Because the lung receives all of the blood flow returned from the venous system, the pulmonary vascular bed serves as a “sieve” for all particulate substances entering the venous blood and is the first vascular bed to be exposed to any toxic substance injected intravenously. As a result of its strategic position, the pulmonary vascular bed is, therefore, exposed to a wide variety of potentially obstructing and injurious agents.
An increasingly common form of nonthrombotic embolism in the United States is venous air embolism. The increasing frequency of the problem reflects the wide variety of invasive surgical and medical procedures now available, the broad use of indwelling central venous catheters, the use of positive pressure ventilation with high levels of positive end-expiratory pressure, and the frequency of thoracic and other forms of trauma. The simple inadvertent transection or loss of closure of a large-bore intravenous catheter, particularly in the jugular or subclavian vein, can result in ingress of substantial quantities of air. Air bubbles enter the pulmonary vascular bed and, from there, can enter the arterial system and are diffusely distributed throughout the body by way of either an intracardiac shunt (atrial septal defect, patent foramen ovale) or, more likely, through microvascular pulmonary shunts.
Physiologic consequences are related to the volume of air entrainment and rate of accumulation. An abrupt rise in pulmonary artery pressure and noncardiogenic pulmonary edema may develop, lung compliance falls, and hypoxemia ensues. The symptoms of venous air embolism are variable and nonspecific, and may include alterations in sensorium, chest pain, dyspnea, or a sense of impending doom.159 These and other consequences appear to be due to two phenomena: actual lodgment of the bubbles in capillary beds that interfere with nutrient supply to the affected organs, and the formation of platelet–fibrin aggregates, creating diffuse microthrombi. Thrombocytopenia may be seen as a consequence of this latter event. The most serious consequences result from cerebral or coronary artery air embolism, the severity of the consequences depending upon the rate and volume of air gaining access to the circulation.
The best approaches to air embolism are prevention and early detection. Treatment consists of measures designed to restore flow and promote reabsorption of the intravascular air.160 Measures designed to restore flow include patient positioning (Trendelenburg position with the left side down), removal of air through central venous catheters or direct needle aspiration, and closed chest cardiac massage. Measures designed to increase absorption include the use of 100% oxygen and hyperbaric oxygen therapy. Using such aggressive measures, mortality from venous air embolism has been dramatically reduced.
Fat embolism represents another form of nonthrombotic embolism.161,162 In its full-blown form, a rather characteristic syndrome follows entry of neutral fat into the vascular system, consisting of dyspnea, hypoxemia, petechiae, and mental confusion. Seizures and focal neurologic deficits have been described. There is a variable lag time of 24 to 72 hours in the onset of the syndrome following the inciting event; rarely, cases occur within 12 hours or as late as 2 weeks after the event.
By far, the most common inciting event is traumatic fracture of long bones, with incidence rising with the number of fractures. However, orthopedic procedures and trauma to other fat-laden tissues (e.g., fatty liver) occasionally can lead to the same syndrome. Although considerably less common, fat embolism syndrome has been reported following both liposuction and lipoinjection procedures.
The basis for the variability in the incidence and severity of the syndrome after apparently comparable injuries has not been well defined, nor has the delay in clinical presentation. The pathophysiologic consequences appear to derive from two events: (1) actual vascular obstruction by neutral particles of fat; and (2) the injurious effects of free fatty acids released by the action of lipases on the neutral fat. The latter effect is probably the more important, causing diffuse vasculitis with leakage from cerebral, pulmonary, and other vascular beds. The time necessary to produce toxic intermediaries may explain the delay from the inciting event to clinical presentation.
The diagnosis of fat embolism syndrome is a clinical one suggested by the constellation of dyspnea, neurologic abnormalities, petechiae, and fever in the proper clinical context. Petechiae, typically distributed over the head, neck, anterior chest, and axillae, are present in only 20% to 50% of cases. Therefore, their absence should not preclude consideration of the disease. No laboratory test is diagnostic of the syndrome. Fat can be demonstrated in the serum of a majority of fracture patients with evidence of fat embolism syndrome. The finding of lipid-laden cells in bronchoalveolar lavage fluid appears to occur commonly in patients with traumatic injuries irrespective of the presence of fat embolism syndrome.
Although a variety of treatments have been suggested (e.g., intravenous ethanol, albumin, dextran, heparin), none has proved effective. The role of corticosteroid therapy to prevent the onset of fat embolism syndrome after an inciting event remains controversial.163 Supportive treatment, including mechanical ventilatory support when necessary, is the primary approach, and survival is now the rule with meticulous support.
Another special form of embolism is amniotic fluid embolism, a rare, unpredictable and potentially catastrophic complication of pregnancy. Amniotic fluid embolism is reported to occur in approximately 2.0 per 100,000 deliveries and represents a leading cause of maternal mortality.164 This disorder occurs during or after delivery when amniotic fluid gains access to uterine venous channels and, therefore, to the pulmonary and general circulations. The delivery may be either spontaneous or by Cesarean section and usually has been uneventful. Most cases occur during labor, but delayed onset of symptoms up to 48 hours after delivery can occur. Advanced maternal age, multiparity, premature placental separation, fetal death, and meconium staining of amniotic fluid have been associated with increased risk of amniotic fluid embolism.
Amniotic fluid embolism syndrome should be suspected with the sudden onset of severe respiratory distress, cyanosis, hypotension, cardiovascular collapse and, often, disseminated intravascular coagulation.165 Occasionally, seizure activity occurs. It has been postulated that there is a biphasic pattern of hemodynamic disturbance: an initial period of pulmonary hypertension, commonly seen in animal models, followed by left ventricular dysfunction and cardiogenic shock. Patients who survive the first several hours develop noncardiogenic pulmonary edema coincident with improvement in left ventricular dysfunction.166
Amniotic fluid contains particulate materials that can cause pulmonary vascular obstruction, but the major pathogenetic mechanism of the syndrome remains uncertain. Amniotic fluid has thromboplastic activity that leads to extensive fibrin deposition in the pulmonary vasculature and, occasionally, other organs. As a consequence of fibrin deposition, severe consumptive coagulopathy develops, including marked hypofibrinogenemia and thrombocytopenia. Following the acute event, an enhanced fibrinolytic state often occurs.
The diagnosis of amniotic fluid embolism is based on a compatible clinical picture, often enhanced by finding amniotic fluid components in the pulmonary circulation. The presence of squamous cells in pulmonary arterial blood, once considered pathognomonic, has proved to be a nonspecific finding. Serologic assays and immunohistochemical staining techniques have been described as having high sensitivity for amniotic fluid embolism.
Although various forms of therapy have been suggested (e.g., antifibrinolytic agents such as aminocaproic acid, cryoprecipitate), the best approach is supportive. Pulmonary artery catheterization is useful to monitor left ventricular function and volume status and to guide the appropriate use of inotropic and vasoactive agents. Even in the setting of aggressive supportive measures, however, maternal mortality has approached 80%.
Septic embolism is another special disorder that, unfortunately, is increasing in frequency owing to widespread intravenous drug abuse and the expanding use of indwelling intravenous devices. Previously, septic embolism was almost exclusively a complication of septic pelvic thrombophlebitis due to either septic abortion or postpuerperal uterine infection.167 However, almost any venous structure can be involved, either as a focus of primary infection or from intravascular or contiguous spread: septic cavernous sinus thrombosis resulting from meningitis, sinusitis, or facial cellulitis; septic portal venous thrombosis resulting from diverticulitis or liver abscess; septic tonsillar or internal jugular venous thrombosis (Lemmiere syndrome) resulting from oropharyngeal infection. Increasingly common causes are those related to intravenous drug use and those that are iatrogenic; namely, infections secondary to indwelling catheters inserted for a variety of diagnostic or therapeutic purposes.168–170
Microscopically, septic phlebitis consists of purulent material admixed with fibrin thrombus. Embolization from such material does occur and can result in obstruction of small pulmonary vessels, but the major consequence is pulmonary infection. Characteristically, the chest roentgenogram displays scattered pulmonary infiltrates that undergo cavitation. An increasing number of such infiltrates develop over periods of hours to a few days. Symptoms and signs include fever, dyspnea, cough, pleuritic chest pain, and hemoptysis. Initial treatment consists of appropriate antibiotics. If an indwelling catheter is the source of the infection, it should be removed. If there is not a prompt response to this regimen, surgical isolation of the septic vein, if present, should be considered. The role of systemic anticoagulation remains uncertain. Endocarditis may complicate septic phlebitis, or mimic it, particularly in drug addicts.
Involvement of the pulmonary vascular bed by tumor cells is not unusual given the frequency with which circulating tumor cells can be identified in patients with a wide range of malignancies and the frequency with which tumor emboli are discovered as an incidental finding at autopsy.171 Tumor embolism becomes clinically apparent, however, in only a minority of patients with malignancy.
Microvascular tumor embolism is associated with a wide range of malignancies, the most common of which are breast, lung, prostate, stomach, and liver cancer. Tumor embolism of large fragments occurs rarely and may mimic acute thromboembolic disease. In this setting, survival following tumor embolectomy has been reported.
The clinical presentation of microvascular tumor embolism is typically subacute and involves progressive dyspnea, tachycardia, and tachypnea. Jugular venous distention, a prominent P2, tricuspid regurgitation or a right-sided S3 may be present on physical examination if the extent of pulmonary vascular obstruction is sufficient to cause pulmonary hypertension.
The development of pulmonary hypertension is a common accompaniment of symptomatic, microvascular tumor embolism and remains a major cause of mortality. Pulmonary hypertension appears to result from an obliteration of the pulmonary vascular bed by an admixture of tumor cells and thrombus as well as the development of medial hypertrophy, intimal fibrosis, and fibrinoid necrosis encountered in other etiologies of pulmonary hypertension.
Hypoxemia and a compensated respiratory alkalosis are commonly present. The chest radiograph is most often normal but focal or diffuse infiltrates, which may be fleeting, have been described. V/Q scanning most commonly demonstrates a mottled appearance or peripheral, subsegmental defects; segmental or larger defects, indistinguishable from those associated with thromboembolic embolism, may occur in those rare instances of large-vessel involvement. CT may demonstrate peripheral, wedge-shaped defects consistent with infarcts; a pattern of multifocal dilatation and beading of the peripheral pulmonary arteries has been described.172
Pulmonary angiographic findings may include delayed vascular filling, pruning, and tortuosity, similar to that seen in other forms of small-vessel pulmonary hypertension. The angiographic findings in large fragment tumor embolism may be indistinguishable from those seen in acute thromboembolic disease.
Pulmonary microvascular cytology on specimens aspirated through a wedged pulmonary artery catheter may demonstrate malignant cells. Positive cytologies, however, can also be obtained in the setting of lymphangitic carcinomatosis. The misidentification of megakaryocytes as tumor cells obtained in this manner has been reported to lead to false-positive results.
Although diagnosis by transbronchial biopsy has been reported, diagnostic confirmation may require surgical lung biopsy. Before proceeding to that step, however, it must be stressed that the impact of early diagnosis on outcome is uncertain. This intervention should only be considered in the setting of a primary malignancy for which effective chemotherapeutic options are available.
The differential diagnosis of tumor embolism includes thrombotic embolism, parenchymal metastasis, lymphangitic carcinomatosis, malignant pericardial effusion, and chemotherapy-related lung toxicity. The premortem diagnosis is often one of exclusion. Parenchymal metastasis, lymphangitic carcinomatosis and chemotherapy-related lung toxicity can be differentiated from tumor embolism by findings on high-resolution CT. Differentiation of tumor embolism from thrombotic embolism may be somewhat more problematic, especially if there is large-vessel involvement.
Sickle cell disease affects the lungs by causing local thrombosis and occasionally by embolization of bone marrow elements. Small pulmonary arteries, arterioles, and capillaries are generally affected.173,174 Thrombosis in the pulmonary circulation is part of the general proclivity of red blood cells containing S hemoglobin to sickle under appropriate circumstances, particularly hypoxia; stagnation and clotting follow sickling. In some instances, the thrombus organizes, the vascular lumen is obliterated, and perivascular fibrosis ensues in the adjacent lung; in others, the thrombus recanalizes. Occasionally, infarction occurs.
Of the factors that predispose to thrombosis in the lungs in sickle cell disease, the most important is the low oxygen saturation of mixed venous blood. Not only is the mixed venous oxygen inordinately low but also the O2 dissociation curve is shifted to the right, thereby handicapping O2 uptake in the lungs. Patients with sickle cell disease are prone to develop pneumonia, which, in turn, can lead to local areas of hypoxia favoring sickling and thrombosis in the lung. Patients with severe sickle cell anemia and large fractions of hemoglobin S in their red blood cells are particularly susceptible to intense sickling and thrombosis anywhere, including the lungs. However, vulnerability is not restricted to states of hemoglobin S. In some heterozygous sickle states – for example, hemoglobin SC, S-thalassemia, and hemoglobin SA – enough hemoglobin S is present to cause extensive thrombosis and infarction during an episode of severe hypoxemia, acidosis, or septicemia associated with fever and leukocytosis.
The clinical picture of pulmonary infarction in patients with sickle cell disease can mimic or coexist with bronchopneumonia. An episode often begins with chest pain, fever, and sputum that is blood streaked but fails to disclose any specific bacterial cause. A fleeting episode of breathlessness is usually overlooked. The subsequent course is characterized by an unconvincing response to antibiotics and slow clearing; often a linear scar in the lungs remains as a residue of the infarction.
Distinguishing between in situ thrombosis and thromboembolism can be difficult clinically and even with invasive procedures such as angiography, although in situ thrombosis tends to be in small, distal vessels. Moreover, because radiographic contrast materials may promote sickling, they have to be used cautiously. To complicate matters, some patients with sickle cell disease are also at increased risk of thromboembolism because of predisposing factors, such as bed rest, congestive heart failure, and dehydration.
Sometimes, occlusive disease is sufficiently extensive to cause pulmonary hypertension and cor pulmonale. For this sequence to evolve, many severe episodes of sickling are required. The cor pulmonale that results is unusual because of its association with a high cardiac output (due to anemia) and with the intrinsic myocardial damage that generally complicates sickle cell disease.175
Management of the patient with pulmonary thrombosis and infarction in sickle cell disease is largely supportive and includes supplemental oxygen, intravenous hydration, and pain control.
Simple or exchange transfusions are recommended for patients with significant hypoxemia and pulmonary infiltrates (i.e., acute chest syndrome). Anticoagulants are generally not used in sickle cell crisis. Their utility in larger-vessel pulmonary artery thrombosis is uncertain since there are no data to substantiate their effectiveness. Because it implicates large vessels’ occlusion, pulmonary artery thrombosis during acute chest syndrome should be amenable to the same therapeutic approach as currently used for venous thromboembolic disease.174
Because of its sieve function, the lung may also be the target of embolization by a wide variety of other materials.176–179 Trophoblastic tissue can escape the uterus and lodge in the pulmonary circulation during pregnancy. After head trauma, brain tissue has been found in the lungs; the same is true of liver cells following abdominal trauma and bone marrow after cardiopulmonary resuscitation.
Finally, noninfectious vasculitic–thrombotic complications are seen in association with the intravenous use of drugs intended for oral use. Medications associated with pulmonary complications include methylphenidate hydrochloride, oral opiates (pentazocine, meperidine), and antihistamines. Particulate and irritant drug carriers (e.g., talc, cellulose) and occasionally the drugs themselves may cause vascular inflammation and secondary thrombosis. The clinical presentation may be diverse and includes lower lobe emphysema, diffuse interstitial fibrosis, and progressive massive fibrosis. Repetitive insults may lead to severe and irreversible pulmonary hypertension. In many intravenous drug users, perfusion scans demonstrate segmental or smaller defects. Distinguishing these defects from those due to venous thromboembolism may be difficult.
The diagnosis is often suggested by the clinical history. Radiographic findings include small, diffuse, well-defined nodular densities. These nodules can progress and massive fibrosis may ensue. Lower lobe emphysematous changes may also be present. Diagnostic confirmation often requires transbronchial or surgical lung biopsy. Occasionally, fine crystalline deposits may be seen in the retinal microvasculature on funduscopic examination, confirming the diagnosis noninvasively. The prognosis is generally poor with most patients experiencing progressive pulmonary disease.