13: Pulmonary embolism

OUTLINE

Etiology and Pathogenesis, 172

Pathology, 173

Pathophysiology, 174

Clinical Features, 175

Diagnostic Evaluation, 175

Treatment, 179

Pulmonary embolism is one of the most important disorders that affect the pulmonary vasculature. It not only is found in a significant number of unselected autopsies in which a careful search is made but also has the potential both for “overdiagnosis” when not present and “underdiagnosis” when present.

The term pulmonary embolism or, more precisely, pulmonary thromboembolism, refers to movement of a blood clot from a systemic vein through the right side of the heart to the pulmonary circulation, where it lodges in one or more branches of the pulmonary artery. The clinical consequences of this common problem are quite variable, ranging from none to sudden death, depending on the size of the embolus and the underlying cardiopulmonary condition of the patient. Although pulmonary embolism is intimately associated with the development of a thrombus elsewhere in the circulation, this chapter focuses on the pulmonary manifestations of thromboembolic disease, and not on the clinical effects or diagnosis of the clot at the site of formation, usually in the deep veins of the lower extremities.

Etiology and pathogenesis

A thrombus—that is, a blood clot—is the material that travels to the pulmonary circulation in pulmonary thromboembolic disease. Other material can also travel via the vasculature to the pulmonary arteries, including tumor cells or fragments, fat, amniotic fluid, and a variety of foreign materials that can be introduced into the circulation. This text does not consider these other (much less common) types of embolism, which usually have quite different clinical presentations than thromboemboli.

In the majority of cases, the lower extremities are the source of thrombi that embolize to the lungs. Although these thrombi frequently originate in the veins of the calf, extension of the clots proximally to involve the larger veins of the thigh is necessary to produce sufficiently sized thromboemboli that can obstruct major portions of the pulmonary vascular bed and become clinically important. Rarely do

pulmonary emboli originate in the arms, pelvis, or right-sided chambers of the heart; combined, these

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sources probably account for less than 10% of all pulmonary emboli. However, the source of thrombi in embolic disease may not be clinically apparent. In fact, only about 50% of patients with pulmonary emboli have previous clinical evidence of venous thrombosis in the lower extremities or elsewhere.

Thrombi in the deep veins of the lower extremities are the usual source of pulmonary emboli.

Three factors are commonly cited as potential contributors to the genesis of venous thrombosis: (1) alteration in the mechanism of blood coagulation (i.e., hypercoagulability), (2) damage to the vessel wall endothelium, and (3) venous stasis or stagnation of blood flow. In practice, many specific risk factors for thromboemboli have been identified, including immobilization (e.g., bed rest, prolonged sitting during travel, immobilization of an extremity after fracture), the postoperative state, heart failure, obesity, underlying malignancy, pregnancy and the postpartum state, the use of oral contraceptives, and chronic deep venous insufficiency. Patients at particularly high risk are those who had trauma or surgery related to the pelvis or lower extremities, especially hip fracture, or hip or knee replacement.

A number of genetic predispositions to hypercoagulability are recognized. They include deficiency or abnormal function of proteins with antithrombotic activity (e.g., antithrombin III, protein C, protein S) or the presence of abnormal variants of some of the clotting factors that are part of the coagulation cascade, especially factor V and prothrombin (factor II). The most common genetic defect associated with hypercoagulability is called factor V Leiden. It is usually due to a single base pair substitution leading to replacement of an arginine residue by glutamine, causing the activated factor V protein to become more resistant to degradation by activated protein C. Individuals who are heterozygous for factor V Leiden have a threeto fivefold increased lifetime risk for venous thrombosis. The much less common homozygous state confers a significantly higher risk. In the genetic variant of prothrombin often called the prothrombin gene mutation, there is a single base pair deletion that appears to affect posttranslational mRNA processing, leading to increased plasma levels of prothrombin and predisposition to venous thrombosis.

Although deficiencies of the antithrombotic proteins (antithrombin III, protein C, and protein S) are rare, factor V Leiden may have a prevalence of up to 5% in European, North American, Lebanese, and Greek populations. Both factor V Leiden and the prothrombin gene mutation are relatively common in the North American White population but are rare among Black and Asian populations in the United States. The fact that factor V Leiden is found in some 20% of patients with a first episode of venous thromboembolism suggests that it is an important risk factor.

Pathology

Pathologic changes that result from occlusion of a pulmonary artery branch depend to a large extent on the location of the occlusion and the presence of other disorders that compromise O2 supply to the pulmonary parenchyma. There are two major consequences of vascular occlusion in the lung parenchyma distal to the site of occlusion. First, if minimal or no other O2 supply reaches the parenchyma, either from the airways or from the bronchial arterial circulation, frank necrosis of lung tissue (pulmonary infarction) will result. According to one estimate, only 10% to 15% of all pulmonary emboli result in pulmonary infarction. It is sometimes said that compromise of two of the three O2 sources to the lung (pulmonary artery, bronchial artery, and alveolar gas) is necessary before infarction results. Second, even when parenchymal integrity is maintained and infarction does not result, hemorrhage and edema often occur in lung tissue supplied by the occluded pulmonary artery.

Embolic occlusion of a vessel may lead to infarction, hemorrhage, and/or edema of the lung parenchyma.

Either with or without frank pulmonary infarction, the pathologic process generally extends to the visceral pleural surface, so corresponding radiographic changes are often pleura-based. In some cases, pleural effusion also may result. As part of the natural history of infarction, there is generally contraction of the infarcted parenchyma and eventual formation of a scar. When infarction of the affected lung has not occurred, resolution of the process and resorption of the blood may leave few or no permanent pathologic sequelae.

In many cases, neither of these pathologic changes occurs, and relatively little alteration of the distal lung parenchyma is found, presumably because of incomplete occlusion or sufficient oxygen from other sources. Frequently, the thrombus quickly fragments or undergoes a process of lysis, with smaller fragments moving progressively distally in the pulmonary arterial circulation. Whether this rapid process of clot dissolution occurs is important in determining the pathologic consequences of pulmonary embolism.

With clots that do not fragment or lyse, generally a slower process of organization in the vessel wall and eventual recanalization are seen. Webs may form within the arterial lumen and sometimes are detected on a pulmonary arteriogram or on postmortem examination as the only evidence for prior embolic disease.

Pathophysiology

When a thrombus migrates to and lodges within a pulmonary vessel, a variety of consequences ensue. They relate not only to mechanical obstruction of one or more vessels but also to the secondary effects of various mediators released from the thrombus and ischemic tissue. The effects of mechanical occlusion of the vessels are discussed first, followed by a consideration of how chemical mediators contribute to the clinical effects.

When a vessel is occluded by an embolus and forward blood flow through the vessel stops, the perfusion of pulmonary capillaries normally supplied by that vessel ceases. If ventilation to the corresponding alveoli continues, it is wasted and this region of lung serves as dead space. The combination of wasted ventilation and redistribution of blood flow away from the embolized region of

lung can contribute to mismatch, which is the primary mechanism for hypoxemia in pulmonary embolism. As discussed in Chapter 1, assuming that total minute ventilation remains constant, increasing the dead space automatically decreases alveolar ventilation and hence CO2 elimination. However, despite the potential for CO2 retention in pulmonary embolic disease, hypercapnia is an unusual consequence of pulmonary embolism, mainly because patients routinely increase their minute ventilation after an embolism occurs and more than compensate for any increase in dead space. In fact, the usual consequence of a pulmonary embolus is hyperventilation and hypocapnia, rather than hypercapnia. Hyperventilation is believed to occur because of the stimulation of respiratory drive by mediator release and activation of irritant receptors in the lung. However, if minute ventilation is fixed (e.g., in an unconscious or anesthetized patient whose ventilation is controlled by a mechanical ventilator), a PCO2 rise may result from the increase in dead space caused by a relatively large pulmonary embolus.

In addition to creating an area of dead space, another potential consequence of mechanical occlusion of one or more vessels is an increase in pulmonary vascular resistance. As discussed in Chapter 12, the pulmonary vascular bed is capable of recruitment and distention of vessels. Experimental evidence

indicates that there is no increase in resistance or pressure in the pulmonary vasculature until

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approximately 50% to 70% of the vascular bed is occluded. However, the experimental model is somewhat different from the clinical setting because the release of chemical mediators may cause vasoconstriction and additional compromise of the pulmonary vasculature.

Pulmonary emboli are typically associated with hypocapnia resulting from an increase in overall minute ventilation.

With further limitation of the vascular bed by the combination of mechanical occlusion and the effects of chemical mediators, the pulmonary vascular resistance may increase enough that the right ventricle cannot overcome the acute increase in its afterload. As a result, the forward output of the right ventricle may diminish, blood pressure may fall, and the individual may have a syncopal (fainting) episode or develop cardiogenic shock. In addition, “backward” failure of the right ventricle may occur, which manifests acutely with an elevation of systemic venous pressure and appears on physical examination as distention of the jugular veins.

The hemodynamic consequences of acute pulmonary embolism depend, to a large extent, on the presence of preexisting emboli and whether underlying pulmonary vascular disease or cardiac disease is present. When emboli have occurred previously, the right ventricular wall has already thickened (hypertrophied), and higher pressures can be generated and maintained. On the other hand, an additional embolus in an already compromised pulmonary vascular bed may act as “the straw that broke the camel’s back” and induce decompensation of the right ventricle.

In addition to the direct mechanical effects of vessel occlusion, thrombi result in the release of chemical mediators that have secondary effects on both the airways and blood vessels of the lung. Platelets that adhere to the thrombus are an important source of mediators, such as histamine, serotonin, and prostaglandins. Injury to the pulmonary arterial endothelium by the clot results in the increased release of endothelin-1, a potent vasoconstrictor, and the decreased production of nitric oxide, a vasodilator. Bronchoconstriction—largely at the level of small airways—appears to be an important consequence of mediator release and is thought to contribute to the hypoxemia that commonly accompanies pulmonary embolism. In addition, areas of low ventilation and inappropriately high perfusion appear to develop because the process of hypoxic vasoconstriction becomes compromised by mediators related to thromboemboli. However, if vasoconstriction of pulmonary arteries and arterioles predominates, this adds to the likelihood of significant cardiovascular compromise.

Three additional features of the pathophysiology of pulmonary embolism are noteworthy. First, as a result of vascular compromise to one or more regions of lung, synthesis of the surface-active material surfactant in the affected alveoli is compromised. Consequently, alveoli may be more likely to collapse, and liquid more likely may leak into alveolar spaces. Second, hypocapnia appears to have the effect of inducing secondary bronchoconstriction of small airways. With the hypocapnia that occurs in pulmonary embolism, and particularly with the low alveolar PCO2 in the dead space regions of lung, secondary bronchoconstriction results. Both of these mechanisms, along with the small airway constriction induced by chemical mediators, may contribute to the volume loss or atelectasis frequently observed on chest radiographs of patients with pulmonary embolism. Shunt physiology also may contribute to hypoxemia because of either perfusion of the atelectatic lung or elevation of the right heart pressures producing intracardiac shunting across a patent foramen ovale.

A variety of bioactive substances are inactivated in the lung (see Chapter 12). Whether pulmonary embolism disturbs some of these nonrespiratory metabolic functions of the lung is not clear, and whether clinical consequences might ensue from such a potential disturbance is unknown.