score and the revised Geneva score

 

 

Diagnostic algorithm for patients with suspected high-risk PE

 

 

History

 

The presentation of pulmonary embolism (PE) may vary from sudden catastrophic hemodynamic collapse to gradually progressive dyspnea. The diagnosis of pulmonary embolism should be sought actively in patients with respiratory symptoms unexplained by an alternate diagnosis. The symptoms of pulmonary embolism are nonspecific; therefore, a high index of suspicion is required, particularly when a patient has risk factors for the condition/

The presentation of patients with pulmonary embolism can be categorized into 4 classes based on the acuity and severity of pulmonary arterial occlusion. These categories are (1) massive pulmonary embolism, (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 clinically indistinguishable from ischemic myocardial pain, normal electrocardiogram findings and no response to nitroglycerin rules it out.

Acute embolism without infarction: Patients have nonspecific symptoms of unexplained dyspnea and/or substernal discomfort.

Multiple pulmonary emboli

This group comprises 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 has 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 pulmonary embolism have no obvious symptoms at presentation. In contrast, patients with symptomatic DVT commonly have pulmonary embolism confirmed on diagnostic studies in the absence of pulmonary symptoms.

 

The most common symptoms of pulmonary embolism in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study were dyspnea (73%), pleuritic chest pain (66%), cough (37%), and hemoptysis (13%).7 However, patients with pulmonary embolism may present with atypical symptoms. In such cases, strong suspicion of pulmonary embolism based on the presence of risk factors can lead to consideration of pulmonary embolism 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

Flank pain

Delirium (in elderly patients)

 

Pleuritic chest pain without other symptoms or risk factors may be a presentation of pulmonary embolism.

 

Physical

 

Physical examination findings are quite variable in pulmonary embolism 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 of the extremities, tachycardia, and tachypnea.

Additionally, signs of pulmonary hypertension such as palpable impulse over the second left intercostal space, 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 the involved hemithorax, palpable or audible pleural friction rub, and even localized tenderness.

Signs of pleural effusion, such as dullness to 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 pulmonary embolism 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 pulmonary embolism. Finally, chest wall tenderness upon palpation, without a history of trauma, may be the sole physical finding in rare cases.

 

Causes

 

The causes for pulmonary embolism 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, resulting in thrombus formation.

The risk of pulmonary embolism increases with prolonged bed rest or immobilization of a limb in a cast.

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 pulmonary embolism.

A prospective study by Geerts and colleagues in 1994 indicated that major trauma was associated with a 58% incidence of DVT in the lower extremities and an 18% incidence in proximal veins.10

Pulmonary embolism 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 pulmonary embolism, in descending order of frequency, are pancreatic carcinoma; bronchogenic carcinoma; and carcinomas of the genitourinary tract, colon, stomach, and breast.

In the PIOPED II study, immobilization (usually because of surgery) was the risk factor most commonly assessed in patients with pulmonary embolism; 94% of all patients with pulmonary embolism had 1 or more of the following risk factors11 :

Immobilization

 

Travel of 4 hr or more in the past month

 

Surgery within the last 3 months

 

Malignancy, especially lung cancer

 

Current or past history of thrombophlebitis

 

Trauma to the lower extremities and pelvis during the past 3 months

 

Smoking

 

Central venous instrumentation within the past 3 months

 

Stroke, paresis, or paralysis

 

Prior pulmonary embolism

 

Heart failure

Chronic obstructive pulmonary disease

 

Other recognized risk factors include the following:

 

Obesity

 

Varicose veins

 

Inflammatory bowel disease

 

 

Laboratory Studies

 

Clinical signs and symptoms for pulmonary embolism (PE) are nonspecific; therefore, patients suspected of having pulmonary embolism—because of unexplained dyspnea, tachypnea, or chest pain or the presence of risk factors for pulmonary embolism—must undergo diagnostic tests until the diagnosis is ascertained or eliminated or an alternative diagnosis is confirmed. Further, routine laboratory findings are nonspecific and are not helpful in pulmonary embolism, although they may suggest another diagnosis.

 

Evidence-based literature supports the practice of determining the clinical probability of pulmonary embolism before proceeding with testing. A clinical practice guideline from the American Academy of Family Physicians (AAFP) and the American College of Physicians (ACP) recommends that validated clinical prediction rules be used to estimate pretest probability of pulmonary embolism and to interpret test results. The guideline, Current diagnosis of venous thromboembolism in primary care, advocates use of the Wells prediction rule for this purpose, but notes that the Wells rule performs better in younger patients without comorbidities or a history of venous thromboembolism.

 

Table 1. Wells Prediction Rule for Diagnosing Pulmonary Embolism: Clinical Evaluation Table for Predicting Pretest Probability of Pulmonary Embolism

 

Another validated clinical prediction rule for use in the diagnosis of pulmonary embolism is the revised Geneva score. The performance of the revised Geneva score appears equivalent to that of the Wells score.

 

Table 2 The Revised Geneva Score

 

 

Simplified versions of the Wells score and the revised Geneva score have been developed. Initial studies support the validity of these scores, which assign 1 point to each of the criteria.

 

D-dimer testing

 

When clinical prediction rule results indicate that the patient has a low or moderate pretest probability of pulmonary embolism, D-dimer testing is the usual next step. Negative results on a high-sensitivity D-dimer test in a patient with a low pretest probability of pulmonary embolism indicate a low likelihood of venous thromboembolism and reliably exclude pulmonary embolism. A large prospective randomized trial found that in patients with a low probability of pulmonary embolism who had negative D-dimer results, forgoing additional diagnostic testing was not associated with an increased frequency of symptomatic venous thromboembolism during the subsequent 6 months.20

D-dimer, a degradation product produced by plasmin-mediated proteases of cross-linked fibrin, is measured by a variety of assay types, including quantitative, semiquantitative, and qualitative rapid enzyme-linked immunosorbent assays (ELISAs); quantitative and semiquantitative latex; and whole-blood assays. A systematic review of prospective studies of high methodologic quality concluded that the ELISAs—especially the quantitative rapid ELISA—dominate the comparative ranking among the D-dimer assays for sensitivity and negative likelihood ratio. The quantitative rapid ELISA has a sensitivity of 0.95 and negative likelihood ratio of 0.13; the latter is similar to that for a normal to near-normal lung scan in patients with suspected pulmonary embolism.

D-dimer testing is most reliable for excluding pulmonary embolism in younger patients who have no associated comorbidity or history of venous thromboembolism and whose symptoms are of short duration.14 D-dimer testing is of questionable value in patients who are older than 80 years, are hospitalized, or have cancer and in pregnant women, because nonspecific elevation of D-dimer concentrations is common in such patients. D-dimer test should not be used when the clinical probability of pulmonary embolism is high, because the test has low negative predictive value in such cases.

 

Troponins

 

Serum troponin levels can be elevated in up to 50% of patients with a moderate-to-large pulmonary embolism, presumptively due to acute right ventricular myocardial stretch.

Although not currently recommended as part of the diagnostic workup, studies have shown that elevated troponin levels in the setting of pulmonary embolism correlate with increased mortality. Currently, further studies need to be performed to identify subsets of patients with pulmonary embolism who might benefit from this testing.

A meta-analysis by Jimenez et al suggests that in acute symptomatic pulmonary embolism (PE), elevated troponin levels do not distinguish between patients who are at high risk for death and those who are at low risk. Pooled results from studies including 1366 normotensive patients with acute symptomatic PE showed that elevated troponin levels were associated with a 4.26-fold increased odds of overall mortality (95% confidence interval [CI], 2.13-8.50; heterogeneity chi2 = 12.64; degrees of freedom = 8; P = .125). Summary receiver operating characteristic curve analysis showed a relationship between the sensitivity and specificity of troponin levels to predict overall mortality (Spearman rank correlation coefficient = 0.68; P = .046). Pooled likelihood ratios (LRs) were not extreme (negative LR, 0.59 [95% CI, 0.39-0.88]; positive LR, 2.26 [95% CI,1.66-3.07]).

 

Braiatriuretic peptide

 

Although neither sensitive nor specific, patients with pulmonary embolism tend to have higher levels of braiatriuretic peptide (BNP). In one case-control study of 2213 hemodynamically stable patients with suspected acute pulmonary embolism, BNP testing had a sensitivity and specificity of only 60% and 62%, respectively.

Elevated levels of BNP or its precursor, N -terminal pro-braiatriuretic peptide (NT-proBNP), do correlate with an increased risk of subsequent complications and mortality in patients with acute pulmonary embolism. One meta-analysis revealed that patients with a BNP level greater than 100 pg/mL or an NT-proBNP level greater than 600 ng/L had an all-cause in-hospital mortality rate 6- and 16-fold higher than those below these cutoffs, respectively. In a second smaller observational study, serum BNP levels greater than 90 pg/mL were associated with a higher rate of complications, such as the need for cardiopulmonary resuscitation, need for mechanical ventilation, need for vasopressor therapy, and death.28

BNP testing is not currently recommended as part of the standard evaluation of acute pulmonary embolism, and future studies may aid in defining its role in this setting.

 

Arterial blood gases

 

Arterial blood gas determinations 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 pulmonary embolism.

Nonetheless, in high-risk settings such as patients in postoperative states in whom other respiratory conditions can be ruled out, a low PaO2 in conjunction with dyspnea may have a strong positive predictive value.

 

 

Imaging Studies

 

Chest radiography

The American College of Radiology (ACR) recommends chest radiography as the most appropriate study for ruling out other causes of chest pain in patients with suspected pulmonary embolism.

Initially, the chest radiography findings are normal in most cases of pulmonary embolism. However, in later stages, radiographic signs may include a Westermark sign (dilatation of pulmonary vessels and a sharp cutoff), atelectasis, a small pleural effusion, and an elevated diaphragm.

Although chest radiography findings may indicate an alternate diagnosis, this study alone is not sufficient to confirm the diagnosis of pulmonary embolism.

 

 

Fig. 4. Posteroanterior and lateral chest radiograph findings are normal, which is the usual finding in patients with pulmonary embolism

 

 

Fig. 5. A chest radiograph with normal findings in a 64-year-old woman who presented with worsening breathlessness.

 

 

Fig.6. A posteroanterior chest radiograph showing a peripheral wedge-shaped infiltrate caused by pulmonary infarction secondary to pulmonary embolism. Hampton hump is a rare and nonspecific finding

 

Computed tomography

 

CT angiography (CTA) is the initial imaging modality of choice for stable patients with suspected pulmonary embolism. The ACR considers chest CTA the current standard of care for the detection of pulmonary embolism.29

In patients with a negative CTA, the likelihood for subsequent thromboembolic events is extremely small.

The Christopher study, a prospective trial, used CT as part of a management algorithm for 3306 outpatients with suspected acute pulmonary embolism. Patients in whom the Wells rule indicated that pulmonary embolism was unlikely underwent D-dimer testing; if the result was normal, pulmonary embolism was considered excluded. All other patients underwent multidetector CT arteriography, and pulmonary embolism was considered present or excluded based on the results. Among patients with negative scan results who did not receive anticoagulation therapy, the 3-month incidence of venous thromboembolism was 1.3%; death, possibly from pulmonary embolism, occurred in 0.5%.30

Similarly, a meta-analysis published in 2004 reviewed 23 studies reporting on 4657 patients with negative pulmonary CTA results for pulmonary embolism who did not receive anticoagulation. The rate of venous thromboembolism was 1.4% and the rate of fatal pulmonary embolism was 0.51% at 3 months. These results are similar to negative results on conventional pulmonary angiography. These investigators concluded that withholding anticoagulation after negative pulmonary CTA results appears to be safe.31

Spiral CT can visualize main, lobar, and segmental pulmonary emboli with a reported sensitivity of greater than 90%. Spiral CT scanning can help detect emboli as small as 2 mm that are affecting up to the seventh border division of the pulmonary artery. A further benefit of spiral CT scanning is that the results may suggest an alternative diagnosis in up to 57% of patients. A significant limitation of spiral CT scanning is that small subsegmental emboli may not be detected.

The technique is as follows:

Spiral CT examination is performed immediately after infusion of 150-200 mL of 30% contrast material.

Scanning 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 or her breath at full inspiration.

If the patient is not able to hold his or her breath for 20-30 seconds, scanning may be performed during gentle breathing.

 

Sensitivity and specificity of spiral CT scanning for pulmonary embolism are as follows:

The reported sensitivity is 53-100%.

The reported specificity is 78-96%.

The negative predictive value is 81-100%, and the positive predictive value is 60-100% for detecting emboli in segmental or larger arteries.

 

Positive findings on CT imaging 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. In the lung parenchyma, signs of pulmonary embolism include oligemia, pulmonary hemorrhage (ground-glass attenuation), and pulmonary infarction (peripheral wedge-shaped pleural-based opacification).

 

Pitfalls include the following:

Technically inadequate scans may result from patients’ dyspnea and/or obliquely or horizontally oriented vessels within the right middle lobe and left lingula.

False filling defects may result from breathing artifact cardiac motion or unilateral extensive air space consolidation as a result of the significant decrease in blood flow through pulmonary arteries in these areas.

 

Combined spiral CT scanning for detection of pulmonary embolism and deep venous thrombosis (DVT)

 

A combined CT scan for PE/DVT enhances the utility of spiral CT scanning 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 scanning 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 on CT scanning examination for pulmonary embolism have been identified to have DVT

 

 

Fig. 7. A spiral CT scan shows thrombus in bilateral main pulmonary arteries.

 

 

Fig. 8. A spiral CT scan shows thrombus in bilateral main pulmonary arteries

 

 

Fig. 9. CT scan

 

Ventilation-perfusion (V/Q) scanning of the lungs: This is an important diagnostic modality for establishing the diagnosis of pulmonary embolism. However, V/Q scanning should be used only when CT scanning is not available or if the patient has a contraindication to CT scanning or intravenous contrast material.

 

New criteria for V/Q scanning diagnosis of pulmonary embolism, from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II trial:

 

High probability criteria are as follows:

Two large (more than 75% of a segment) segmental perfusion defects without corresponding ventilation or chest radiographic abnormalities

One large segmental perfusion defect and 2 moderate (25-75% of a segment) segmental perfusion defects without corresponding ventilation or radiographic abnormalities

Four moderate segmental perfusion defects without corresponding ventilation or chest radiographic abnormalities

 

Intermediate probability criteria are as follows:

 

One moderate to fewer than 2 large segmental perfusion defects without corresponding ventilation or chest radiographic abnormalities

 

Corresponding V/Q defects and radiographic parenchymal opacity in lower lung zone

 

Single moderate matched V/Q defects with normal chest radiographic findings

 

Corresponding V/Q and chest radiography small pleural effusion

 

Difficult to categorize as normal, low, or high probability

 

Low probability criteria are as follows:

Multiple matched V/Q defects, regardless of size, with normal chest radiographic findings

 

Corresponding V/Q defects and radiographic parenchymal opacity in upper or middle lung zone

 

Corresponding V/Q defects and large pleural effusion

 

Any perfusion defects with substantially larger radiographic abnormality

Defects surrounded by normally perfused lung (stripe sign)

 

More than 3 small (less than 25% of a segment) segmental perfusion defects with normal chest radiographic findings

 

Nonsegmental perfusion defects (cardiomegaly, aortic impression, enlarged hila)

 

Very low criterion is 3 small (less than 25% of a segment) segmental perfusion defects with normal chest radiograph findings.

 

Normal finding is no perfusion defects and perfusion outlines the shape of the lung seen on a chest radiograph.

 

In the PIOPED II study, very low-probability V/Q scans in patients whose Wells score indicated low pretest probability of pulmonary embolism reliably excluded pulmonary embolism.

 

 

 

Fig. 10. High-probability perfusion lung scan shows segmental perfusion defects in the right upper lobe and subsegmental perfusion defects in right lower lobe, left upper lobe, and left lower lobe

 

 

Fig. 11. A normal ventilation scan will make the above-noted defects in Image 5 a mismatch and, hence, a high-probability ventilation-perfusion scan

 

 

Fig. 12. Anterior views of perfusion and ventilation scans are shown here. A perfusion defect is present in the left lower lobe, but perfusion to this lobe is intact, making this a high-probability scan

 

 

Fig. 13. A segmental ventilation perfusion mismatch evident in a left anterior oblique projection.

 

Noninvasive tests for lower extremity DVT

These may be helpful in the evaluation of patients who have nondiagnostic V/Q scan patterns of intermediate and low probability.

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 definitively rule out pulmonary embolism.

 

Pulmonary angiography

 

Pulmonary angiography remains the criterion standard for the diagnosis of pulmonary embolism.

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 pulmonary embolism.

 

 

Fig. 14. A pulmonary angiogram shows the abrupt termination of the ascending branch of the right upper-lobe artery, confirming the diagnosis of pulmonary embolism

 

Magnetic resonance imaging

 

With 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 pulmonary embolism. However, this remains a problem in pulmonary hypertension.

Magnetic resonance angiography is performed following intravenous administration of gadolinium. Gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). The disease has occurred in patients with moderate to end-stage renal disease after being given a gadolinium-based contrast agent to enhance MRI or magnetic resonance angiography scans.

NSF/NFD is a debilitating and sometimes fatal disease. Characteristics include red or dark patches on the skin; burning, itching, swelling, hardening, and tightening of the skin; yellow spots on the whites of the eyes; joint stiffness with trouble moving or straightening the arms, hands, legs, or feet; pain deep in the hip bones or ribs; and muscle weakness.

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 pulmonary embolism.

Transesophageal echocardiography may identify central pulmonary embolism, and the sensitivity for central pulmonary embolism is reported to be 82%.

Overall sensitivity and specificity for central and peripheral pulmonary embolism is 59% and 77%.

Echocardiography may demonstrate right ventricular dysfunction in acute pulmonary embolism, predicting a higher mortality and possible benefit from thrombolytic therapy. Vanni et al reported that a right ventricular strain pattern is associated with a worse short-term outcome.

 

Differential Diagnoses

 

Acute Coronary Syndrome

 

Acute Respiratory Distress Syndrome

 

Anxiety Disorders

 

Aortic Stenosis

 

Atrial Fibrillation

 

Atrial Fibrillation, Diagnosis and Management

 

Cardiogenic Shock

 

Cardiomyopathy, Dilated

 

Cardiomyopathy, Restrictive

 

Chronic Obstructive Pulmonary Disease

 

Congestive Heart Failure and Pulmonary Edema

 

Cor Pulmonale

 

Emphysema

 

Extrinsic Allergic Alveolitis

 

Fat Embolism

 

Lung, Arteriovenous Malformation

 

Mitral Stenosis

 

Myocardial Infarction

 

Myocardial Ischemia

 

Pericarditis and Cardiac Tamponade

 

Pneumothorax

 

Pulmonary Edema, Noncardiogenic

 

Pulmonary Hypertension, Primary

 

Pulmonary Hypertension, Secondary

 

Sudden Cardiac Death

 

Sudden Cardiac Death

 

Superior Vena Cava Syndrome

Syncope

 

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. Current guidelines recommend starting unfractionated heparin (UFH), low molecular weight heparin (LMWH) or fondaparinux (all grade 1A) in addition to an oral anticoagulant (warfarin) at the time of diagnosis, and to discontinue UH, LMWH, or fondaparinux only after the international normalized ratio (INR) is 2.0 for at least 24 hours, but no sooner than 5 days after warfarin therapy has been started (grade 1C recommendation).34  The recommended duration of UH, LMWH, and fondaparinux is based on evidence suggesting that the relatively long half-life of factor II, along with the short half-lives of protein C and protein S, may provoke a paradoxical hypercoagulable state if these agents are discontinued prematurely.

 

Thrombolytic therapy

 

Thrombolytic therapy should be considered for patients who are hemodynamically unstable, patients who have right-sided 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 with heparin.

Until randomized clinical trials demonstrate a clear morbidity or mortality benefit, the role of thrombolytic therapy in the management of acute pulmonary embolism 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.

If intravenous UFH is chosen, an initial bolus of 80 U/kg or 5000 U followed by an infusion of 18 U/kg/h or 1300 U/h should be given, with the goal of rapidly achieving and maintaining the aPTT at levels that correspond to therapeutic heparin levels. Fixed-dose and monitored regimens of subcutaneous UFH are available and  are acceptable alternatives.

 

Low molecular weight heparin

 

Current guidelines for patients with acute nonmassive pulmonary embolism recommend LMWH over UFH (grade 1A). In patients with massive pulmonary embolism, if concerns regarding subcutaneous absorption arise, severe renal failure exists, or if thrombolytic therapy is being considered, intravenous UFH is the recommended form of initial anticoagulation (grade 2C).34

LMWHs have many advantages over UFH. 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 with UFH have shown that LMWH is at least as effective and as safe as UFH.

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 pulmonary embolism are treated at home, at substantial cost savings.

 

Fondaparinux

 

Fondaparinux is a synthetic polysaccharide derived from the antithrombin binding region of heparin. Fondaparinux catalyzes factor Xa inactivation by antithrombin without inhibiting thrombin.

Fondaparinux has not been directly compared with subcutaneous UFH or LMWH, but one randomized open-label study of 2213 patients with symptomatic pulmonary embolism compared once daily subcutaneous fondaparinux with intravenous UFH. The 2 regimens were found to have similar rates of recurrent pulmonary embolism, bleeding, and death.35

With the exception of patients presenting with massive pulmonary embolism (defined by hemodynamic compromise), LMWH or fondaparinux is recommended over intravenous UFH. This is because of a more predictable bioavailability, more rapid onset of full anticoagulant effect, and benefit of not typically needing to monitor anticoagulant effect.

However, in cases in which an anticoagulant with a shorter half-life is more desirable (ie, patients at particularly high risk of bleeding) or in patients with impaired renal function, intravenous UFH may be preferred (grade 2C).34

 

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 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 at least 3 months. Among patients with idiopathic (or unprovoked) first events, 2 studies have compared 6 versus 3 months of anticoagulant therapy and no difference in the rate of recurrence was observed in either study.36,37 The current recommendation is anticoagulation for at least 3 months in these patients, and the need for extending the duration of anticoagulation should be reevaluated at that time.

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 pulmonary embolism 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.

Compression stockings: For patients who have had a proximal DVT, elastic compression stockings with a pressure of 30-40 mm Hg at the ankle for 2 years following the diagnosis is recommended (grade 1A) to reduce the risk of postphlebitic syndrome.

 

Surgical Care

 

Indication of Surgical Removal of Thrombi

When acute pulmonary thromboembolism is diffuse, the bilateral main pulmonary arteries are rapidly occluded and most patients could die within hours after onset. Furthermore, many mortalities due to acute pulmonary thromboembolism are caused by circulatory collapse in the stage immediately after the onset and by early recurrence. Therefore, in cases of circulatory failure or shock the main objective of treatment is to recanalize the occluded pulmonary arteries as quickly as possible. Generally, the indications for pulmonary thrombectomy in this situation are (1) cases whose hemodynamics are extremely unstable and who do not respond to medication, (2) cases with angiogram or CT scan findings of obstructions over a wide area of the pulmonary arteries, (3) cases showing rapid progression of heart failure or respiratory failure, (4) cases in which thrombolytic therapy is contraindicated, and (5) cases with thrombi suspended from the right atrium to the right ventricle.

Many cases that fall into sudden shock before this disease is diagnosed cannot be operated on. Postoperative cases or long-term clinical patients who experience sudden dyspnea or who show signs of hypoxemia or right ventricular dilatation in their echocardiograms should be suspected of acute pulmonary thromboembolism, and percutaneous cardiopulmonary support (PCPS) should start immediately at the bedside. Furthermore, if there are no fatal cerebrovascular complications, and circulatory collapse due to the thromboembolism is identified, pulmonary artery thrombectomy should be carried out. Patients may include some who have thromboembolism (subacute pulmonary thromboembolism) of more than  2 weeks duration. Such cases are difficult to treat with conventional thrombectomy and should be diagnosed and their surgical indication determined with care.

 

Surgical Treatment of Acute Pulmonary Thromboembolism

 

Surgical treatment of this condition involves removal of the thromboemboli by transvenous thrombectomy or open thrombectomy.

Transvenous Thrombectomy (Catheter Intervention)

 

This is a method whereby the thromboemboli are removed by suction using a catheter inserted transvenously into the pulmonary artery. Catheters used in this method are the Greenfield catheter, guiding catheter for percutaneous transluminal coronary angioplasty (PTCA), and the HYDROLYSER embolectomy catheter. This method can be used for patients in whom thrombolytic therapy is contraindicated, and there are many reports, such as that of Greenfield et al. , of its efficacy. Still, because of the ever-present danger of circulatory collapse, transvenous embolectomy should be carried out under conditions where open embolectomy or PCPS is possible.

 

Open Thrombectomy

With extracorporeal circulation using an artificial heart-lung, namely under cardiopulmonary bypass, the pulmonary artery is opened and the thromboemboli are removed. If the patient has respiratory failure or poor hemodynamics preoperatively, extracorporeal circulation is quickly initiated using the femoral artery and vein. In cases of shock in the ward where hemodynamics cannot be maintained, the patient is transported to the operating room with PCPS. In cases of circulatory collapse with this disease, the speed of initiation of extracorporeal circulation is the key determinant of survival.

As for the surgical technique, extracorporeal circulation is initiated after median sternal incision, incisions are made bilaterally in the main pulmonary arteries, and open thrombectomy is carried out. Thrombi of acute pulmonary thromboembolism cases, in contrast to the organized thrombi of chronic cases, are soft and rod shaped, and the removed thrombi are relatively new and red. Although it is preferable to remove the thrombi as peripherally as possible, remaining thrombi can be treated postoperatively by thrombolytic methods if the major central thrombi have been removed. If they include those of more than  2 weeks duration (subacute pulmonary thromboembolism) that are firmly attached to the pulmonary arterial wall, care must be takeot to injure the arterial wall during the thrombectomy. The surgery can take place with the heart beating, but cardiac arrest is recommended for cases with multiple small thrombi in the segmental arteries or cases with thrombi firmly attached to the arterial wall.

 

 

The current grade 1A recommendation is that patients with acute pulmonary embolism should not routinely receive vena cava filters in addition to anticoagulants.

 

Inferior vena cava (IVC) interruption by the insertion of an IVC filter (Greenfield filter) is only indicated in the following settings: 

 

Patients with acute venous thromboembolism who have an absolute contraindication to anticoagulant therapy (eg, recent surgery, hemorrhagic stroke, significant active or recent bleeding)

 

Patients with massive pulmonary embolism who survived but in whom recurrent embolism invariably will be fatal

Patients who have objectively documented recurrent venous thromboembolism, adequate anticoagulant therapy notwithstanding

 

An ideal IVC filter should have the following characteristics38 : 

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 pulmonary embolism. 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-sided heart chambers and perforation of the IVC.

 

Temporary inferior vena cava

 

Complications of temporary IVC filter

aPE may recur asymptomatically, and aPE recurrence has no specific symptoms. Even if any symptoms appear and are recorded by echocardiography, blood flow scintigraphy, CT, etc., similar records of the patient immediately before the events must be available for comparison to confirm that they are indeed symptoms of recurrence. That would be impossible, and there are many obstacles to obtaining an accurate recurrence rate.We therefore evaluated symptoms that appeared anew during acute-stage management of aPE which, although not perfect, are highly reliable indicators of aPE recurrence.

The results suggested that tIVCF users present fewer new symptoms during use and are easier to control. The tIVCF user who had a recurrence and died had a giant ovarian cancer with the tip of the tumor extending to the epigastrium. The inferior vena cava was extruded directly below the diaphragm by the tumor, and the tIVCF had to be placed inside the flattened inferior vena cava.When the Neuhaus Protect, which is made of Teflon, is dilated inside a flattened inferior vena cava it is easily distorted, so its ability to capture thrombi must have been compromised. On the other hand, we thought it was highly probable that a metallic tIVCF would injure the vascular wall and decided against it. Secondary  prevention in cases like this is considered to be an important issue for the future.

The most frequent complication of tIVCF was bleeding/hematoma of the puncture site. Because the basic treatments for aPE are anticoagulant therapy and fibrinolytic therapy, and the shaft of the tIVCF is extracorporeal, caution is constantly required to prevent this complication. The best way to prevent it is to improve the attending clinician’s technique and to puncture the vein at the first attempt. The complications that are generally cited in connection with tIVCF use are hemorrhagic complications caused by basic aPE therapy, filter displacement, venous thrombus, infections, air embolism, and filter breakage.Thrombus in the filter site is another complication that should be considered.When contrast radiography of the filter site at the time of removal revealed a thrombus occupying more than one-fourth of thelumen, we administered fibrinolytic treatment from the filter tip. The thrombus size was reduced in all cases, and the filter could be removed in a few days without any problems.

The major reason for using a pIVCF was poor ADL in the tIVCF users and APE recurrence in the nonusers.ADL is determined by the underlying diseasecondition and poor ADL is a major risk factor for DVT, so the use of pIVCF was inevitable in such cases. pIVCF use due to aPE recurrence could be avoided by using tIVCF,which is considered to be clinically effective in acute-stage control.

The basic principle of aPE prevention is extended ADL. Long-term bed rest slows the venous blood flow rate and encourages the formation of venous thrombi, so it should be avoided as much as possible. Although recurrence could easily occur when shifting from bed rest to expanded ADL, we believe that if unstable DVT entering the venous bloodstream are captured by the tIVCF, expanded ADL can proceed safely in the acute phase.

As retrievable filters that can be removed with certainty are developed in the future, we can look forward to fewer complications of bleeding and infections and the realization of aPE acute-stage management that is safer than ever before.

 

 

 

 

 

Activity

 

Activity is recommended as tolerated. Early ambulation is recommended over bed rest when feasible (grade 1A recommendation).

 

Medication

 

Immediate therapeutic anticoagulation is initiated for patients with suspected deep venous thrombosis (DVT) or pulmonary embolism (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-sided heart strain, and (3) those who have limited cardiopulmonary reserve.

 

Chronic anticoagulation is critical to prevent relapse of DVT or pulmonary embolism 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.

 

Thrombolytics

 

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

 

Thrombolytic regimens currently in use for pulmonary embolism 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.

 

Wang et al conducted a prospective, randomized, multicenter trial in 118 patients with acute pulmonary thromboembolism (PTE) and either hemodynamic instability or massive pulmonary artery obstruction.40 Patients were randomly assigned to receive either alteplase (rt-PA) at 50 mg IV infused over 2 h (n = 65) or the current FDA-approved dose of 100 mg IV infused over 2 h (n = 53). Efficacy was measured by improvements of right ventricular dysfunction (RVD) on echocardiograms, lung perfusion defects on ventilation perfusion lung scans, and pulmonary artery obstructions on CT angiograms. Adverse events, including death, bleeding, and PTE recurrence, were also evaluated.

 

Progressive improvements in RVDs, lung perfusion defects, and pulmonary artery obstructions were found to be similarly significant in both treatment groups. No difference in outcome was observed for patients with hemodynamic instability or massive pulmonary artery obstruction. Three (6%) patients in the 100-mg group and 1 (2%) in the 50-mg group died as the result of either PTE or bleeding. The 50-mg regimen resulted in less bleeding tendency than the 100 mg/2 h regimen (3% vs 10%), especially in patients with a body weight of less than 65 kg (14.8% vs 41.2%, P = .049). Fatal recurrent PTE did not occur in either group.

 

Rarely, empiric thrombolysis may be indicated in selected patients who are hemodynamically unstable, eg, the clinical likelihood of pulmonary embolism 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.

 

Reteplase (Retavase)

 

Second-generation recombinant plasminogen activator that forms plasmin after facilitating cleavage of endogenous plasminogen. In clinical trials, shown to be comparable to t-PA in achieving TIMI, 2 or 3 patency, at 90 min. Given as a single bolus or as 2 boluses administered 30 min apart.

As a fibrinolytic agent, seems to work faster than its forerunner, t-PA, and may be more effective in patients with larger clot burdens. Also reported to be more effective than other agents in lysis of older clots. Two major differences help explain these improvements. Compared with t-PA, r-PA does not bind fibrin so tightly, allowing the drug to diffuse more freely through the clot. Another advantage seems to be that it does not compete with plasminogen for fibrin-binding sites, allowing plasminogen at the site of the clot to be transformed into clot-dissolving plasmin.

The FDA has not approved r-PA for use in patients with PE. Studies for PE have used the same dose approved by the FDA for coronary artery fibrinolysis.

 

Alteplase (Activase)

 

Used in management of AMI, acute ischemic stroke, and PE. Drug most often used to treat patients with PE in the ED. Usually given as a front-loaded infusion over 90-120 min. FDA-approved for this indication. Most ED personnel are familiar with its use because it is widely used for treatment of patients with AMI. An accelerated 90-min regimen is widely used, and most believe it is both safer and more effective than the approved 2-h infusion. Accelerated regimen dose is based on patient weight.

Heparin therapy should be instituted or reinstituted near the end of or immediately following infusion, when the aPTT or thrombin time returns to twice normal or less.

 

Urokinase (Abbokinase)

 

Direct plasminogen activator produced by human fetal kidney cells grown in culture. Acts on the endogenous fibrinolytic system and converts plasminogen to the enzyme plasmin, which, in turn, degrades fibrin clots, fibrinogen, and other plasma proteins. Advantage is that this agent is nonantigenic; however, more expensive than streptokinase and, thus, limits use. When used for localized fibrinolysis, given as local catheter-directed continuous infusion directly into area of thrombus with no loading dose. When used for PE, loading dose is necessary.

 

Streptokinase (Kabikinase, Streptase)

 

Acts with plasminogen to convert plasminogen to plasmin. Plasmin degrades fibrin clots, fibrinogen, and other plasma proteins. Increase in fibrinolytic activity that degrades fibrinogen levels for 24-36 h takes place with IV infusion of streptokinase. Highly antigenic. Highly likely that treatment will be interrupted due to allergic drug reactions.

Chills, fever, nausea, and skin rashes are frequent (up to 20%). Blood pressure and heart rate drop in approximately 10% of cases during or shortly after treatment.

Late complications may include purpura, respiratory distress syndrome, serum sickness, Guillain-Barré syndrome, vasculitis, and renal or hepatic dysfunction.

 

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 pulmonary embolism. Heparin does not dissolve an existing clot, but it does prevent clot propagation and embolization. Recurrence or extension of DVT and pulmonary embolism may occur despite therapeutic anticoagulation with heparin.

 

With proper dosing, several LMWH products have been found to be safer and more effective than UFH for prophylaxis and treatment of patients with DVT and pulmonary embolism. Not necessary or useful to monitor aPTT while using LMWH. Drug is most active in tissue phase, and, as opposed to UFH, 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 United States (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 pulmonary embolism and are endorsed by the experts.

 

Enoxaparin (Lovenox)

 

Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. In addition, preferentially increases inhibition of factor Xa. First LMWH in United States. Only LMWH approved by FDA for treatment and prophylaxis of DVT and PE. Widely used in pregnancy, although clinical trials are not yet available to demonstrate that it is as safe as UFH.

 

Dalteparin (Fragmin)

 

LMWH with many similarities to enoxaparin but with a different dosing schedule. Approved for DVT prophylaxis in patients undergoing abdominal surgery. Except in overdoses, no utility exists in checking PT or aPTT because aPTT does not correlate with anticoagulant effect of fractionated LMWH.

 

Ardeparin (Normiflo)

 

LMWH recently released in United States for DVT prophylaxis in patients undergoing hip and knee surgery. Except in overdoses, no utility exists in checking PT or aPTT because the aPTT does not correlate with anticoagulant effect of fractionated LMWH.

 

Heparin (Hep-Lock, Liquaemin)

 

Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. Does not actively lyse but is able to inhibit further thrombogenesis. Prevents reaccumulation of clot after spontaneous fibrinolysis. When UFH is used, the aPTT should not be checked until 6 h after the initial heparin bolus because an extremely high or low value during this time should not provoke any action.

 

Interferes with hepatic synthesis of vitamin K–dependent coagulation factors. Used for prophylaxis and treatment of venous thrombosis, PE, and thromboembolic disorders. Never administer to patients with thrombosis until after fully anticoagulated with heparin (first few days of warfarin therapy produce a hypercoagulable state). Failing to anticoagulate with heparin before starting warfarin causes clot extension and recurrent thromboembolism in approximately 40% of patients, compared with 8% of those who receive full-dose heparin before starting warfarin. Heparin should be continued for the first 5-7 d of oral warfarin therapy, regardless of the PT time, to allow time for depletion of procoagulant vitamin K–dependent proteins.

Tailor dose to maintain an INR in the range of 2.5-3.5. Risk of serious bleeding (including hemorrhagic stroke) is approximately constant when the INR is 2.5-4.5 but rises dramatically when the INR is >5. In the United Kingdom, higher INR target of 3-4 often is recommended.

Evidence suggests that 6 mo of anticoagulation reduces rate of recurrence to half of the recurrence rate observed when only 6 wk of anticoagulation is given. Long-term anticoagulation is indicated for patients with an irreversible underlying risk factor and recurrent DVT or recurrent PE.

Procoagulant vitamin K–dependent proteins are responsible for a transient hypercoagulable state when warfarin is first started and stopped. This is the phenomenon that occasionally causes warfarin-induced necrosis of large areas of skin or of distal appendages. Heparin is always used to protect against this hypercoagulability when warfarin is started; but, when warfarin is stopped, the problem resurfaces, causing an abrupt temporary rise in the rate of recurrent venous thromboembolism.

At least 186 different foods and drugs reportedly interact with warfarin. Clinically significant interactions have been verified for a total of 26 common drugs and foods, including 6 antibiotics and 5 cardiac drugs. Every effort should be made to keep the patient adequately anticoagulated at all times because procoagulant factors recover first when warfarin therapy is inadequate.

Patients who have difficulty maintaining adequate anticoagulation while taking warfarin may be asked to limit their intake of foods that contain vitamin K.

Foods that have moderate to high amounts of vitamin K include Brussels sprouts, kale, green tea, asparagus, avocado, broccoli, cabbage, cauliflower, collard greens, liver, soybean oil, soybeans, certain beans, mustard greens, peas (black-eyed peas, split peas, chick peas), turnip greens, parsley, green onions, spinach, and lettuce.

 

Fondaparinux sodium (Arixtra)

 

Synthetic anticoagulant that works by inhibiting factor Xa, a key component involved in blood clotting. Provides highly predictable response. Bioavailability is 100%. Has a rapid onset of action and a half-life of 14-16 h, allowing for sustained antithrombotic activity over 24-h period. Does not affect prothrombin time or activated partial thromboplastin time, nor does it affect platelet function or aggregation.

 

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 the lower extremities inevitably reduces the frequency of pulmonary embolism; 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

 

 

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 meta-analysis calculated a DVT risk ratio of 0.28 for gradient compression stockings (compared with no prophylaxis) in patients undergoing abdominal surgery, gynecologic surgery, or neurosurgery. Other studies have reported that gradient compression stockings and low molecular weight heparin (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 pulmonary embolism.

 

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 prevent DVT and 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 pulmonary embolism, a study has showo benefit from prescribing bed rest. Therefore, strict bed rest for 5 days is not justified if adequate therapy with LMWH 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 pulmonary embolism 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 pulmonary embolism is 30%.

Elevated plasma levels of natriuretic peptides (braiatriuretic peptide and N -terminal pro-braiatriuretic peptide) have been associated with higher mortality in patients with pulmonary embolism.41 In one study, levels of N -terminal pro-braiatriuretic peptide greater than 500 ng/L was independently associated with central pulmonary embolism and was a possible predictor of death from pulmonary embolism.

In the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) (PIOPED) study, the 1-year mortality rate was 24%.7 The deaths occurred due to cardiac disease, recurrent pulmonary embolism, infection, and cancer.

The risk of recurrent pulmonary embolism is due to the recurrence of proximal venous thrombosis; approximately 17% of patients with recurrent pulmonary embolism were found to have proximal DVT.

In a small proportion of patients, pulmonary embolism does not resolve; hence, chronic thromboembolic pulmonary arterial hypertension results.

 

Medicolegal Pitfalls

 

Pulmonary embolism (PE) is an extremely common disorder. It presents with nonspecific clinical features and requires specialized investigations for confirmation of diagnosis. Therefore, many patients die from unrecognized pulmonary embolism. The other common pitfalls are as follows: 

Disregarding patient’s complaints of unexplained dyspnea as anxiety or hyperventilation

Blaming complaints of unexplained chest pain on musculoskeletal pain

Failing to recognize, diagnose, and treat deep vein thrombosis (DVT)

Failing to initiate an appropriate diagnostic workup in patients with symptoms consistent with pulmonary embolism

Failing to initiate therapeutic anticoagulant therapy with heparin in patients suspected to have pulmonary embolism, before the V/Q scan or other investigations

 

The role of thrombolytic therapy in patients who are hemodynamically stable remains uncertain. No particular diagnostic strategy appears to be superior to another at present. More clinical studies are needed to evaluate the utility of new diagnostic approaches for pulmonary embolism. The availability of the diagnostic tests, the expertise of the radiologists, cost-effective analysis, and local traditions appear to be the considerations in the workup of a patient suspected to have pulmonary embolism.

 

Special Concerns

 

Pregnancy

 

The risk of venous thromboembolism is increased during pregnancy and the postpartum period. Pregnant women who are in a hypercoagulable state or have had previous venous thromboembolism should receive prophylactic anticoagulation during pregnancy.

Pulmonary embolism is the leading cause of death in pregnancy. Guidelines by the professional societies make this difficult diagnosis easier and reduce the risks of radiation to the fetus. If the patient has a low pretest probability for pulmonary embolism and a normal D-dimer test result, clinical exclusion from further investigations is recommended. When the suspicion is high, the patients should have bilateral leg Doppler assessment. If the results are positive, the patient should be treated for pulmonary embolism. If the results are negative, CT pulmonary angiography is the next step. To rule out contrast-induced hypothyroidism, all neonates exposed to the iodinated contrast in utero should have their serum thyrotropin level checked in the first week of life.

Pregnant patients diagnosed with DVT or pulmonary embolism are treated with unfractionated heparin or LMWH throughout their pregnancy. Warfarin is contraindicated because it crosses the placental barrier and can cause fetal malformations. Therefore, either subcutaneous unfractionated heparin or LMWH at full anticoagulation doses should be continued until delivery. Women experiencing a thromboembolic event during pregnancy should receive therapeutic treatment with unfractionated heparin or LMWH during pregnancy, with anticoagulation continuing for 4-6 weeks postpartum, and for a total of at least 6 months.

 

Heparin-induced thrombocytopenia

 

Heparin-induced thrombocytopenia (HIT) is a transient prothrombotic disorder initiated by heparin.

Main features are (1) thrombocytopenia resulting from immunoglobulin G–mediated platelet activation and (2) in vivo thrombin generation and increased risk of venous and arterial thrombosis.

The highest frequency of HIT, 5%, has been reported in post-orthopedic surgery patients receiving up to 2 weeks of unfractionated heparin. HIT occurred in approximately 0.5% of post-orthopedic surgery patients receiving LMWH for up to 2 weeks.

HIT may manifest clinically as extension of the thrombus or formation of new arterial thrombosis. HIT should be suspected whenever the patient’s platelet count falls to less than 100,000/µL or less than 50% of the baseline value, generally after 5-15 days of heparin therapy. The definitive diagnosis is made by performing a platelet activation factor assay.

The treatment of patients who develop HIT is to stop all heparin products, including catheter flushes and heparin-coated catheters, and to initiate an alternative nonheparin anticoagulant, even when thrombosis is not clinically apparent. Preferred agents include direct thrombin inhibitors such as lepirudin or argatroban. Start warfarin while the patient receives an alternative nonheparin anticoagulant and only when the platelet count has recovered to at least 100,000/µL, preferably 150,000/µL.

 

Resistance to heparin

 

Few patients with venous thromboembolism require large doses of heparin for achieving an optimal activated partial thromboplastin time (aPTT). These patients have increased plasma concentrations of factor VIII and heparin-binding proteins. Increased factor VIII concentration causes a dissociation between aPTT and plasma heparin values. The aPTT is suboptimal, but patients have adequate heparin levels upon protamine titration. This commonly occurs in patients with a concomitant inflammatory disease.

Monitoring the antifactor Xa assay results in this situation is safe and effective and results in less escalation of the heparin dose when compared with monitoring with aPTT. Whenever a therapeutic level of aPTT cannot be achieved with large doses of unfractionated heparin administration, either determination of plasma heparin concentration or therapy with LMWH should be instituted.

 

Elderly individuals

 

Pulmonary embolism is increasingly prevalent among elderly patients, yet the diagnosis is missed more often in this population because respiratory symptoms often are dismissed as being chronic.

Even when the diagnosis is made, appropriate therapy frequently is inappropriately withheld because of bleeding concerns.

An appropriate diagnostic workup and therapeutic anticoagulation with a careful risk-to-benefit assessment is recommended in this patient population.

 

Future research

 

The advances over the past several decades have significantly improved diagnostic abilities and have refined the treatment of patients with pulmonary embolism. However, several areas need further research and properly conducted therapeutic trials. The role of LMWH and the optimal duration of anticoagulant therapy in different subgroups of patients with venous thromboembolism require further study.

Future studies should determine whether less intense warfarin therapy (international normalized ratio [INR] less than 2), which will result in less bleeding, is effective in preventing recurrences.

Whether drugs that inhibit the action of thrombin (eg, hirudin) are useful in treating patients with venous thromboembolic disease needs to be determined by future trials.