CHAPTER 75: PULMONARY EMBOLISM

Venous thromboembolism (VTE) comprises deep vein thrombosis (DVT) and pulmonary embolism (PE). It is the third most frequent cardiovascular disease, with an overall annual incidence rate between 75 and 270 cases per 100,000 inhabitants.¹ The risk of VTE approximately doubles with each subsequent decade after the age of 40 years; therefore, a larger number of patients are expected to be diagnosed with VTE in aging societies in the coming future.¹ PE is the most serious clinical presentation of VTE with 1- and 3-month mortality between 9% and 11% and up to 17%, respectively.^2,3,4 Following the acute PE episode, resolution of emboli is frequently incomplete despite optimal anticoagulant therapy,⁵ which may lead to the development of chronic thromboembolic pulmonary hypertension (CTEPH).⁶ Although a number of patients die of comorbidities that predispose them to the thromboembolic event, approximately one-third of patients who die from PE do so within the first hours of presentation, often before the diagnosis can be confirmed and therapy initiated or because the diagnosis was overlooked.⁷ Despite advances in diagnostic imaging tests and therapeutic interventions, PE remains underdiagnosed, and prophylaxis continues to be dramatically underused. Globally, improvements in length of stay and changes in the initial treatment are being accompanied by a reduction in short-term all-cause and PE-specific mortality.^8,9

Over the past decade, a number of valuable insights into the natural history of venous thrombosis and PE have enhanced our diagnostic and therapeutic approaches.¹⁰ One such insight is the awareness that patients hospitalized for medical problems face a thromboembolic risk similar to that of their surgical counterparts. Another is an understanding of the substantial thromboembolic recurrence risk among patients with idiopathic or unprovoked venous thrombosis.¹¹ Yet another insight is the awareness that the presence of right ventricular (RV) dysfunction and increased levels of troponins and/or natriuretic peptides in the setting of PE may be associated with an increased risk of adverse consequences, including subsequent cardiovascular collapse and death.¹² Anticoagulation with heparin, low-molecular-weight heparin (LMWH), or fondaparinux as a “bridge” to oral anticoagulation is still considered the standard treatment for PE. The spectrum of anticoagulant drugs has been expanded recently with the new generation of oral direct thrombin inhibitors and factor Xa inhibitors.

In 1856, Virchow proposed his triad of factors leading to intravascular coagulation, including stasis, vessel wall injury, and hypercoagulability. Risk factors for VTE are based on these processes (Table 75–1). VTE is considered to be provoked in the presence of a temporary or reversible, usually acquired, risk factor (eg, surgery, trauma, immobilization, pregnancy) within the last 3 months before the diagnosis and unprovoked in the absence thereof.¹³ The presence of a persistent, sometimes inherited, risk factor may affect the decision of the duration of anticoagulation therapy after a first episode of VTE. The overwhelming majority of emboli originate from the deep veins of the lower extremities, although any venous bed can be involved. Although thrombi may form at any point along the vein wall, most originate in valve pockets. The veins of the calf are the most common site of origin, with subsequent extension of the clot prior to embolization.¹⁴ Eventually, the thrombus may expand to fill the vessel entirely, with both retrograde and proximal extension. If embolization does not occur, the thrombosis can partially or completely resolve via three mechanisms: recanalization, organization, and lysis. Post-thrombotic syndrome occurs in 20% to 50% of patients and involves chronic pain, swelling, edema, and skin changes, which reduce quality of life and incur significant health care costs.¹⁵

Acquired Risk Factors

Frequently, more than one risk factor for venous thrombosis is present; knowledge of these risk factors provides the rationale for both prophylaxis and clinical suspicion. Comorbidities enhance the risk of VTE. In the DVT FREE prospective registry of 5451 patients with ultrasound-confirmed DVT, the most common comorbidities were systemic hypertension (50%), surgery within 3 months (38%), immobility within 30 days (34%), cancer (32%), and obesity (27%).¹⁶

Although studies to date have yielded inconsistent results, long automobile or airplane trips appear to be risk factors for VTE. The proportion of subjects who develop acute PE during or after airplane travel appears to be associated with other thrombotic risk factors, such as the presence of the factor V Leiden mutation or the use of oral contraceptive agents, and correlates with the flight distance. The risk of PE significantly increases with a flight distance of greater than 3107 miles (5000 km) or a duration longer than 8 hours.¹⁷

Obesity merits further investigation because recent studies implicate obesity as a risk factor for VTE, particularly in developed countries, where obesity represents a major health issue.^18,19,20 The Nurses’ Health Study explored risk factors for PE in women and found that a body mass index of 29 kg/m² or greater was an independent risk factor.²¹ The Framingham Study has confirmed that obesity is a risk factor for PE, particularly in women.²² In addition to increased venous stasis, obesity may also increase the risk for VTE as a consequence of elevated plasma levels of certain clotting factors, such as fibrinogen, factor VII, and plasminogen activator inhibitor-1, and as a result of platelet activation caused by enhanced lipid peroxidation.²³

An abundance of literature documents that the risk of VTE and its mortality increases with age, with a relative risk for those 70 years of age approximately 25-fold greater than the risk for those 20 to 29 years of age.²⁴

Prior VTE substantially increases the risk of subsequent events. Surgical patients with a previous history of VTE who do not receive prophylaxis are at particularly high risk for DVT. Surgery itself significantly enhances the risk. The risk of VTE is highest during the first two postoperative weeks, but remains elevated for 2 to 3 months. Spinal surgery, pelvic surgery (and joint replacement in general), and neurosurgery place patients at a particularly high risk for VTE.^25,26 Prophylactic anticoagulation may be initiated either before surgery or shortly thereafter to prevent the development of intraoperative and early postoperative thrombosis. The incidence of VTE is reduced with increasing duration of thromboprophylaxis after major orthopedic surgery and cancer surgery, whereas this association has not been observed for general surgery.²⁷ Trauma, particularly major trauma and trauma of the lower extremities and pelvis, heightens the risk of DVT.^25,26

Upper extremity DVT has become more important because of an increasing use of pacemakers; implantable defibrillators; and long-term, indwelling, central venous catheters.²⁸ Symptomatic PE may originate from upper extremity thrombi, although this appears much less common than embolization from lower extremity DVT. Upper extremity DVT poses the risk of superior vena cava syndrome and loss of vascular access.²⁹ Effort-related, upper extremity axillosubclavian thrombosis (Paget-von Schroetter syndrome) may occur spontaneously or be associated with an underlying thrombophilic tendency and may result in significant, long-term functional impairment.²⁸

Epidemiologic analyses suggests that patients with cardiac disease are predisposed to VTE.³⁰ Myocardial infarction and heart failure increase the risk of PE³¹; conversely, patients with VTE are at increased risk of subsequent myocardial infarction and stroke.³² Cancer clearly augments the risk of VTE, although the precise pathogenesis of thromboembolism in cancer is not well understood. Numerous mechanisms, including intrinsic tumor procoagulant activity and extrinsic factors such as chemotherapeutic agents and indwelling access catheters, contribute to this process. The thrombophilic tendency associated with cancer is often amplified by clinical factors such as patient weakness and immobility. An analysis based on data from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study found that of 399 patients with PE, 73 (18.3%) had cancer.³³ The risk of VTE varies with different types of cancer.³⁴ Hematologic malignancies, lung cancer, gastric and pancreatic malignancies, brain cancer, genitourinary tract cancer, and breast malignancies are associated with a particularly high risk of DVT and PE.^35,36 About half of all cancer patients and approximately 90% of those with metastases exhibit abnormalities of one or more coagulation parameters.³⁷ After the administration of various chemotherapeutic agents, changes in the levels of coagulation factors, suppression of anticoagulant and fibrinolytic activity, and direct endothelial damage have been documented clinically and experimentally.³⁸ Hormonal therapy, particularly tamoxifen in breast cancer adjuvant therapy, is also associated with an increased risk of thromboembolism, particularly when combined with chemotherapy.³⁹ Neutropenia and sepsis, which often accompany chemotherapeutic regimens, often necessitate hospitalization and bedrest, which contribute further to the risk of VTE. A subsequent malignancy has been reported to occur within 2 to 3 years in approximately 5% to 10% of patients presenting with idiopathic venous thrombosis.⁴⁰ Although some data suggest that a limited approach (abdominal/pelvic computed tomography [CT], mammography, sputum cytology) to search for cancer may be cost effective,⁴¹ it does not appear to be routinely warranted in patients presenting with unprovoked VTE.⁴²

Oral contraception, pregnancy and the postpartum period are the most common settings in which women younger than 40 years of age acquire thromboembolic disease. Venous thrombosis develops in these settings three to six times more often than in age-matched women not on oral contraceptives.⁴³ When occurring during pregnancy, VTE is a major cause of maternal mortality.⁴⁴ The risk is highest in the third trimester of pregnancy and over the 6 weeks of the postpartum period,⁴⁴ but the risk is considerable throughout pregnancy.⁴⁵ Cesarean section further augments the risk. In vitro fertilization further increases the risk of pregnancy-associated VTE, particularly during the first trimester of pregnancy.⁴⁶ Oral contraceptives are associated with an increased relative risk of VTE, although the absolute risk (approximately 1-3 cases per 10,000 woman-years) remains small.⁴³ Third-generation agents (agents containing desogestrel or gestodene as the progestogen component) appear to cause acquired resistance to activated protein C and double the risk of VTE. Oral contraceptive use should be avoided by women with protein C, protein S, and antithrombin III deficiency, as well as those who are homozygous carriers of the factor V Leiden mutation. Results from a clinical trial evaluating hormone replacement therapy indicated that such therapy increased the incidence of VTE in women 45 to 64 years of age. The best available evidence suggests a two- to four-fold increased relative risk of VTE among oral hormone replacement therapy users compared with nonusers,⁴³ although the risk of VTE varies widely depending on the formulation used in postmenopausal women who receive hormone replacement.⁴⁷ The risk of VTE also appears to be highest during the first year of exposure to hormone replacement. Although such therapy is associated with quality-of-life benefits in women who require postmenopausal symptom control, physicians must balance this benefit against the risk of VTE, cardiovascular disease, and breast cancer before prescribing hormone replacement therapy. Whether routine screening should be performed before the initiation of oral contraceptive agents or hormone replacement therapy remains controversial.⁴⁸ Given the low absolute risk, especially among users of oral contraceptive agents, the general consensus is that such an approach would not be cost effective.⁴⁹

Antiphospholipid antibodies represent a diverse family of immunoglobulins that includes anticardiolipin antibodies and the lupus anticoagulant and are targeted against anionic surfaces such as β₂-glycoprotein I and prothrombin. Antiphospholipid antibodies, notably the lupus anticoagulant and high-titer anticardiolipin antibodies, are associated with both arterial and venous thrombi.⁵⁰

Inherited Risk Factors

Inherited thrombophilias result in variable degrees of VTE risk.^51,52 Antithrombin III deficiency was first described in 1965 and was the first inherited trait associated with thrombophilia. Functional and quantitative abnormalities of protein C and protein S were subsequently described. The factor V Leiden mutation, a single base mutation (substitution of A for G at position 506), is a far more common genetic polymorphism associated with activated protein C resistance. It is present in approximately 4% to 6% of European populations and is less common among those of Asian, Indian, or African descent.^53,54 The relative risk of a first idiopathic DVT among men heterozygous for the mutation is three- to seven-fold higher than that of those not affected.⁵³ This genetic mutation is also a risk factor for recurrent pregnancy loss, probably because of placental thrombosis.⁵⁵ Oral contraceptive use in patients with heterozygous factor V Leiden mutation is associated with a 10-fold higher risk of VTE.⁵⁶

Another less frequent thrombophilic mutation has been identified in the 3′ untranslated region of the prothrombin gene (substitution of A for G at position 20210).⁵⁷ This mutant allele is present in 2% to 4% of the general population and causes increased levels of prothrombin. This prothrombin gene defect increases the risk of DVT by a factor of 2.7 to 3.8.^57,58 It appears that carriers of both factor V Leiden and the prothrombin G20210A defect have an increased risk of recurrent DVT after a first episode and are candidates for lifelong anticoagulation.⁵⁹

Homocysteine has potential thrombogenic effects, including injury to vascular endothelium and antagonism of the synthesis and function of nitric oxide.⁶⁰ Coexisting hyperhomocysteinemia has been shown to increase the risk for thrombosis in patients with factor V Leiden.⁶¹ However, the thermolabile methylenetetrahydrofolate reductase gene variant is not independently associated with thrombosis, emphasizing that the precise role of homocysteine in venous thrombosis is unclear. Thus, interactions between the genetic factors (defects in enzymes) that control homocysteine metabolism and nutritional factors (folate, vitamin B₆, and vitamin B₁₂ deficiencies) that affect homocysteine metabolism warrant additional investigation with regard to VTE.⁶²

Recently, elevated levels of clotting factors VII, VIII, IX, XI, and XII have been associated with an increased risk for venous thrombosis. In particular, elevated factor VIII levels have been demonstrated to be a strong and independent risk factor for both acute and recurrent venous thrombosis.^63,64 Factor VIII, may, however, be an acute phase reactant, so if used to determine treatment duration, it should be repeated at some point months after the acute PE episode.

Gas-Exchange Abnormalities

The effect of PE on oxygenation and hemodynamics depends on the extent of obstruction of the pulmonary vascular bed and the severity of underlying cardiopulmonary disease.¹² Hypoxemia develops in the preponderance of patients with PE and has been attributed to various mechanisms, including intrapulmonary or intracardiac right-to-left shunting, elevated alveolar dead space, ventilation-perfusion (V/Q) inequality, and decreases in the mixed venous oxygen level, thereby magnifying the effect of the normal venous admixture. The two latter mechanisms are proposed to account for the majority of hypoxemia and hypocarbia associated with acute embolism. Shunt may occur as a consequence of atelectasis related to loss of surfactant, alveolar hemorrhage, or bronchoconstriction related to regional areas of hypocarbia. Hypoxemia leads to an increase in sympathetic tone with systemic vasoconstriction and may actually increase venous return with augmentation of stroke volume, at least initially, if there is no significant underlying cardiac or pulmonary pathology already present.

Hemodynamic Alterations

The hemodynamic effects of embolism are related to three factors: the degree of reduction of the cross-sectional area of the pulmonary vascular bed, the pre-existing status of the cardiopulmonary system, and the physiologic consequences of both hypoxic and neurohumorally mediated vasoconstriction.¹² Obstruction of the pulmonary vascular bed by embolism acutely increases the workload on the right ventricle, a chamber ill-equipped to deal with high-pressure load. In patients without pre-existing cardiopulmonary disease, obstruction of less than 20% of the pulmonary vascular bed results in a number of compensatory events that minimize adverse hemodynamic consequences. Recruitment and distension of pulmonary vessels occur, resulting in a normal or near-normal pulmonary artery pressure and pulmonary vascular resistance; cardiac output is maintained by increases in the RV stroke volume and increases in the heart rate. As the degree of pulmonary vascular obstruction exceeds 30% to 40%, increases in pulmonary artery pressure and modest increases in right atrial pressure occur. The Frank-Starling mechanism maintains RV stroke work and cardiac output. When the degree of pulmonary artery obstruction exceeds 50% to 60%, compensatory mechanisms are overcome, cardiac output begins to decrease, and right atrial pressure increases dramatically. With acute obstruction beyond this amount, the right heart dilates, RV wall tension increases, RV ischemia may develop, the cardiac output decreases, and systemic hypotension develops. In patients without prior cardiopulmonary disease, the maximal mean pulmonary artery pressure capable of being generated by the right ventricle appears to be 40 mm Hg. The correlation between the extent of pulmonary vascular obstruction and the pulmonary vascular resistance appears to be hyperbolic, reflecting, at its lower end, the expansible nature of the pulmonary vascular bed and, at its upper end, the precipitous decline in cardiac output that may occur as the right ventricle fails.⁶⁵

The hemodynamic response to acute PE in patients with pre-existing cardiopulmonary disease may be considerably different.⁶⁶ Patients with prior cardiopulmonary disease demonstrate degrees of pulmonary hypertension that are disproportionate to the degree of pulmonary vascular obstruction. As a result, severe pulmonary hypertension may develop in response to a relatively small reduction in pulmonary artery cross-sectional area. Thus, evidence of RV hypertrophy (rather than RV dilatation) associated with a mean pulmonary artery pressure in excess of 40 mm Hg should suggest an element of chronic pulmonary hypertension resulting from a potentially diverse group of etiologic possibilities (eg, CTEPH, left ventricular [LV] failure, valvular disease, right-to-left cardiac shunts).

History and Physical Examination

Erythema, warmth, pain, swelling, and tenderness are not specific for DVT, but suggest the need for further evaluation. PE must always be considered when unexplained dyspnea is present. Pleuritic chest pain and hemoptysis are also common in patients with PE. Coughing may be present, and although it is sometimes caused by PE, it more commonly occurs with bronchitis or pneumonia. Anxiety and lightheadedness are symptoms that may be caused by PE, but may also be caused by a number of other entities that result in hypoxemia or hypotension. Severe dyspnea and syncope are the principal symptoms that may suggest massive, life-threatening PE.^67,68,69 Tachypnea and tachycardia are the most common signs of PE, but they are also nonspecific. A pleural rub may suggest pulmonary infarction, and accentuated pulmonic component of the second heart sound may suggest PE, but can also be explained by other disorders. With embolism of sufficient magnitude to cause RV dysfunction, a murmur of tricuspid regurgitation, systemic hypotension, or jugular venous distension might be present.

A major advance in the diagnostic approach to both venous thrombosis and PE has been a transition from a technique-oriented approach to one that uses Bayesian analysis. In doing so, the pretest probability of the disease, calculated independently of a particular test result through either empiric means or through a standardized prediction rule, is calculated. This pretest probability aids in the selection and interpretation of further diagnostic tests to create a post-test probability of the disease. This post-test probability can then be used as a basis for clinical decision making. For PE, three such scores have been developed and validated. Wells and coworkers⁷⁰ prospectively tested a rapid seven-item bedside assessment to estimate the clinical pretest probability for PE. An alternative scoring system, the Geneva score, involved seven variables and required gas exchange and radiographic information.⁷¹ Recently, a revised Geneva score requiring eight clinical variables without gas exchange or radiographic information was validated and published.⁷² Although such scoring systems have not proven to be more accurate than implicit assessment, they have been adequately validated^73,74,75 and do provide a means of standardization that compensates for variability in physician experience and judgment. Both the Wells score and the revised Geneva rule were simplified in an attempt to increase their adoption into clinical practice,^76,77 and these simplified versions have been adequately validated as well.^74,78 Thus, in the absence of hemodynamic instability at presentation, the diagnostic workup of a patient with suspected PE should begin with the assessment of the clinical or pretest probability. Table 75–2 summarizes clinical prediction rules for PE.

Differential Diagnosis

PE may mimic a large spectrum of diseases. The most common differential diagnoses are pneumonia, musculoskeletal pain, pneumothorax, costochondritis, congestive heart failure, chronic lung disease, asthma/bronchitis, acute myocardial infarction, aortic dissection, pericarditis, and anxiety states.

Nonimaging Studies for Pulmonary Embolism

d-Dimer

The plasma d-dimer is a specific derivative of cross-linked fibrin. Measurement of circulating plasma d-dimer has been comprehensively evaluated as a diagnostic test for acute VTE.⁷⁹ A normal enzyme-linked immunosorbent assay (ELISA) or ELISA-derived assays result is highly sensitive in excluding PE and DVT. When an ELISA d-dimer level is below an established cutoff level, the sensitivity and negative predictive value for VTE are 95% or above.⁷⁹ Therefore, it can be used to exclude PE in patients with either a low or a moderate pretest probability. Importantly, d-dimer measurement is not recommended in patients with high clinical probability, because a normal result does not safely exclude PE. Increased levels of cross-linked fibrin degradation products are an indirect, but suggestive, marker of intravascular thrombosis, indicating endogenous fibrinolysis. An increased d-dimer level is nonspecific for PE and may be seen with advancing age and in patients with various conditions, including infections and other inflammatory states, cancer, myocardial infarction, the postoperative state, and the second and third trimesters of pregnancy. Thus, the specificity of d-dimer in suspected PE decreases steadily with age, to almost 10% in patients older than 80 years.⁸⁰ Recent evidence suggests using age-adjusted cutoffs (instead of the standard 500 μg cutoff) to improve the performance of d-dimer testing in the elderly.^81,82 In a contemporary meta-analysis, age-adjusted cutoff values (age × 10 μg/L above 50 years) resulted in increased specificity while retaining sensitivity above 95%.⁸³ Similar results were obtained in a recent prospective study that showed increased specificity and no additional false-negative results after using an age-adjusted cutoff.⁸⁴ In addition, it has been suggested that the height of d-dimer level correlates with the likelihood of PE⁸⁵ and with increased mortality, especially in noncancer patients.⁸⁶

It is important to recognize that the usefulness of d-dimer testing in inpatients is still limited as a result of comorbidities in this population that elevate d-dimer levels. However, the negative predictive value of a (negative) d-dimer test remains high in these situations.

Arterial Blood Gas Analysis

Although hypoxemia is common in acute PE, some patients, particularly young individuals without underlying cardiopulmonary disease, may have a normal arterial oxygen partial pressure (PaO₂). In a retrospective study of hospitalized patients with PE, the PaO₂ was greater than 80 mm Hg in 29% of patients who were younger than 40 years compared with 3% in the older group.⁶⁸ However, the alveolar-arterial difference was elevated in all patients. An important tenet should be that unexplained hypoxemia, particularly in the setting of risk factors for DVT, suggests the possibility of PE.

Electrocardiography

Electrocardiography (ECG) findings in acute PE are generally nonspecific and include T-wave changes, ST-segment abnormalities, incomplete or complete right bundle branch block, right-axis deviation in the extremity leads, and clockwise rotation of the QRS vector in the precordial leads. The changes that do occur are likely caused by right-heart dilation. In milder cases, the only anomaly may be sinus tachycardia, present in approximately 40% of patients. Atrial arrhythmias, most frequently atrial fibrillation, may be associated with acute PE. Approximately 20% of patients with PE have no ECG changes. Therefore, ECG cannot be relied upon to rule in or rule out PE, although ECG proof of a clear alternative diagnosis, such as myocardial infarction, is useful when PE is among the possible diagnoses. The “classic” S₁Q₃T₃ pattern described by McGinn and White⁸⁷ in 1935 in seven patients with acute cor pulmonale secondary to PE was subsequently demonstrated to be present in approximately 10% of PE cases.⁸⁸ In patients without underlying cardiac or pulmonary disease from the Urokinase Pulmonary Embolism Trial, ECG abnormalities were documented in 87% of patients with proven PE.⁸⁹ These findings were not specific for PE, however. In this clinical trial, 26% of patients with massive or submassive PE and 32% of those with massive PE had manifestations of acute cor pulmonale, such as the S₁Q₃T₃ pattern, right bundle branch block, a P-wave pulmonale, or right-axis deviation. The low frequency of specific ECG changes associated with PE was confirmed in the PIOPED study.⁶⁸

Despite its lack of diagnostic accuracy, ECG may be helpful in predicting adverse clinical outcomes in patients with PE. It was recently suggested that a T-wave inversion in V₂ or V₃ is the most frequent ECG sign of massive PE.⁹⁰ In another PE study, both the pseudoinfarction pattern (Qr in V₁) (Fig. 75–1) and T-wave inversion in V₂ were closely related to the presence of RV dysfunction and were independent predictors of adverse clinical outcome.⁹¹ In a recent trial, abnormal ECG at presentation proved to be an independent predictor of an adverse outcome, although no individual abnormality appeared capable of predicting such an outcome after being adjusted for the patients’ clinical symptoms and findings on admission and for the presence of pre-existing cardiac or pulmonary disease.⁹²

Imaging Studies for Pulmonary Embolism

Chest Radiography

The chest radiograph is abnormal in the majority of patients with PE, but the findings are nonspecific and often subtle. Atelectasis, cardiomegaly, pulmonary infiltrates, small pleural effusions, and mild elevation of a hemidiaphragm may be present.^68,93 Classic radiographic evidence of pulmonary infarction (Hampton hump) or decreased vascularity (Westermark sign) is suggestive, but uncommon. A normal chest radiograph in the presence of significant dyspnea and hypoxemia without evidence of bronchospasm or anatomic cardiac shunt is strongly suggestive of PE. In most situations, however, the chest radiograph cannot be used to definitively diagnose or exclude PE. Although exclusion of other processes such as pneumonia, congestive heart failure, pneumothorax, or rib fracture (which may cause symptoms similar to acute PE) is important, it is crucial to recognize that PE often coexists with other underlying lung diseases.

Computed Tomography of the Chest

Since the introduction of multidetector computed tomography (MDCT) angiography, contrast-enhanced CT of the chest has become the most useful imaging test in patients with clinically suspected acute PE. It allows adequate visualization of the pulmonary arteries down to at least the segmental level.

First-generation scanners had poor resolution in the segmental pulmonary arteries and a limited sensitivity for subsegmental clots. However, a negative scan appeared to predict a benign clinical course over the ensuing 3 months.⁹⁴

Second-generation scanners involve continuous movement of the patient through the scanner with concurrent scanning by a constantly rotating gantry and detector system.⁹⁵ A helix of projecting data is obtained. Continuous volume acquisitions can be obtained during a single breath. Rapid scans can be obtained, facilitating imaging in critically ill patients.

The latest generation of MDCT scanners (Figs. 75–1 and 75–2) permits image acquisition of the entire chest with 1-mm or submillimeter resolution with a breath hold of less than 10 seconds.⁹⁶

Limitations of chest CT in early clinical studies included poor visualization of horizontally oriented vessels in the right middle lobe and lingula because of volume averaging.⁹⁵ The peripheral areas of the upper and lower lobes were inadequately scanned, and the presence of intersegmental lymph nodes resulted in false-positive study results. Multiplanar reconstructions in coronal, sagittal, or oblique planes aid in distinguishing lymph nodes from emboli. Based on studies with earlier generation scanners, CT was capable of revealing emboli in the main, lobar, or segmental pulmonary arteries with more than 90% sensitivity and specificity.^95,96 However, for subsegmental emboli, the sensitivity and specificity were, and still remain, lower. The incidence of isolated subsegmental emboli with first- and second-generation scanners appeared to be approximately 6% to 30%.⁹⁷

When MDCT is used for PE diagnosis, it is ideal to incorporate the scan into an overall diagnostic strategy that includes pretest probability, d-dimer testing, and in certain specific settings, ultrasound examination of the deep leg veins.⁹⁶ An additional advantage of MDCT is the ability to evaluate a patient for the entire spectrum of VTE in one imaging session by scanning the legs and pelvis as well as the lungs. In PIOPED II, combining CT venography with CT angiography increased sensitivity for PE from 83% to 90% and had a similar specificity (around 95%)^98,99; however, the corresponding increase in negative predictive value was not clinically significant. CT venography adds a significant amount of irradiation, which may be a concern, especially in younger women.¹⁰⁰ As CT venography and ultrasonography yielded similar results in patients with signs or symptoms of DVT in PIOPED II,⁹⁸ ultrasonography should be used instead of CT venography if indicated.

Outcome studies have demonstrated that PE can be safely excluded using a clinical assessment tool, d-dimer testing, and MDCT except in patients who present with a high clinical likelihood of embolism.^{99,101,102,103} In the PIOPED II trial, the sensitivity of CT was 83%, a finding somewhat at odds with published outcome data.⁹⁹ PIOPED II did confirm the usefulness of clinical assessment in that the negative predictive value of a normal CT scan was 96% in patients with a low probability of embolism and 89% for those with an intermediate probability, but only 60% in those with a high clinical probability. In 2016, MDCT alone, with “wide detectors” of 256 to 320 rows, appears to be highly sensitive and specific for acute PE, and additional studies to confirm or refute the diagnosis are rarely required unless the quality of the CT is suboptimal. As demonstrated in the initial PIOPED trial, a negative V/Q scan or contrast pulmonary angiogram would also achieve this end.¹⁰⁴ Sequential, noninvasive, lower extremity examinations in patients with adequate cardiopulmonary reserve, although not confirming that embolism did not occur, would render the probability of recurrence unlikely. This approach is exceedingly impractical nowadays. Additional testing can be considered in patients with a low clinical probability of PE and a CT scan that is suggestive, but not clearly diagnostic, of PE. Another important advantage of chest CT is the concomitant ability to define nonvascular and vascular structures such as airway, parenchymal, and pleural abnormalities; lymphadenopathy; and cardiac and pericardial disease. This is very important for rapid detection of alternative diagnoses (eg, aortic dissection, pneumonia, pericardial tamponade) in patients with acute “chest syndromes” in the emergency setting. Disadvantages of MDCT include the potential for contrast-induced renal failure in patients with renal disease. Patients with a history of allergy to contrast agents should receive preprocedure treatment with steroids administered at least 6 hours before the procedure if possible. H₁ and H₂ histamine blockers may be used in addition to corticosteroids.

CT can expose patients to clinically significant doses of radiation. Younger women who have a known elevated incidence of PE are particularly at risk from radiation damage to the breast and lungs. In addition, the amount of contrast required for CT scanning (100-150 mL) poses a substantial risk of radiocontrast-induced nephropathy for patients with pre-existing renal disease (serum creatinine ~2 mg/dL or creatinine clearance < 60 mL/min), especially when it is associated with diabetes mellitus.¹⁰⁵ In such patients, a strategy using duplex ultrasonography and V/Q scanning would appear prudent, followed by selective conventional pulmonary angiography if the noninvasive techniques do not yield a diagnosis. Although multiple pharmacologic agents have been used, only periprocedural hydration, the use of nonionic, iso-osmolar contrast agents, and perhaps N-acetylcysteine are of proven benefit in preventing dye nephropathy.¹⁰⁵

Ventilation-Perfusion Scanning

V/Q scanning was the pivotal diagnostic test for suspected PE for many years. Although clinical indications for the study remain (contrast allergy, renal insufficiency, pregnancy), chest CT has now virtually replaced lung scanning. When the chest radiograph is normal or near normal, a V/Q scan can be performed; any perfusion defect in this situation will be considered to be a mismatch. Otherwise (eg, in the common clinical scenario involving an abnormal baseline chest x-ray), CT should be obtained. An additional advantage of the V/Q scan is that a portable study can be done in very ill patients who are too unstable to undergo CT.

The test is based on the intravenous injection of technetium (Tc)-99m–labeled albumin particles, which block a small fraction of the pulmonary capillaries and thereby enable scintigraphy assessment of lung perfusion. Perfusion scans are combined with ventilation studies, for which multiple tracers can be used. The purpose of the ventilation scan is to increase specificity; in acute PE, ventilation is expected to be normal in hypoperfused segments (mismatch). The radiation exposure from regular lung V/Q scanning is significantly lower than that of CT angiography.¹⁰⁶

V/Q scanning is nondiagnostic in up to 70% of patients with suspected PE, which has been a cause for criticism, since this necessitates further diagnostic testing. Normal and high-probability scans are considered diagnostic. A normal perfusion scan excludes the diagnosis of PE with enough certainty that further diagnostic testing is unnecessary.

In the PIOPED study, the usefulness of lung scanning combined with clinical assessment of patients with suspected PE was prospectively evaluated.¹⁰⁴ Patients with PE had scans that were of high, intermediate, or low probability, but so did most individuals without PE. Although the specificity of high-probability scans was 97%, the sensitivity was only 41%. Of interest, 33% of patients with intermediate-probability scans and 12% of those with low-probability scans were diagnosed definitively with PE by pulmonary arteriography. Forty percent of low-probability scans in patients with high clinical suspicion were followed by documentation of PE at angiography. When the clinical suspicion of PE was considered very high, the positive predictive value of high-probability scans for PE was 96%. In patients with nondiagnostic lung scans, further diagnostic testing for PE should be undertaken. Recent studies suggest that data acquisition in single-photon emission CT imaging may reduce the frequency of nondiagnostic scans¹⁰⁶; however, large-scale prospective studies are lacking and are needed to validate these new approaches.

Pulmonary Angiography

Standard contrast pulmonary arteriography (Fig. 75–3) has been considered the established “gold standard” imaging test for the diagnosis of PE. However, it is rarely performed now because MDCT offers similar diagnostic accuracy. Contrast injections may be useful, however, as a guide to percutaneous catheter-directed treatment of acute PE. The risk of subsequent VTE in patients with a negative test result and without anticoagulation has been shown to be less than 2%. In the current era when pulmonary arteriography is so rarely done, it is unclear whether this technique still remains this accurate.

Pulmonary angiography is not free of risk, with estimated rates of procedure-related mortality, major nonfatal complications, and minor complications of 0.5%, 1%, and 5%, respectively,¹⁰⁷ with the majority of deaths occurring in patients with hemodynamic compromise or respiratory failure.

Magnetic Resonance Imaging

Gadolinium-enhanced magnetic resonance angiography (MRA) is also occasionally used to evaluate clinically suspected PE.¹⁰⁸ Earlier studies demonstrated that when MRA was performed under optimal conditions, it appeared to be highly sensitive and specific even for segmental PE compared with pulmonary angiography.^108,109 MRA has several attractive advantages over chest CT, including no requirement of ionizing radiation or iodinated contrast agents. Furthermore, magnetic resonance technology also allows detailed assessment of RV size and function, which is potentially important for the risk stratification of PE patients. Large-scale studies have been recently published.^110,111 The results show that MRA, although promising, is not ready for current clinical practice in suspected PE as a result of its low sensitivity, the high proportion of nondiagnostic scans, required scanning time, cost, and low availability in most emergency settings. Notably, the substantially longer time required for image acquisition is an important limitation with current MRA sequences. This is especially relevant in the acute setting when acutely ill patients may not be able to tolerate the imaging protocol.

Echocardiography

Transthoracic echocardiography (Fig. 75–4A-C) has emerged as a potentially important tool for risk assessment and treatment guidance in patients with acute PE. Acute PE may lead to RV pressure overload and dysfunction, which can be detected by echocardiography. Because of the reported negative predictive value of 40% to 50%, a normal result cannot exclude PE.^112,113 On the other hand, signs of RV overload or dysfunction may also be found in the absence of acute PE and be a result of concomitant cardiac or respiratory disease.¹¹⁴ The presence of RV dysfunction on a baseline echocardiogram in normotensive patients appears to represent an independent predictor of an adverse outcome or early death.^112,115,116 Patients with severe RV dysfunction may demonstrate McConnell’s sign, which is severe hypokinesis of the RV free wall combined with preserved systolic contraction of the RV apex.¹¹⁷ A disturbed RV ejection pattern (“60/60 sign”) consisting of an RV acceleration time ≤ 60 ms in the presence of a tricuspid insufficiency pressure gradient ≤ 60 mm Hg may suggest PE, but is not highly sensitive or specific. When combined, the two latter signs were 94% specific and 36% sensitive in diagnosing acute PE, even in the presence of pre-existing cardiorespiratory disease.¹¹⁸

Approximately 40% of normotensive patients with symptomatic PE have echocardiographic evidence of RV dysfunction. Echocardiography is also useful to diagnose patent foramen ovale in patients with suspected paradoxical embolism, directly visualizing thrombi in the main pulmonary artery (Fig. 75–4D), right heart chambers, and vena cava.¹¹⁵ In hemodynamically unstable (hypotensive) patients with suspected acute PE, the absence of echocardiographic signs of RV overload or dysfunction significantly reduces the likelihood of acute PE as the cause of the hemodynamic instability.¹¹³ In the latter case, echocardiography may be of further help in the differential diagnosis of the cause of shock, by detecting pericardial tamponade, acute valve dysfunction, severe global or regional LV dysfunction, aortic dissection, or hypovolemia. In a carefully evaluated hemodynamically compromised patient with suspected PE, unequivocal signs of RV pressure overload and dysfunction may justify the consideration of aggressive therapy for PE if immediate CT angiography is not feasible.¹¹⁹

Imaging Studies for Deep Venous Thrombosis

In the majority of cases, PE originates from lower extremity DVT. A number of diagnostic techniques can be used to evaluate patients with suspected DVT. Compression ultrasonography (duplex ultrasonography) is the most commonly used technique. Impedance plethysmography is rarely used now even though number of important clinical trials have been performed using this now-outdated technique. Magnetic resonance imaging (MRI) appears to be very accurate, but has not generally been used as a first-line test because of cost and inconvenience. CT venography used alone or in conjunction with CT angiography appears to have a sensitivity and specificity equivalent to that of duplex ultrasonography, but exposes the patient to additional radiation. Contrast venography remains the gold standard, but is rarely used. Each diagnostic technique has advantages and limitations. Although diagnostic algorithms may be suggested for suspected DVT, these are institution specific, depending on resources and available expertise with certain techniques.

Ultrasonography

Compression ultrasonography with venous imaging is a portable, accurate, and widely available diagnostic technique for DVT.¹²⁰ The primary criterion to diagnose DVT by ultrasonography is the noncompressibility of the vein. Combined with a Doppler reading, this technique is referred to as duplex ultrasonography. Ultrasound technology has been further improved by the development of color duplex instrumentation that displays Doppler frequency shifts as color superimposed on the grayscale image. The color duplex images display both mean blood flow velocity, expressed as a change in hue or saturation, and direction of blood flow, displayed as red or blue. Ultrasound imaging techniques can also identify or suggest the presence of pathology other than DVT, such as Baker cysts, hematomas, lymphadenopathy, arterial aneurysms, superficial thrombophlebitis, and abscesses.¹²¹ The sensitivity and specificity of ultrasonography for symptomatic proximal DVT has been well above 90% in most recent clinical trials.^{122,123,124,125} However, there are limitations, including lower sensitivity for asymptomatic DVT, operator dependence, the inability to accurately distinguish acute from chronic DVT in symptomatic patients, and the lower sensitivity for calf vein thrombosis. Compared with other technologies, ultrasonography is relatively inexpensive and is the preferred diagnostic modality for symptomatic suspected proximal DVT.

Proven DVT by ultrasonography is strongly suggestive of PE in patients with symptoms suggesting PE, but it is not diagnostic. However, approximately 50% of patients with CT-confirmed embolism have no imaging evidence of residual lower extremity venous thrombosis.^122,123,126 Thus, PE cannot safely be ruled out in patients with suspected PE on the basis of a negative lower extremity duplex ultrasonography. In patients with suspected PE and a negative MDCT examination of the chest, the addition of duplex ultrasonography appears to only minimally increase diagnostic yield. Recent evidence suggests that multiorgan (lung, heart, and leg vein) ultrasonography might increase the accuracy of clinical pretest probability estimation in patients with suspected PE and may safely reduce the need for MDCT.¹²⁷ This strategy seems to be especially helpful for patients with multiorgan ultrasonography negative for PE plus an alternative ultrasonographic diagnosis or a negative d-dimer result.

Contrast Venography

Contrast venography is a costly and invasive procedure that may result in superficial phlebitis or hypersensitivity reactions, but it is generally safe and accurate. Although contrast venography is the gold standard for DVT diagnosis, it is now rarely performed, except in clinical trials because of its higher sensitivity in detecting asymptomatic thrombi than duplex ultrasonography.¹²⁸ Venography is far more often done during procedures such as insertion of an inferior vena cava (IVC) filter than to simply diagnose suspected DVT.

Impedance Plethysmography

Impedance plethysmography has been used in patients presenting with suspected acute DVT, but is rarely obtained in the era of ultrasonography. It measures the change in blood volume in the calf while a thigh cuff is inflated and deflated. Its sensitivity for proximal DVT ranges around 65%. Impedance plethysmography may not detect nonocclusive proximal DVT or occlusive proximal DVT present in parallel venous systems, such as duplicated femoral or popliteal veins, and cannot detect DVT isolated to the calf veins.¹²⁰

Magnetic Resonance Imaging

Magnetic resonance venography (MRV) has clear advantages as a diagnostic test for suspected DVT, and appears to be an accurate, noninvasive alternative to venography.¹²⁹ A major feature of this technique is excellent resolution of the IVC and pelvic veins.¹⁰⁸ Preliminary experience with MRV suggests that it is at least as accurate as contrast venography or ultrasound imaging, and more sensitive than ultrasonography, for pelvic vein and calf-limited thrombosis.^129,130 Simultaneous bilateral lower extremity imaging can be accomplished, and MRV appears to accurately distinguish acute from chronic DVT. This technique is also useful in differentiating other entities, such as cellulitis or a Baker cyst, from acute DVT. As with many other diagnostic techniques, its usefulness depends to a certain degree on the experience of the reader. As is the case with PE diagnosis, required scanning time and expense lessen its utility.

The overall diagnostic approach depends on the hemodynamic presentation of the patient. Although rapid diagnosis and therapeutic intervention are required in patients with shock and suspected massive PE, there is sufficient time to obtain imaging tests in hemodynamically stable patients with suspected PE.

Patients With Suspected Pulmonary Embolism and Shock or Hypotension

In patients with hypotension or cardiogenic shock associated with suspected massive PE, rapid initiation of therapy is potentially lifesaving. The definition of massive PE should be based on hemodynamic considerations (systolic blood pressure < 90 mm Hg or a drop in systolic blood pressure by ≥ 40 mm Hg from baseline) rather than purely anatomic considerations.¹² Irrespective of the degree of vascular obstruction, patients with PE who present with shock have a mortality that approaches 30%, but those with cardiopulmonary arrest have a mortality that exceeds 70%. Ideally, PE should be proven with imaging whenever possible.

While in patients with suspected massive PE and evidence of severe acute RV dysfunction by echocardiography, thrombolysis or embolectomy may be considered, extreme caution is advised in the absence of a firm diagnosis. Clues to the chronicity of RV dysfunction include a history of chronic rather than acute dyspnea, the presence of RV hypertrophy rather than simple dilation, or estimated pulmonary artery systolic pressures by echocardiography that are greater than approximately 70 mm Hg. A diagnostic algorithm in patients presenting with shock or persistent hypotension is summarized in Fig. 75–5.

Patients With Suspected Pulmonary Embolism Without Shock or Hypotension

PE cannot be excluded without objective testing. The history, physical examination, and diagnostic studies (eg, chest radiography, ECG, arterial blood gas analysis) can raise or lower the clinical suspicion of PE, but are incapable of excluding or confirming it unless a clearly identifiable condition (eg, pneumothorax) is identified to account for the patient’s complaints. Noninvasive strategies have been investigated and algorithms constructed that are capable of confirming or excluding the diagnosis of embolism under most circumstances. A diagnostic algorithm in patients presenting without shock or persistent hypotension is summarized in Fig. 75–6. In emergency department patients and other outpatients, the clinical pretest probability for PE should be calculated by implicit assessment or, preferably, through a standardized technique.^70,71,72,89 PE can be excluded by a highly sensitive d-dimer result below the assay-specific cutoff level, except in patients with a high pretest clinical probability. In patients with elevated d-dimer levels or a high clinical probability of embolism, MDCT should be obtained (see Fig. 75–7). In patients with significant impairment of renal function, pregnancy, or allergy to contrast agents, V/Q perfusion scanning is preferred as the primary chest imaging test, particularly when the chest radiograph is normal or near normal. A V/Q scan can also be performed in patients with a nondiagnostic or negative chest CT when the clinical suspicion of PE persists. A normal V/Q is capable of excluding the diagnosis, and a high-probability scan is capable of confirming the diagnosis in patients with a high or intermediate probability of disease. If a high clinical suspicion for PE persists, leg ultrasonography and even pulmonary angiography can be performed (Fig. 75–7). This strategy is safe and requires pulmonary angiography in fewer than 10% of patients.¹³¹ In conclusion, as of 2016, a negative MDCT alone can exclude PE under most circumstances. Although comparative studies of modern-day MDCT with standard pulmonary angiography are lacking, MDCT is recognized as extremely accurate and a stand-alone test, unless the images are suboptimal in quality. When uncertainty remains after a negative MDCT, a V/Q scan can be considered. If both tests are nondiagnostic, a negative lower extremity ultrasound may offer more reassurance. Because many patients with acute PE have no residual DVT, when the MDCT is inconclusive, a negative ultrasound cannot guarantee the absence of PE.

In hospitalized patients, clinical findings suggestive of PE may be more likely to be misleading as a result of comorbid conditions. At present, the safe exclusion of PE in inpatients using a clinical prediction rule and d-dimer result remains to be established. d-Dimer testing may have even less clinical utility in inpatients because of its poor specificity. Furthermore, translation of a standardized clinical prediction rule validated in outpatients to an inpatient population is problematic.

At present, PE can be safely excluded in patients with a low or intermediate probability of PE by a normal, highly sensitive d-dimer assay, a normal or near-normal V/Q scan result, a negative MDCT angiography result, or a negative contrast pulmonary angiography result. In patients with a high probability of PE, the clinical outcome appears to be acceptable after a negative MDCT angiography alone if the quality of the study is adequate. A normal V/Q scan or negative contrast pulmonary angiography is also acceptable. Under this circumstance, clinical judgment must come into play with the risk of possible recurrence balanced against the risk of additional diagnostic procedures.^75,113

PE can be confirmed in patients with an intermediate or high probability of PE by a high-probability V/Q scan or a positive MDCT angiography result.¹¹³ Finally, the diagnostic utility of “triple rule-out” CT angiography (for coronary artery disease, PE, and aortic dissection) is under debate. This technique has recently shown to be associated with slightly higher yield of PE and aortic dissection, specifically in the emergency department, but comes with higher nondiagnostic image quality, radiation, and contrast doses.¹³² The appropriate use of “triple rule-out” CT needs to be further defined.

Risk Stratification

An important advance in the therapeutic approach to PE has been the development of predictive models capable of stratifying patients by risk of death. In-hospital mortality associated with PE depends on clinical features at admission and increases significantly when RV dysfunction is present. Accurate risk stratification in patients with PE is important in selecting the optimal management strategy for each individual patient and to potentially improve patient outcome. A bedside prediction rule based on 11 simple patient characteristics capable of classifying patients with PE into classes of increasing risk has been devised—the PE Severity Index (PESI) (Table 75–3).^2,133A simplified version known as sPESI has also been developed and validated (Table 75–4).^134,135

Echocardiography

Transthoracic echocardiography is the most important tool for risk stratification in PE because RV dysfunction on the echocardiogram is a powerful and independent predictor of mortality.^3,136 From a prognostic point of view, echocardiography helps to classify PE into three groups: (1) low-risk PE (no RV dysfunction) with a hospital mortality of less than 4%, (2) submassive PE (RV dysfunction and a preserved systemic arterial pressure) with a hospital mortality of 5% to 10%, and (3) hemodynamically massive PE (RV dysfunction and cardiogenic shock) with a hospital mortality of approximately 30%. A major limitation of echocardiography is its poor discriminative value. Approximately 40% to 50% of patients with symptomatic PE have echocardiographic evidence of RV dysfunction. Additional limitations are its limited availability on a 24-hour, 365 days per year basis and its cost. Another problem is the occasional poor imaging quality of the right ventricle, particularly in obese patients and those with chronic lung disease.

Cardiac Biomarkers

Troponins and natriuretic peptides are similarly accurate in identifying low-risk PE patients (Figs. 75–8, 75–9, 75–10).¹³⁷ RV pressure overload is associated with increased myocardial stretch, which leads to the release of brain natriuretic peptide (BNP) or N-terminal (NT)-proBNP. Thus, the plasma levels of natriuretic peptides reflect the severity of hemodynamic compromise and RV dysfunction in acute PE.¹³⁸ The plasma cutoff values for the identification of elevated risk appear to be around 50 to 100 pg/mL and 500 to 600 pg/mL for BNP¹³⁹ and NT-proBNP,¹⁴⁰ respectively. The positive predictive value of elevated BNP or NT-proBNP concentration for early mortality is low. Conversely, low levels can identify patients with a favorable short-term clinical outcome based on their high negative predictive value.^139,141

Similar findings have been reported with troponins. Thus, elevated plasma troponin concentrations on admission have been shown in connection with PE as associated with poor prognosis. Similarly, the reported positive predictive value of troponin elevation for PE-related early mortality is low, while the negative predictive value of normal levels is high. The cutoff levels for troponins are the lower detection limits for myocardial ischemia reported by the manufacturer. Recently developed high-sensitivity assays have further improved the prognostic performance of this biomarker, particularly with regard to normal values of troponin and the exclusion of patients with an adverse short-term outcome.^142,143

Computed Tomography

A number of methods have been proposed to quantify the extent of vascular obstruction and RV enlargement/dysfunction by CT scanning. Following a number of early retrospective studies with divergent results,¹⁴⁴ the prognostic value of an enlarged right ventricle on MDCT (right ventricle to left ventricle ratio ≥ 0.9) was confirmed by a prospective multicenter cohort study.¹⁴⁵ In this study, RV enlargement was an independent predictor for an adverse in-hospital outcome, both in the overall population and in hemodynamically stable patients. Interventricular septal bowing on CT has been shown to have the same prognostic value. Additional recent publications have confirmed these findings.^146,147

At present, both the PE-related risk and the patient’s clinical status and comorbidities should be taken into consideration for prediction of early (in-hospital or 30-day) outcome in patients with acute PE. The definition for level of clinical risk (early mortality) and the risk-adjusted therapeutic strategies recommended on the basis of this classification are summarized in Table 75–5. Hemodynamically unstable patients with shock or persistent hypotension should immediately be identified as high-risk patients; they require an emergency diagnosis and, if PE is confirmed, pharmacologic (or alternatively, surgical or interventional) reperfusion therapy.

Patients without shock or hypotension are not at high risk of adverse early outcomes, and further risk stratification should be considered after diagnosis of PE has been confirmed, as this may influence the therapeutic strategy and the duration of hospitalization. In these patients, risk assessment should begin with the evaluation of the PESI or sPESI clinical prognostic score to distinguish between intermediate-risk and low-risk patients. Accordingly, normotensive patients in PESI class ≥ III or with an sPESI ≥ 1 are considered as being in the intermediate-risk group. In these patients, further risk assessment should be considered, focusing on the status of the right ventricle (by echocardiography or CT) and cardiac biomarkers level. Patients who display evidence of both RV dysfunction and elevated cardiac biomarker levels (particularly cardiac troponin) should be classified into an intermediate-/high-risk category. These patients should be closely monitored to permit early detection of hemodynamic decompensation and the need of rescue reperfusion therapy.¹⁴⁸ On the other hand, patients in whom the right ventricle is normal on echocardiography or CT, and/or in whom cardiac biomarker levels are normal, belong to an intermediate-/low-risk group.

Finally, routine performance of imaging or laboratory tests in the presence of PESI class I or II or an sPESI of 0 is not considered necessary at present, since it has not been shown to have therapeutic implications. If performed, available data suggest that patients in PESI class I-II or with an sPESI score of 0, but with elevated cardiac biomarkers or signs of RV dysfunction on imaging tests, should be classified into the intermediate-/low-risk category.^143,149

Supportive Measures

When massive PE associated with hypotension or severe hypoxemia is suspected, supportive treatment is immediately initiated. Intravenous (IV) saline can be infused rapidly, but caution is recommended. Excess fluid may result in further RV dilatation, increased RV wall tension, and a decreased cardiac output that may result in RV ischemia.¹² Dopamine and norepinephrine appear to be the favored choices of vasoactive therapy in massive PE, and should be administered if the blood pressure is not rapidly restored.¹⁵⁰ Death from massive PE results from RV failure, and dobutamine may augment RV output.¹⁵⁰ A vasopressor, such as norepinephrine, combined with dobutamine might offer optimal results. However, there is a lack of large randomized data evaluating the use of vasopressor/inotropic drugs in the setting of massive PE.

Hypoxemia and hypocapnia are frequently encountered in patients with PE, in most cases of moderate severity, and are usually reversed with administration of oxygen. Mechanical ventilation may be instituted to decrease systemic oxygen demands or manage respiratory failure. Intubation in the setting of a decompensated right ventricle, however, is fraught with risk. Premedications may cause systemic vasodilatation, and positive-pressure ventilation may abruptly reduce preload and cardiac output. Therefore, positive end-expiratory pressure should be applied with caution, and low tidal volumes (approximately 6 mL/kg lean body weight) should be used in an attempt to keep the end-inspiratory plateau pressure < 30 cm H₂O.

Anticoagulation

In patients with acute PE, anticoagulation is recommended with the objective of preventing early death and recurrent VTE. The standard duration of anticoagulation should be at least 3 months. Acute-phase treatment consists of parenteral anticoagulation (unfractionated heparin [UFH], LMWH, or fondaparinux) over the first 5 to 10 days overlapped with a vitamin K antagonist (VKA), or, after 5 days of parenteral therapy, initiation of dabigatran, or edoxaban. A simpler alternative in stable patients is oral anticoagulation initiated immediately with rivaroxaban or apixaban alone instead of the standard parenteral/VKA regimen. Often, parenteral therapy is used for 24 to 48 hours until it is clear that surgery or other invasive procedures are not necessary. Extended anticoagulation beyond the first 3 months, or even indefinitely, may be necessary for secondary prevention, after weighing a patient’s risk of recurrence and bleeding. If a VKA is used, it may be initiated as soon as the activated partial thromboplastin time (aPTT) is therapeutic or after the administration of a LMWH. The parenteral agent should be maintained at therapeutic levels for at least 5 days and until a therapeutic international normalized ratio (INR) of 2.0 to 3.0 has been achieved for 2 consecutive days. This initial anticoagulation approach applies to both acute DVT and PE.¹⁵¹

Parenteral anticoagulation should be initiated while awaiting the results of diagnostic tests in patients with intermediate or high clinical probability for PE. LMWH or fondaparinux is preferred over UFH for initial anticoagulation in PE, except for patients in whom primary reperfusion is considered and those with creatinine clearance < 30 mL/min or severe obesity, in whom UFH is recommended.

Standard Unfractionated Heparin

Heparin is generally favored when anticoagulation is deemed safe, but when the bleeding risk is still potentially higher than usual, and when invasive procedures are definitely or potentially planned. Heparin is cleared within 4 hours of stopping the infusion and is reversible with protamine. When IV UFH is instituted, the aPTT should be aggressively followed at 6-hour intervals until it is consistently in the therapeutic range of 1.5 to 2.0 times control values. Heparin can be administered by several protocols, but a weight-based approach substantially enhances the chances of attaining the therapeutic range quickly. Heparin can be administered as an IV bolus of 5000 U followed by a maintenance dose of at least 30,000 U every 24 hours by continuous infusion.¹⁵² This aggressive approach decreases the risk of subtherapeutic anticoagulation and, although excessive levels are sometimes achieved initially, bleeding complications do not appear to be increased.¹⁵² An alternative regimen consisting of a bolus of 80 U/kg followed by 18 U/kg/h has been recommended.¹⁵³ Subsequent adjusting of the heparin dose should also be weight based (Table 75–6).

Low-Molecular-Weight Heparin

LMWHs are commonly used for acute VTE. These agents differ in a number of respects from standard UFH (Tables 75–7 and 75–8). A major advantage of these preparations over UFH is substantially enhanced bioavailability, and thus, they are more predictable than standard UFH.

Numerous clinical trials have demonstrated the efficacy and safety of LMWHs for the treatment of patients with acute proximal DVT, using recurrent symptomatic VTE as the primary outcome measure.¹⁵⁴ Treatment with LMWHs is more convenient for the patient and the nursing staff. A continuous IV line is not required because these agents can be administered once or twice per day subcutaneously at fixed therapeutic doses, usually without laboratory monitoring.

In certain settings, therapy can be monitored by measuring anti-Xa levels.¹⁵⁵ Prophylactic doses of LMWH usually result in anti-Xa levels of 0.1 to 0.3 U/mL. The therapeutic target peak anti-Xa level drawn 4 hours after administration should be in the range of 0.6 to 1 IU/mL for twice-daily administration and 1 to 2 IU/mL for once-daily administration. The peak anti-Xa level is useful for monitoring heparin therapy under the following circumstances: (1) a baseline elevated aPTT because of antiphospholipid antibodies or other circulating anticoagulants in patients being treated with UFH, (2) extremes of body weight (< 40 kg and ≥ 150 kg), (3) renal failure or insufficiency (creatinine clearance < 30 mL/min), (4) pregnancy, and (5) the occurrence of an unexpected bleeding or clotting event during therapy.¹⁵⁵

Unlike regimens for prophylaxis, in which a fixed dose of LMWH is used, a weight-based dosing regimen is used for the treatment of patients with established VTE. In addition to being more convenient, the LMWH preparations appear to be cost effective, particularly when outpatient therapy is used. Table 75–9 lists some of the different LMWH products and their prophylaxis and treatment regimens. The advent of newer oral anticoagulants has reduced the use of LMWH preparations.

Fondaparinux

Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa. It is approved by the US Food and Drug Administration (FDA) and in Europe for the initial treatment of VTE, including PE. In hemodynamically stable patients with acute symptomatic PE, fondaparinux is as safe and effective as IV UFH.¹⁵⁶ Fondaparinux is administered subcutaneously on a once-daily basis in fixed doses of 5 mg for patients weighing less than 50 kg, 7.5 mg for those weighing 50 to 100 kg, and 10 mg for those weighing greater than 100 kg. Like LMWH, fondaparinux is administered in a fixed dose and does not require dose adjustment with laboratory coagulation tests. Also like the LMWHs, fondaparinux is cleared via the renal route and is contraindicated in patients with severe renal disease (creatinine clearance < 30 mL/min). In patients with creatinine clearance of 30 to 50 mL/min, the dose should be reduced by 50%.¹⁵¹ In contrast to heparin compounds, fondaparinux does not cause heparin-induced thrombocytopenia (HIT).

Complications of Heparin

Heparin-Induced Thrombocytopenia

HIT typically develops 5 or more days after the initiation of heparin therapy and occurs in 5% to 10% of patients.¹⁵⁷ If a patient is placed on heparin for VTE and the platelet count progressively decreases either by 50% or to 100,000/μL or less, heparin therapy should be discontinued and another agent initiated. Although the risk of HIT appears to be lower with LMWH, it is important for clinicians to realize that HIT can occur with the use of either form of heparin.¹⁵⁷

Prolonged administration of UFH may cause asymptomatic osteopenia, osteoporosis, and (rarely) pathologic bone fractures. After discontinuation of heparin, bone metabolism by densitometry usually improves within 1 year. Epidural catheter placement should be delayed for at least 12 hours after LMWH injection, because of the risk of epidural or spinal hematoma, which can cause permanent paraplegia. LMWH should be delayed for at least 2 hours after epidural catheter removal.

Vitamin K Antagonists

VKA therapy should be initiated with concomitant UFH or LMWH; otherwise, the first few days of VKA administration may lead to a prothrombotic state because of rapid depletion of anticoagulant proteins C and S. The procoagulant effect of VKA can be prevented by overlapping heparin with warfarin for at least 5 days.

Warfarin can be started at a dose of 10 mg for 2 days, with monitoring performed daily, in younger (eg, 60 years of age), otherwise healthy outpatients.¹⁵¹ A dose of 5 mg is recommended for older patients (> 60 years of age) and in those who are hospitalized, debilitated, or malnourished.^151,158 A standardized nomogram has been developed and can be used to make dose adjustments based on INR values obtained on days 3 and 5.¹⁵⁸ A small percentage of patients have extremely low daily warfarin dose requirements of 1 to 2 mg, with an increased bleeding risk because of CYP2C9 and VKORC1 variant alleles.¹⁵⁹ At present, however, data indicate that pharmacogenetic-based dosing, used on top of clinical parameters, does not improve the quality of anticoagulation (more effective and/or less risky than empiric, clinically based dosing).^160,161,162

In selected patients, self-management of VKA therapy using INR measurement with point-of-care devices may be effective and safe.¹⁶³

Adverse Effects of Vitamin K Antagonists

VKAs have a narrow therapeutic window, and the risk of bleeding increases with increasing INR. A large retrospective survey of more than 42,000 patients who were taking VKAs suggested that an INR of 2.2 to 2.3 has the highest benefit-to-risk ratio.¹⁶⁴ In this study, a two-fold increase in the hazard of death per unit INR elevation greater than 2.5 was observed. Risk factors for VKA-related bleeding include hepatic disease, renal dysfunction, alcoholism, drug interactions, trauma, cancer, and a history of gastrointestinal bleeding. The risk of bleeding is greatest in the first month after initiation of anticoagulation.¹⁶⁵

Depending on the extent and site, patients with major bleeding can routinely be treated with fresh-frozen plasma or prothrombin complex concentrates. Although vitamin K should be administered, it can take many hours to take effect. In patients with excessive INR values without bleeding, withholding one or two doses of warfarin with elective administration of oral vitamin K 2.5 mg is an effective strategy.

Rare complications of VKAs are skin necrosis and cholesterol microembolization, causing the “purple toes” syndrome by enhancing crystal release from ulcerated plaques.¹⁶⁶

Reliable contraception and patient education are mandatory in women of childbearing potential because VKAs are teratogenic, particularly during weeks 6 to 12 of gestation.⁴⁵

Direct-Acting Oral Anticoagulants

The latest generation of oral anticoagulants was initially called novel oral anticoagulants, or NOACs. However, an Institute for Safe Medication Practices safety alert noted that “NOAC” had been interpreted as “no anticoagulation” and thus designated “NOAC” a potentially dangerous abbreviation, discouraging its use. The acronym DOAC, for direct-acting oral anticoagulant, provides a reasonably short, easily pronounced, accurately descriptive abbreviation that distinguishes the class from warfarin, which acts indirectly. This has also been advocated by the International Society of Thrombosis and Haemostasis. Several phase III clinical trials on the acute-phase treatment and duration of anticoagulation after VTE (DVT or PE) with DOACs have been recently published.^{167,168,169,170,171,172} The overall results of these trials indicate that these agents are noninferior (in terms of efficacy) and possibly safer (particularly in terms of major bleeding) than the standard parenteral/VKA regimen.¹⁷³ Although experience with DOACs is still limited, at present, they can be viewed as an alternative to standard treatment. Four DOACs have been approved for the treatment of VTE in United States and Europe: rivaroxaban, dabigatran, apixaban, and edoxaban. Rivaroxaban and apixaban allow for single-drug therapy, eliminating the need for initial parenteral anticoagulation, whereas dabigatran and edoxaban are initiated after a short course of parenteral anticoagulation regimen. Practical recommendations for their dosing and for the handling of their bleeding complications are summarized in Table 75–10. Importantly, some reversal agents for DOACs are under investigation. Recent data suggest that the monoclonal antibody idarucizumab, which binds dabigatran, is effective in emergency situations, and it is now FDA approved¹⁷⁴; however, phase III clinical trials are currently ongoing with other compounds that may serve as universal antidotes for a broad range of oral factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban).¹⁷⁵ Andexanet is likely to be approved in the near future for Xa inhibitor reversal.¹⁷⁶

New Anticoagulation Strategies

Recent preclinical and preliminary clinical data suggest that reduction of factor XI levels might be a promising strategy to achieve effective thrombosis prevention and/or treatment without significant increase in the risk of bleeding.^177,178 These results need confirmation in larger trials for further prophylactic or therapeutic indications of this new target.

Thrombolytic Therapy

Systemic Thrombolysis

Thrombolytic therapy of acute PE restores pulmonary perfusion more rapidly than anticoagulation alone, leading to a prompt reduction in pulmonary vascular resistance and a concomitant improvement in RV function.^179,180 Thrombolytic therapy seems to reduce total mortality, PE recurrence, and PE-related mortality in patients with acute PE, particularly in hemodynamically unstable patients or patients with massive PE. However, it has not been clearly proven that these agents decrease overall mortality in hemodynamically stable patients with acute PE.^181,182

FDA- and European-approved thrombolytic agents include recombinant tissue plasminogen activator (rtPA), streptokinase, and urokinase. Table 75–11 presents thrombolytic regimens for the treatment of PE. Accelerated regimens administered over 2 hours with rtPA are preferable to prolonged infusions of first-generation thrombolytic agents over 12 to 24 hours. Thrombolytic therapy is associated with an increase in major and fatal or intracranial hemorrhage.¹⁸¹ Primary contraindications for thrombolytic therapy include medical conditions that increase the possible risk of bleeding complications, such as recent bleeding, surgery, stroke, or gastrointestinal hemorrhage. Table 75–12 lists the contraindications to thrombolysis in PE.¹⁵¹ Most contraindications to thrombolysis should be considered relative in patients with life-threatening PE. In these cases, an alternative approach may consist of local, catheter-delivered therapy, using reduced doses of a thrombolytic agent (rtPA).

Heparin should be withheld until the thrombolytic infusion is completed if streptokinase or urokinase is used; it can be continued during rtPA infusion. The aPTT is then determined, and heparin is initiated without a loading dose if this value is less than twice the upper limit of normal. If the aPTT exceeds this value, the test is repeated every 4 hours until it is safe to proceed with heparin. Given the bleeding risk associated with thrombolysis, it appears reasonable to continue with anticoagulation with UFH for several hours after the end of thrombolytic therapy before switching to LMWH or fondaparinux. In patients receiving LMWH or fondaparinux at the time thrombolysis is initiated, infusion of UFH should be delayed until 12 hours after the last LMWH injection (if given twice daily) or until 24 hours after the last LMWH or fondaparinux injection (given once daily).

In the absence of hemodynamic compromise, the clinical benefits of thrombolysis have remained controversial for many years. Recent evidence suggests that hemodynamically stable patients with evidence of RV enlargement/dysfunction and elevated troponins and no contraindications may benefit from thrombolytic therapy,^116,148,183 but potentially at a cost of higher rates of major hemorrhage.¹⁴⁸ Some of these trials used tenecteplase as the thrombolytic agent,^148,183 which is not approved yet for the treatment of PE. Accordingly, systemic thrombolysis is not routinely recommended as primary treatment for patients with intermediate-/high-risk or submassive PE, but should be considered if clinical signs of hemodynamic decompensation appear. The efficacy of reduced-dose systemic fibrinolysis has been recently explored in small trials with preliminary modest positive results^184,185; however, the 50-mg dose of IV tissue plasminogen activator is not FDA approved for use. Therefore, if anticipated bleeding risk under systemic thrombolysis is high in these cases, surgical pulmonary embolectomy or percutaneous catheter-directed treatment should be considered.

Catheter-Based Therapies

Percutaneous catheter-directed treatment should be considered as an alternative to surgical pulmonary embolectomy for patients in whom full-dose systemic thrombolysis is contraindicated or has failed, if appropriate expertise and resources are available on site.^186,187,188 Interventional options include the following: thrombus fragmentation with a pigtail or balloon catheter; rheolytic thrombectomy with hydrodynamic catheter devices; suction thrombectomy with aspiration catheters; and rotational thrombectomy. If the bleeding risk is not exceedingly high, catheter fragmentation/embolectomy may be combined with local thrombolysis. Recent small studies suggest that a catheter-directed ultrasound-assisted delivery of a reduced dose of rtPA may be beneficial and safe when compared to heparin alone in patients with PE at intermediate/high or high risk.^{187,189,190,191,192} Most of the devices appear to be effective, safe, and potentially lifesaving in the presence of large “fresh” clots. However, none of the devices has been investigated in a large controlled trial, and all commercially available devices have important limitations.¹⁹³

Surgical Embolectomy

Urgent surgical embolectomy should be considered in patients with hemodynamically massive PE or right-heart thrombus who have an absolute contraindication to anticoagulant or thrombolytic therapy; in patients with impending paradoxical embolism; and in patients in whom aggressive medical therapy, including the use of thrombolysis, has proven ineffective. Aortic cross-clamping and cardioplegic cardiac arrest should be avoided.¹⁹⁴ Current mortality with a rapid multidisciplinary approach, including the use of peripheral extracorporeal membrane oxigenators,¹⁹⁵ and individualized indications before hemodynamic collapse has been reported to be less than 10%.^196,197 Preoperative thrombolysis increases the risk of bleeding, but it is not an absolute contraindication to surgical embolectomy.

Vena Cava Filters

Routine use of vena cava filters in patients with PE is not recommended. The essential indications for filter placement include contraindications to anticoagulation, recurrent embolism while on adequate therapy, and significant bleeding complications during anticoagulation in the acute phase.¹⁵¹

Although IVC filters can be potentially lifesaving by preventing early recurrence of PE, patients with filters may be at higher mid- and long-term risk for recurrent VTE, but appear to be at lower risk of PE-related death.¹⁹⁸

Consequently, anticoagulation is generally continued when a filter is placed, unless it is contraindicated. These devices can be inserted via the jugular or femoral vein and are usually placed in the infrarenal portion of the IVC. Complications associated with IVC filters are common, although rarely fatal.^199,200 Possible mechanisms of IVC filter failure include filter migration; improper filter positioning, allowing thrombi to bypass the filter; and formation of thrombosis proximal to the filter or on the proximal tip of the filter with subsequent embolization. Rare complications include clinically significant perforation of the IVC, migration to the heart, and displacement of the filter during insertion. Occasionally, these devices may erode into the wall of the IVC. In some cases, IVC obstruction caused by thrombosis at the filter site may occur. The use of temporary filters can obviate the problems associated with permanent filter insertion. Depending on the filter type, retrievable filters can be removed within weeks to months of placement or can remain permanently, if necessary because of a trapped large thrombus or a persistent contraindication to anticoagulation. However, when nonpermanent IVC filters are used, it is recommended that they be removed within the first few months after placement. Although some studies have suggested that IVC filters may be associated with significantly lower mortality in patients with PE who were hemodynamically unstable whether or not they were treated with fibrinolysis,^201,202 several recent studies have investigated the use of retrievable filters with no convincing data.^198,203 Therefore, the use of cava filters beyond the indications listed above is not supported by evidence at present and is a matter of great controversy.^204,205

Finally, in the meta-analysis by Becattini and colleagues, concomitant/residual DVT had a significant association with 30-day all-cause mortality in all patients.²⁰⁶ Thus, although IVC filter placement has not yet been proven to improve mortality in this setting, some clinicians feel that placement of an IVC filter in patients with extensive residual DVT is justified. The clot burden in the legs and in the lungs, together with the overall stability of the patient, may help clinicians to make this decision.

A small percentage of patients with acute PE progress to CTEPH.²⁰⁷ Estimates of the incidence of CTEPH range from 0.5% to 3.8% after an initial episode of embolism and 13.4% after recurrent episodes of PE, with an estimated incidence of five individuals per million population per year.^207,208 Approximately 30% of patients who develop CTEPH have no documented history of acute DVT or PE, and this feature greatly impedes the diagnosis. Anticardiolipin antibodies or a lupus anticoagulant has been detected in approximately 10% of patients, and elevated factor VIII levels have been detected in 40%.²⁰⁹ Apart from major pulmonary vascular obstruction, the pathophysiology of CTEPH includes pulmonary microvascular disease, pulmonary vascular remodeling, immune phenomena, and inflammation.²¹⁰

The median age of patients at diagnosis of CTEPH is 63 years, and both genders are equally affected.²¹¹ Clinical symptoms and signs are nonspecific or absent in early CTEPH, with signs of right heart failure only becoming evident in advanced disease. As in other forms of pulmonary hypertension (PH), progressive exertional dyspnea and exercise intolerance are characteristic. Later in the course of the disease, exertional chest pain, presyncope, or syncope may occur. Diagnostic delay, particularly in the absence of a history of acute VTE, occurs commonly.²¹¹

The chest radiograph usually reveals RV enlargement and enlarged main pulmonary arteries. ECG changes are consistent with RV hypertrophy. Arterial blood gases generally reveal hypoxemia with a widened alveolar-arterial difference, although some patients may demonstrate only exercise-induced hypoxemia. Echocardiography documents the presence of PH, as well as RV hypertrophy.

V/Q lung scanning represents a simple, noninvasive means of differentiating disorders of the peripheral pulmonary vascular bed from those of the central vascular bed and remains the first-line imaging modality for patients with PH being evaluated for CTEPH, since V/Q lung scanning has been shown to have superior sensitivity compared with CT imaging for the diagnosis of CTEPH.^212,213 In chronic thromboembolic disease, at least one segmental or larger mismatched perfusion defect is present. For CTEPH to occur, however, there are generally more extensive perfusion abnormalities. In disorders of the distal pulmonary vascular bed, perfusion scans either are normal or exhibit a “mottled” appearance characterized by subsegmental defects. Mismatched segmental or larger defects in patients with PH may also arise from other processes that result in obstruction of the central pulmonary arteries or veins, such as pulmonary artery sarcoma, large-vessel pulmonary vasculitides, extrinsic vascular compression by mediastinal adenopathy or fibrosis, and pulmonary veno-occlusive disease.²¹⁴ MDCT angiography has become an established imaging technique for CTEPH after an intermediate- or high-probability V/Q scan. A variety of CT abnormalities have been described in patients with chronic thromboembolic disease, including right-sided cardiac enlargement, enlargement of the pulmonary arteries, a mosaic perfusion pattern, intraluminal thrombi, webs/bands, poststenotic pulmonary artery dilation (“pouch defects”), subpleural densities, and dilated bronchial arteries.²¹⁵ Right-heart catheterization is an essential diagnostic tool because it provides important diagnostic and prognostic information. Finally, contrast pulmonary arteriography can be performed to establish the diagnosis with certainty and to determine operability. The angiographic findings in CTEPH are distinct from those encountered in acute embolism, and considerable experience is required for accurate angiographic interpretation (Fig. 75–11).

Thus, the diagnosis of CTEPH is based on following findings obtained after at least 3 months of anticoagulation in order to discriminate this condition from subacute PE: mean pulmonary arterial pressure ≥ 25 mm Hg with pulmonary arterial wedge pressure ≤ 15 mm Hg plus at least one segmental or large-sized defect detected by V/Q or MDCT scan.

Pulmonary endarterectomy is the treatment of choice for CTEPH. General criteria for the operability of patients include New York Heart Association functional class II to IV and the surgical accessibility of thrombi up to the segmental level. There is no particular age, pulmonary vascular resistance, or RV dysfunction thresholds that absolutely preclude pulmonary endarterectomy, because patients who do not undergo surgery or suffer from persistent residual pulmonary hypertension after surgery face a very poor prognosis. However, all these parameters constitute important prognostic factors after surgery. Pulmonary endarterectomy is performed via median sternotomy on cardiopulmonary bypass with periods of deep hypothermic circulatory arrest, and is technically quite distinct from pulmonary embolectomy for acute embolic disease. The procedure is a true endarterectomy, which requires careful dissection of chronic endothelialized material from the native intima to restore pulmonary arterial patency (Fig. 75–12). The use of pulmonary balloon angioplasty has been explore in selected patients with inoperable CTEPH or rescue therapy after surgery, with promising results, but at the cost of potentially periprocedural complications.^{214,216,217,218} However, this has not been investigated in large controlled trials.

Optimal medical treatment for CTEPH consists of anticoagulants, diuretics, and oxygen. Lifelong anticoagulation is recommended, even after pulmonary endarterectomy. Riociguat, a soluble oral stimulator of guanylate cyclase, has been approved by the FDA for symptomatic patients who have been classified as having inoperable CTEPH by an experienced group/center or have persistent/recurrent CTEPH after surgical treatment.^207,219 The temptation to use riociguat or other drugs approved for pulmonary arterial hypertension, as a therapeutic bridge to endarterectomy in patients considered to be at high risk as a result of poor hemodynamics, should be resisted, except in advanced cases in whom endarterectomy cannot be done or is substantially delayed. It is worthwhile reiterating that pulmonary endarterectomy remains the first-line intervention for CTEPH. At present, the hemodynamic and symptomatic benefits to be accrued from medical therapy, although often positive, are modest compared with those resulting from surgery.

Background

Prophylaxis for DVT is effective. Evidence-based clinical guidelines for the prevention of thromboembolism in a wide range of patient populations have been published by the American College of Chest Physicians.^220,221,222

A substantial reduction in the incidence of DVT can be accomplished when individuals at risk receive appropriate preventive care; however, such measures have historically been grossly underused. A recent review confirmed that prophylaxis can be administered safely, with major bleeding complications occurring in only 0.2% of surgical patients.²²³ Several risk assessment models have been proposed to estimate VTE risk in hospitalized medical patients, such as the Padua Prediction Score,²²⁴ among others.²²⁵ Despite some shared limitations of these risks models (small number of events, suboptimal validation), they may provide some basis for judging such a hospitalized patient’s risk.

Prophylaxis can be pharmacologic or nonpharmacologic. Pharmacologic prophylaxis options include low-dose UFH, LMWH, fondaparinux, warfarin, and new oral anticoagulants.^220,221,222 LMWHs are increasingly used in clinical practice for both the prevention and treatment of established VTE. The LMWH preparations are advantageous in that they have a more predictable dose-response relationship and are administered subcutaneously only once or twice daily (without monitoring), depending on the preparation (see Table 75–9). Aspirin has a slight benefit, but not enough to be used alone as a standard therapy to prevent VTE.²²⁶ Early ambulation whenever possible is always recommended in postoperative patients.

General Medical Patients

Prophylactic measures to prevent VTE are not widely implemented among patients with medical illnesses. In the DVT FREE Registry of 5451 DVT patients, 59% of those who did not receive prophylaxis were medical patients.¹⁶ Recent trials have demonstrated that medical patients have a thrombosis risk equivalent to that of moderate-risk surgical patients and that the use of prophylaxis can significantly reduce the rate of VTE events with an acceptable rate of bleeding.^227,228

Patients should be stratified according to DVT risk, and certain prophylactic measures are more appropriate for some patients than for others. The intensity of a prophylactic regimen should take into account the relative risk for thrombosis. Generally, low-dose anticoagulation with standard UFH, LMWH, or fondaparinux is indicated in medical patients who are deemed to be at risk for DVT. In patients requiring prophylaxis who are bleeding or are at high risk of major bleeding, mechanical thromboprophylaxis with graduated compression stockings or intermittent pneumatic compression can be used. Hospitalized patients with cancer are at high risk for VTE, and prophylaxis in this population should follow the recommendations outlined for medical patients.²²² In outpatients with cancer and no additional risk factors for VTE, routine thromboprophylaxis is not recommended. Anticoagulation together with graduated compression stockings or intermittent pneumatic compression is appropriate in patients who are deemed to be at exceptionally high risk and for those who have multiple risk factors for DVT. Extensive evidence-based recommendations for prevention of VTE in general medical patients (including hospitalized medical patients, outpatients with cancer, the chronically immobilized, long-distance travelers, and those with asymptomatic thrombophilia) can be found elsewhere.²²²

General Surgical Patients

In general surgical patients, a number of prophylactic strategies have been used.^220,221 Approximately one-third of the 150,000 to 200,000 VTE-related deaths per year in the United States occur following surgery.^229,230 The high incidence of postoperative VTE and the availability of effective methods of prevention mandate that thromboprophylaxis be considered in every surgical patient. Thus, an overview of the results of randomized trials in surgical patients demonstrated the substantial benefit of DVT prophylaxis.^220,221 For patients undergoing minor operations who are younger than 40 years of age and who have no additional risk factors for DVT, no prophylaxis other than early ambulation is recommended. Older patients who are undergoing major operations without additional risk factors should receive standard low-dose UFH twice daily or three times daily, LMWH, fondaparinux, or intermittent pneumatic compression. For patients with a high risk of bleeding, mechanical prophylaxis in the form of graduated compression stockings or intermittent pneumatic compression should be substituted for pharmacologic prophylaxis. Extensive evidence-based recommendations for prevention of VTE in general nonorthopedic surgical patients can be found elsewhere.²²¹

Other High-Risk Patients

Total hip arthroplasty and total knee arthroplasty are performed with increasing frequency. The risk for VTE in major orthopedic surgery, in particular total hip or knee arthroplasty and hip fracture surgery, is among the highest for all surgical specialties. For patients undergoing elective total hip or knee arthroplasty, approved regimens include fondaparinux initiated 6 to 8 hours after surgery, LMWH initiated 12 hours before or 12 to 24 hours after surgery, adjusted-dose VKA initiated on the evening of the surgical day, low-dose UFH, aspirin, dabigatran, apixaban, or rivaroxaban (total hip arthroplasty or total knee arthroplasty but not hip fracture surgery). The duration of prophylaxis depends on whether the patient is ambulatory and on additional risk factors, although at least 10 days and as many as 35 days of therapy are recommended.²²⁰

DOACs, including direct thrombin inhibitors (dabigatran etexilate) and factor Xa inhibitors (rivaroxaban, apixaban) appear as effective as enoxaparin in reducing the risk of VTE in patients undergoing total hip or total knee arthroplasty with a similar safety profile, although some studies suggest a trend of increased major bleeding when compared to LMWH.²³¹ The introduction of oral, once-daily forms of thromboprophylaxis that do not require monitoring represents a substantial advance in both pre- and potentially postembolic prophylaxis. Current evidence-based guidelines still recommend the use of LMWH in preference to the other alternative agents in major orthopedic surgery and suggest the use of DOACs in patients who decline injections.²²⁰

In summary, given the effective options available, few patients at risk for venous thrombosis cannot be protected. Optimal use of prophylaxis must occur if a substantial impact is to be made on the considerable and often unnecessary morbidity and mortality associated with PE. Not only must prophylaxis be applied, but it also must also be applied in a manner proportionate to the patient’s risk of thromboembolism.

Early Discharge and Outpatient Treatment

Early discharge and outpatient treatment in patients with acute PE is a matter of debate. The crucial issue is to select patients who are at low risk of adverse early outcome. A number of risk-prediction models have been developed.²³² Among them, the PESI and the Hestia score are the most extensively validated scores to date. The value of the simplified form of the PESI score (sPESI) for selecting candidates for early discharge and home treatment has not yet been directly evaluated. Several recent multicenter clinical trials (randomized and nonrandomized) have investigated the 3-month clinical outcome of patients with PE who were discharged early or treated entirely at home using different prediction rules with divergent results.^{233,234,235,236} Meta-analysis suggests that pooled incidences of recurrent VTE, major bleeding, and total mortality did not differ significantly between early discharge patients and those treated as inpatients.²³⁷

Although further research is needed,²³⁸ current clinical guidelines recommend that early discharge (within the first 24 hours) and outpatient treatment should be considered in patients with DVT and in those with PE and low risk of adverse early outcomes (PESI class I or II and probably those with sPESI score of 0) plus low bleeding risk, if it appears feasible based on the patient’s anticipated compliance and family/social background.^151,239 The recent approval of DOACs for use in patients with PE may extend the number of patients treated out of the hospital in the future.²⁴⁰ Finally, it should be realized that there are patients who might meet criteria based on PESI, the Hestia criteria, or both who may not be ideal candidates for outpatient PE therapy. An example might be a patient with an extensive PE burden, but who retains normal RV size and function, particularly when extensive residual DVT remains.

Follow-Up and Optimal Duration of Anticoagulation

The duration of outpatient anticoagulation for patients with VTE remains controversial, especially in patients with a first episode of acute unprovoked VTE (ie, occurring in the absence of reversible risk factors such as surgery, trauma, immobilization, or contraception/hormonal therapy).^13,151,241 The incidence of recurrent VTE does not depend on the clinical manifestation of the first event (ie, it is similar after PE compared with after DVT); however, in patients who have suffered PE, VTE more frequently recurs as symptomatic PE, whereas in patients who have suffered DVT, it tends to recur more frequently as DVT.²⁴²

Patients with a clearly defined initial predisposition whose initial thromboembolic risk factors have resolved (“provoked” PE; ie, temporary or reversible risk factors) should receive at least 3 months of anticoagulation. Consideration should be given for a longer course of therapy in those with persistent V/Q or CT scan defects or abnormal lower extremity test results. Treatment beyond this initial period with VKA reduces the risk of recurrent VTE up to 90%, but this benefit is partially offset by at least 1% higher risk of major bleeding.^243,244 Therefore, in patients who receive extended anticoagulation, the risk-benefit ratio of continuing such treatment should be reassessed on a regular basis.

Patients without a clearly defined initial predisposition to thromboembolism (unprovoked PE) should be treated for at least 3 months, although extended oral anticoagulation should always be strongly considered in these patients if the bleeding risk is low.²⁴⁵ Certain patients, such as those with recurrent spontaneous or unprovoked episodes of VTE (two or more episodes), an irreversible clinical risk factor, combined thrombophilic tendencies, antithrombin III deficiency, deficit of protein C or protein S, homozygous factor V Leiden or homozygous prothrombin G20210A, or presence of a lupus anticoagulant, should be treated with an indefinite period of anticoagulation even though such a strategy is associated with an increased risk of bleeding complications. It has been proposed that d-dimer testing, alone²⁴⁶ or integrated in recurrence risk scores,^247,248,249 might identify patients in whom anticoagulation can be and cannot be safely discontinued after a first unprovoked VTE. However, a recent prospective study has questioned the utility of this strategy.²⁵⁰ In patients who refuse or are unable to tolerate any form of oral anticoagulants, aspirin may be considered for extended secondary VTE prevention.^251,252

Finally, four DOACs (dabigatran, rivaroxaban, edoxaban, and apixaban) have been evaluated for the extended treatment of patients with VTE.^{168,169,253,254} The results of these trials indicate that DOACs are both effective (in terms of prevention of recurrent VTE) and safe (particularly in terms of major bleeding). One trial with apixaban (AMPLIFY-EXT) has shown that for patients already treated for 6 to 12 months, extended therapy at a lower dose (2.5 mg every 12 hours) is effective at preventing recurrences and potentially safer than higher dose therapy.²⁵³ The EINSTEIN-CHOICE study is now underway, in which patients already treated for 6 to 12 months are randomized to two once-daily doses of rivaroxaban (20 and 10 mg) or aspirin (100 mg daily).²⁵⁵

Significance of Subsegmental Pulmonary Embolism and Overdiagnosis

The diagnostic value and clinical significance of subsegmental defects on MDCT are still under debate.²⁵⁶ A single subsegmental defect probably does not have the same clinical relevance as multiple, subsegmental emboli. A recent analysis showed similar outcomes (3-month recurrence and death rates) between patients with subsegmental and more proximal PE, but outcomes were largely determined by comorbidities.²⁵⁷ Compression ultrasound of the lower limbs may be helpful in this situation, as the exclusion of proximal DVT in a patient with isolated subsegmental PE could support anticoagulation discontinuation.¹⁵¹ However, this decision should be made on an individual basis, particularly taking into account the patient’s VTE risk factors and bleeding risk.

There is also growing evidence suggesting overdiagnosis of PE.²⁵⁸ Data from the United States show an 80% rise in the apparent incidence of PE after the introduction of MDCT, without a significant impact on mortality.^259,260 Most experts advocate that patients with incidental (unsuspected) PE on CT should be treated with anticoagulants, especially if they have cancer and a proximal clot,²⁶¹ but solid evidence in support of this recommendation is lacking.

Treatment of Isolated Distal Deep Vein Thrombosis and Upper Limb Thrombosis

The optimal treatment of patients with isolated distal DVT remains controversial. Although posing a substantially lower embolic risk than proximal vein thrombosis, calf-limited thrombi may extend into the proximal veins. Furthermore, the symptomatic outcome may be worse in the absence of therapy.²⁶² If a contraindication to anticoagulation exists, noninvasive testing over 10 to 14 days should be performed to detect possible extension into the popliteal vein.

The spectrum of upper extremity venous thrombosis is variable and includes patients with peripherally and centrally placed IV catheters, as well as those with underlying malignancy. Patients with documented upper extremity DVT should be anticoagulated.²⁸ Prophylactic anticoagulation in patients with long-term indwelling catheters is controversial.²⁶³ Effort-related upper extremity venous thrombosis (Paget-Schroetter syndrome) usually affects young, active men and is related to extrinsic compression of the subclavian vein at the thoracic inlet.²⁸ A multidisciplinary approach to management is often required to avoid long-term consequences, including recurrence, embolism, and symptomatic sequelae.

Pulmonary Embolism in Pregnancy

PE is a leading cause of pregnancy-related maternal death in developed countries; the risk of PE is higher in the postpartum period, particularly after a cesarean section.^264,265 Symptoms should be interpreted with caution since pregnant women often complain of breathlessness, and data on clinical prediction rules for PE in pregnancy are scarce. Suspicion of PE in pregnancy warrants formal diagnostic assessment with validated methods.²⁶⁶ If the suspicion for acute PE is high, then lung imaging should be performed directly. When the chest radiograph is normal or near normal, a V/Q scan can be performed. Otherwise, chest CT angiography should be obtained. When PE is suspected and there are symptoms and signs of DVT, bilateral leg ultrasound followed by anticoagulation treatment (if positive) is recommended. A normal d-dimer value has the same exclusion value for PE in pregnant women as for other patients with suspected PE, but is found more rarely, because plasma d-dimer levels physiologically increase throughout pregnancy.²⁶⁷ In general, d-dimer testing is not recommended as part of the diagnostic evaluation in pregnancy.

The treatment of PE in pregnancy is based on heparin anticoagulation, because heparin does not cross the placenta and is not found in breast milk in significant amounts. Weight-adjusted dose of LMWH is the preferred treatment given its safety profile.^264,268 Adaptation according to anti-Xa monitoring may be considered in women at extremes of body weight or with renal disease, but routine monitoring is generally not justified.²⁶⁴ Fondaparinux should not be used in pregnancy because of the lack of data. VKAs should not be administered throughout pregnancy, especially during the first and third trimesters. DOACs are not approved for use in pregnancy; rivaroxaban, edoxaban, and dabigatran have been graded as FDA pregnancy category C and apixaban as category B.

Thrombolytic treatment during pregnancy and the peripartum period should be used only in life-threatening situations.²⁶⁴

The management of labor and delivery requires particular attention. Epidural analgesia cannot be used unless LMWH has been discontinued at least 12 hours before delivery. Treatment can be resumed 12 to 24 hours after removal of the epidural catheter. After delivery, heparin treatment may be replaced by VKAs, including in breast-feeding mothers, which should be continued for at least 3 months.

Pulmonary Embolism in Cancer Patients

The overall risk of VTE in cancer patients is four times greater than in the general population. The risk of VTE varies with different types of cancer.³⁴ Hematologic malignancies, lung cancer, gastric and pancreatic malignancies, brain cancer, genitourinary tract cancer, and breast malignancies are associated with a particularly high risk of DVT and PE.^35,36 The risk is higher in patients receiving chemotherapy; nevertheless, prophylactic anticoagulation is not routinely recommended during ambulatory anticancer chemotherapy, with the exception of thalidomide- or lenalidomide-based regimens in multiple myeloma.²⁶⁹ Bevacizumab has also been shown to be clearly associated with increased risk.²⁷⁰ The risk of VTE is particularly increased after cancer surgery, especially in the first 4 to 6 weeks, although it may remain elevated beyond the third month after surgery.²⁷¹ Continued vigilance is therefore necessary, as currently recommended prophylactic anticoagulation regimens only emphasize the first 1 month after surgery.

Malignancy should be considered when estimating the clinical probability of VTE. A negative d-dimer test has the same diagnostic value as in noncancer patients; therefore, a normal value excludes the diagnosis of VTE in patients with low or intermediate clinical probability of PE. On the other hand, d-dimer levels are nonspecifically increased in many patients with cancer. Thus, in patients with suspected PE and elevated d-dimer or those with high clinical probability of PE, further imaging tests should be performed as in the general population.

Cancer is a risk for adverse outcome in PE, which is mainly a result of the increased bleeding risk during anticoagulation therapy and the high rate of recurrence of VTE.^272,273 LMWH administered in the acute phase (except for high-risk PE) and continued over the first 3 to 6 months should be considered as first-line therapy.^274,275,276 Evidence with fondaparinux or DOACs is limited. Based on a recent meta-analysis, DOACs seem to be as effective and safe as conventional anticoagulation for the treatment of VTE in patients with cancer.²⁷⁷ Further clinical trials in patients with cancer-associated VTE should be performed to confirm these results.

The decision of chronic anticoagulation (continuation of LMWH, transition to VKAs, or discontinuation of anticoagulation) should be assessed individually based on the success of anticancer therapy, estimated risk of recurrence of VTE, bleeding risk, and patient’s preference. In general, treatment with LMWH or VKA beyond the 3- to 6-month initial period is recommended as long as the disease is considered active.

Recurrence of VTE in cancer patients on VKA or LMWH treatment may be managed by changing to the highest permitted dose of anticoagulation or opting for vena cava filter placement. Complications such as filter thrombosis in the absence of anticoagulation can occur in cancer patients, making this solution less ideal. In these cases, the placement of a retrievable filter and its prompt removal may reduce this potential complication.²⁷⁸ These decisions are often difficult based on the continued risk in cancer patients.

Finally, up to 10% of patients with VTE may be diagnosed with cancer within 1 year following the “unprovoked” index event. However, an extended occult cancer screening does not seem superior to a limited-screening strategy based on clinical, exploratory, and laboratory parameters.⁴²

We would like to thank Peter F. Fedullo, who contributed to the previous version of this chapter in the 13th edition.