PULMONARY EMBOLISM AND VENOUS THROMBOEMBOLISM
Pulmonary embolism (PE) and deep venous thrombosis (DVT) are generally considered to be two clinical presentations of venous thromboembolism (VTE). In most cases, PE is a result of embolization of clot from DVT. The diagnosis and management of patients with PE have been addressed in a number of summary articles and guidelines, including guidelines prepared by a Task Force of the European Society of Cardiology.
|PREDISPOSING FACTORS FOR PULMONARY EMBOLISM|
RISK FACTORS FOR PULMONARY EMBOLISM
PE can occur without identiﬁable predisposing factors, but one or more factors are usually identiﬁed, such as age, history of previous DVT, cancer, neurologic disease with paresis, medical disorders associated with prolonged bed rest, thrombophilia, hormone replacement therapy, and oral contraceptive therapy (see Plate 4-114). There may also be associations with obesity, smoking, and systemic hypertension or the metabolic syndrome. Surgery, particularly orthopedic surgery, is associated with an increased risk of PE.
The source of clots is generally the deep veins of the legs and pelvis (i.e., a femoral, popliteal, or iliac vein) (see Plate 4-115). Most often, clots in a thigh vein originate as an extension of a clot in a deep calf vein. Superﬁcial thrombophlebitis in the legs or thighs rarely gives rise to emboli but may signal a DVT. The loose propagating thrombus in the deep veins constitutes the hazard of pulmonary embolization. When broken loose, the clot is carried to the lungs through the venous stream and right side of the heart.
Superﬁcial thrombophlebitis, which may be associated with DVT, occurs in fewer than one-third of patients with PE. Signs of DVT in the calf or thigh are difﬁcult to detect until the venous circulation is extensively compromised (see Plates 4-116 and 4-117). When careful examination fails to implicate veins of the extremities, it is usual to suspect thrombosis of less accessible deep veins, particularly the pelvic veins in women who have had complicated obstetric manipulations, pelvic inﬂammatory disease, or septic abortion associated with suppurative pelvic thrombophlebitis.
Local or systemic disorders that predispose to venous thrombosis in the legs are also potential precursors of pulmonary emboli (see Plate 4-114). Paramount among these is venous stasis. Even in a normal person, a pro-longed ride with ﬂexed knees in an automobile or air plane may lead to venous stasis and thrombosis in the legs.
CLINICAL MANIFESTATIONS OF LEG VEIN THROMBOSIS
Clinical manifestations of thromboses in the leg veins remain an important part of disease recognition and prompt diagnosis (see Plate 4-116).
|SOURCES OF PULMONARY EMBOLI|
Thrombophlebitis is usually brought to the patient’s attention by pain in the muscles of the affected leg. The pain may be diffuse or localized, and the patient usually does not confuse it with joint pain. Patients may notice that the pain is far worse on dependency and, conversely, completely relieved by elevation. There is often swelling of the affected leg and foot; the extremity may be warm locally, and the patient may be febrile.
Certain circumstances are likely to be associated with DVT, and the physician should review these points with the patient. An initial event may be dependency of the leg for several hours. Obesity; chronic illness, particularly carcinoma and most particularly carcinoma of the pancreas; and use of oral contraceptives enhance the possibility of this complication.
The patient should ﬁrst be examined in the standing position. The presence of varicose veins should be noted because they increase the patient’s susceptibility to thrombophlebitis. Enhancement of the pain by dependency may provide a useful diagnostic clue. The patient is then examined in the recumbent position. A valuable method of detecting unilateral thrombophlebitis is to evaluate the tissue consistency of the affected leg compared with that of the unaffected leg. The examination should be preceded by palpation of the calves for tenderness with the patient’s leg slightly ﬂexed. Generalized tenderness of the calf or thigh may be found. In addition, there may be tenderness along the major veins of the calf or thigh and superﬁcial point tenderness of small segments of veins involved with thrombophlebitis. The ﬁnding of superﬁcial phlebitis is most important in that the potential for complicating thromboembolism is much less when a segment of vein is tender and a thrombus can be felt but there is little or no tenderness elsewhere. The area of thrombosis may appear red because of inﬂammation spreading to the skin. Homans sign is difﬁcult to evaluate. The problem is that the tenderness may be bilateral. Elderly people, particularly, experience some pain in their calves with dorsiﬂexion of their feet.
One of the main techniques for diagnosing and following a patient is that of comparative circumferential measurements of the legs at several levels. The aim is to look for minor amounts of edema that are not readily apparent. A difference of as little as 0.5 cm may be signiﬁcant. Normally, the patient’s dominant leg may be slightly larger than the other leg. This normal increase may be as much as 2 cm at the calf and more in the thigh.
Finally, a serious complication (phlegmasia cerulea dolens) that may arise is the absence of arterial circulation in the affected leg. This represents a medical emergency in that the reﬂex reduction of arterial circulation, as a relatively infrequent complication of thrombophlebitis, may lead to gangrene of the tissues of the foot. The diagnosis is made by observation of the deepening blue color of the extremity as well as the lack of arterial pulses and coldness of the distal part of the extremity in contrast to the usual warm state in uncomplicated thrombophlebitis.
DIAGNOSIS OF DEEP VENOUS THROMBOSIS (see Plate 4-117)
In 90% of cases, PE originates from lower extremity DVT. Lower limb compression venous ultrasonography (CUS) has largely replaced venography for diagnosing DVT. For proximal DVT, CUS has a sensitivity of more than 90% and a speciﬁcity of approximately 95%.
Computed Tomography Venography Computed tomography (CT) venography has been recently advocated as a simple way to diagnose DVT in patients with suspected PE because it can be combined with chest CT angiography in a single procedure using only one intravenous injection of contrast dye. However, it appears as though CT venography increases the overall detection rate only marginally in patients with suspected PE and adds a signiﬁcant amount of irradiation.
CLINICAL MANIFESTATIONS OF PULMONARY EMBOLISM
The clinical manifestations of pulmonary embolization are generally subtle, unexplained tachypnea and dyspnea; anxiety; vague substernal pressure; and occasionally syncope. In a patient predisposed to PE by bed rest, surgery, or local thrombophlebitis, these symptoms constitute strong evidence for a pulmonary embolus even though the physical examination is unrewarding, the electrocardiogram (ECG) indeterminate, and the chest radiograph normal.
The most common type of PE is one that does not result in infarction (see Plate 4-118). This is because of the protective effect of the dual pulmonary circulation that protects the lung from infarction except in cases of massive embolus or in patients with concomitant left-sided heart failure.
PE resulting in infarction occurs after less than 10% of pulmonary emboli. The evidence for pulmonary infarction is acute onset of pleural pain, hemoptysis, breathlessness, pleural effusion, or pleural friction rub (see Plate 4-119).
A massive embolus that either lodges in the main pulmonary artery or overrides both branches to the point of compromising the bulk of the pulmonary blood ﬂow is a disaster that elicits circulatory collapse and acute cor pulmonale (see Plate 4-120). This form of pulmonary embolization is a dire emergency, but it is difﬁcult to distinguish from an acute myocardial infarction. The chances of detecting it depend on the physician’s suspicion that the patient is predisposed to pulmonary embolization. After clinical suspicion has been raised, support for the diagnosis is provided by the classic S1-Q3 pattern on the ECG. Almost as convincing is a fresh “P pulmonale” pattern, a new right- axis shift, or a new pattern of incomplete right bundle-branch block.
The effect of one or more massive emboli is a reduction in the cross-sectional area of the pulmonary vascular tree and an increase in pulmonary vascular resistance to blood ﬂow. If most of the pulmonary vascular tree is blocked, marked pulmonary hypertension occurs followed by dilatation and even failure of the right ventricle. In patients with previously normal lungs, the severity of these changes correlates closely on a lung scan with the extent of perfusion defects. Whether the total hemodynamic effect is attributable to the restricted vascular bed or to associated reﬂex or humoral vasoconstrictor mechanisms is unclear. A decrease in cardiac output and a decrease in systemic blood pressure accompany the right ventricular enlargement. Preexisting cardiac or lung disease aggravates these changes and may precipitate intractable heart failure.
When PE is extensive enough to produce acute right-sided heart failure, it often results in syncope and cardiopulmonary arrest. Profound apprehension, central chest pain, and cardiac dysrhythmias (especially atrial ﬂutter) may also occur, and in many patients, death follows within a few hours of the embolic episode. The physical ﬁndings of acute cor pulmonale include tachy- cardia, an elevated jugular venous pressure with prominent A wave, shock, and cyanosis. Wide splitting of the second heart sound may be present and is often ﬁxed. It disappears with the resolution of the embolus and relief of right ventricular failure. Occasionally, a right ventricular gallop can be heard along with a systolic ejection murmur in the pulmonary area. There may be a palpable lift over the right ventricle and a loud pulmonary closure sound.
DIAGNOSIS OF PULMONARY EMBOLISM
The radiographic appearance depends on the size and number of emboli, whether they have produced pulmonary infarction, and whether the infarcted area reaches the pleural surface to cause pleuritis and pleural effusion. A massive embolus located at the origin of a major pulmonary artery causes hypoperfusion of the ipsilateral lung manifested by a decrease in vascular markings. An increase in size of a major hilar vessel or an abrupt cutoff, the “knuckle sign,” is strong supportive evidence when present. If not distinctly oligemic, areas of the lung often show unduly small vessels. Sometimes the only indication of a large embolus is an unusually high diaphragm on the affected side or the presence of a pulmonary inﬁltrate, a consequence of infarction, hemorrhage, or atelectasis. An ipsilateral pleural effusion may also be the only sign of an otherwise unsuspected pulmonary infarction. All of this radiographic evidence takes on a great signiﬁcance if the individual is predisposed to peripheral or pelvic venous thrombosis and has been identiﬁed as a serious c ndidate for PE. Often nothing abnormal can be seen.
Arterial Blood Gases
A mainstay in the diagnosis of massive PE is a decrease in arterial oxygen tension, generally in association with reduced arterial carbon dioxide tension. Whereas the arterial hypoxemia is a consequence of ventilation/perfusion (V/Q) abnormalities, the hypocapnia is caused by hyperventilation that is presumed to be reﬂexly induced by the emboli via the J receptors. Hypoventilated areas probably result from interference with surfactant and resulting atelectasis in small areas of lung.
Plasma D-dimer levels, a measurement of a degradation product of cross-linked ﬁbrin, are elevated in plasma in the presence of an acute clot caused by simultaneous activation of coagulation and ﬁbrinolysis. A normal D-dimer level makes acute PE or DVT unlikely. The negative predictive value of D-dimer is high. Unfortunately, because of the poor speciﬁcity of ﬁbrin for VTE related to the fact that ﬁbrin is produced in a wide variety of conditions, the positive predictive value of D-dimer is low. D-dimer is not useful for conﬁrming PE. When measured by quantitative enzyme-linked immunosorbent assay, D-dimer has a sensitivity of more than 95% and a speciﬁcity of about 40%. D-dimer levels can therefore be used to exclude PE in patients with a low or moderate probability of PE.
Ventilation/Perfusion Lung Scan
A lung scan, using a radioisotope as a marker, is often performed to evaluate patients with a suspected diagnosis of PE. Macroaggregated albumin, labeled with iodine 131 or technetium 99, is commonly used for this purpose. The tracer substance is injected intravenously. The radioactive particles, which are on the order of 50 to 100 m in diameter, are trapped in the microcirculation of the lung. The pattern of distribution of these radioactive particles, detected by an external counter, deﬁnes the pattern of pulmonary blood ﬂow. It is helpful to have V/Q scans performed at the same sitting so that areas of inadequate blood ﬂow may be related to ventilation abnormalities. Most speciﬁc in reaching a diagnosis is the ﬁnding of multiple perfusion defects in normally ventilated lungs.
Lung scans are practical, simple, and safe. They can be repeated as necessary to trace the resolution of defects and to detect fresh emboli. Results are frequently characterized according to criteria established in the North American PIOPED (Prospective Investigation of Pulmonary Embolism Diagnosis) trial into four categories: normal or near-normal, low, intermediate (nondiagnostic), and high probability of PE. A normal perfusion scan virtually excludes PE. A high-probability V/Q scan suggests the diagnosis of PE with a high degree of probability, but further tests may be considered in selected patients with a low clinical suspicion of PE. In other combinations of V/Q scan results and clinical probability, further testing should be performed.
Recent studies have supported the value of CT angiography in the diagnosis of acute PE. Multidetector CT (MDCT) with high spatial and temporal resolution and quality of arterial opaciﬁcation allows adequate visualization of the pulmonary arteries to at least the segmental level. MDCT may be adequate for excluding PE in patients without a high clinical probability (suspicion) of PE. Whether patients with negative CT results and a high clinical probability should be further investigated (with compressive ultrasonography of the lower extremities or V/Q scanning or pulmonary angiography) is controversial. A MDCT showing PE at the segmental or more proximal level is considered adequate proof of PE in patients without a low clinical probability.
The pulmonary angiographic diagnostic criteria for acute PE were deﬁned many years ago and include direct evidence of a thrombus, either a ﬁlling defect or amputation of a pulmonary arterial branch. Pulmonary angiography is, however, invasive and carries some risk. However, when performed by experienced operators, it can be an important conﬁrmatory test.
The echocardiographic ﬁnding of right ventricular dilatation may be useful in risk stratifying patients with suspected high-risk PE presenting with shock or hypotension. A meta-analysis found a more than twofold increased risk of PE-related mortality in patients with echocardiographic signs of right ventricular dysfunction.
Diagnostic Strategies and Algorithms
Pulmonary angiography, the deﬁnitive test, is invasive, costly, and carries some risk. Therefore, noninvasive diagnostic approaches are warranted, and various combinations of clinical evaluation and the above-described tests (including D-dimer measurement, lower extremity compressive ultrasonography, V/Q scanning, and CT scanning) have been evaluated to decrease the need for pulmonary angiography. It is important to note that the diagnostic approach to PE may vary according to the local availability of tests. The most appropriate diagnostic strategy should also be determined by the clinical assessment of risk and severity. Various guidelines have been developed that describe diagnostic strategies and algorithms in detail.
PROPHYLAXIS AND TREATMENT
Prophylaxis of VTE is concerned with the prevention of clot formation in the deep veins of the legs and with the extension of a clot that can break off and travel to the lungs. Because of the morbidity and mortality associated with DVT and PE, appropriate prophylaxis is of paramount importance. Speciﬁc guidelines for prophylaxis of VTE have been published by the American College of Chest Physicians (ACCP).
Anticoagulation After Pulmonary Embolism
Anticoagulant therapy plays a critically important role in the management of patients with PE. The objectives are to prevent death and recurrent events with an acceptable risk of bleeding-related complications. Rapid anticoagulation requires parenteral therapy, such as intravenous unfractionated heparin (UFH), subcutaneous low-molecular-weight heparin, or subcutaneous fondaparinux. Because of the high mortality rate in untreated patients, anticoagulation should be considered in patients with suspected PE while awaiting diagnostic conﬁrmation. Speciﬁc guidelines for anticoagulation after PE have been published by the ACCP and are updated regularly. The use of intravenous UFH requires close monitoring of the activated partial thromboplastin time. Treatment with parenteral anti-coagulants is usually followed by the use of oral vitamin K antagonists, such as warfarin. Chronic anticoagulation with warfarin requires ongoing monitoring of the prothrombin time or the International Normalized Ratio. Protocols to guide anticoagulant dosing and monitoring and follow-up by a dedicated team of experienced professionals may help to optimize the safety and efﬁcacy of therapy. Drug interactions can be troublesome during warfarin therapy, and each new medication must be examined for its effect in enhancing or diminishing the action of warfarin.
Thrombolytic therapy rapidly resolves thromboembolic obstruction and has beneﬁcial effects on hemodynamic parameters. However, the beneﬁts of thrombolysis over anticoagulation with heparin appear to be largely conﬁned to the ﬁrst few days. Thrombolytic therapy carries a signiﬁcant risk of bleeding, especially in patients with predisposing conditions or comorbidities. Nevertheless, thrombolytic therapy may be used in patients with high-risk PE presenting with cardiogenic shock or persistent systemic hypotension. Further studies are needed to more precisely deﬁne the role of thrombolytic therapy for PE.
Surgical Pulmonary Embolectomy for Acute Pulmonary Embolism
Pulmonary embolectomy may be indicated in patients with high-risk PE in whom thrombolysis is absolutely contraindicated or has failed.
Inferior vena cava (IVC) ﬁlters may be used when there are contraindications to anticoagulation and a high risk of VTE recurrence (see Plate 4-121). They are also often placed in patients with chronic thromboembolic pulmonary hypertension (CTEPH) to provide an additional barrier of protection against recurrent PE. Some ﬁlters in use today are retrievable and removable and may be suitable for temporary use.
CHRONIC EFFECTS OF PULMONARY EMBOLISM
Chronic Thromboembolic Pulmonary Hypertension
PEs are occasionally dispatched to the lungs for months to years without clinical evidence of acute embolizations. The patients may present with evidence of severe pulmonary hypertension and often die in right ventricular failure. The course of patients with multiple pulmonary emboli may be so subtle as to mimic that of patients with idiopathic pulmonary arterial hypertension. CTEPH is a relatively rare complication of pulmonary thromboembolic disease. It is often characterized by progressive dyspnea and hypoxemia and ultimately the development of right-sided heart failure (see Plate 4-121).
In these patients with severe pulmonary hypertension, dyspnea and tachypnea, fatigue and syncopal episodes, or precordial pain during exertion are usually found in some combination. On physical examination, an impulse may be felt over the main pulmonary artery, and there is splitting of the second heart sound with accentuation of the pulmonary component. An ejection click and a systolic or diastolic murmur may be present in the pulmonary valve area. Subsequently, evidence of right ventricular hypertrophy is found, with a prominent A wave in the jugular venous pulse and a right ventricular heave and fourth heart sound. As failure develops, a right ventricular gallop can be heard, and there is evidence of tricuspid valve insufﬁciency along with the peripheral consequences of an ineffectively functioning right ventricle. Sudden death caused by transient arrhythmias may occur.
Chest radiographs usually show an enlarged heart with right ventricular and right atrial prominence. The main pulmonary artery shadow is increasingly enlarged as hypertension becomes more severe, and the peripheral lung ﬁelds are oligemic and lack vascular markings. Evidence of right-axis deviation appears on the ECG, with evidence of right ventricular hypertrophy in the precordial leads. There is usually indication of right atrial enlargement, and when changes are severe, inversion of right precordial T waves. Right-sided heart catheterization and radioisotope lung scans provide deﬁnitive evidence of the disease process.
|MECHANICAL DEFENSES AGAINST AND CHRONIC EFFECTS OF PULMONARY EMBOLISM|
Surgical removal of obstructing material related to chronic thromboembolic disease requires a true endarterectomy rather than an embolectomy. The operation is performed on cardiopulmonary bypass, with deep hypothermia and complete circulatory arrest. Selection of appropriate candidates for the operation is extremely important, and criteria include factors such as surgical accessibility and the absence of severe comorbidity. PTE carries substantial risk, but in experienced hands, it may result in dramatic clinical and hemodynamic improvement. Medical therapy for patients with CTEPH is being explored in clinical trials.