Pulmonary Embolism

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Chapter 57 Pulmonary Embolism

Michael P. Gruber, Todd M. Bull

The philosophies of one age have become the absurdities of the next, and the foolishness of yesterday has become the wisdom of tomorrow.

William Osler

Pulmonary embolism (PE) and deep vein thrombosis (DVT) are different manifestations of the same pathologic process best grouped under the designation venous thromboembolism (VTE). As a disease entity, VTE is responsible for significant morbidity and mortality while imparting great socioeconomic impact. Appropriately, much attention has been devoted to its diagnosis and treatment. Although the medical literature has at times presented conflicting opinions, increased numbers of better-designed trials are helping to build consensus toward the optimal approach for the management of PE. This is not to say that significant controversies do not still exist. As in all areas of medicine, as one question is answered, others arise. This chapter presents an overview of the most important literature regarding the clinical approach to PE.

Epidemiology, Risk Factors, and Pathogenesis

Epidemiology

PE is a common clinical problem. In the United States, hospital-based studies estimate the incidence of PE at 1 case per 1000 persons per year, equating to 200,000 to 300,000 hospital admissions per year. Estimates suggest that as many as 30,000 to 50,000 people die from PE annually in the United States, with an estimated 3-month disease-specific mortality rate of 10%. In nearly 20% of cases, the presenting clinical manifestation is sudden death. Data reported from Europe and other parts of the world are broadly similar.

Significant differences in mortality associated with PE for age, gender, and race have been observed. Age-adjusted PE mortality rates are as much as 50% higher among African Americans than whites. Within and between racial strata, PE mortality rates are 20% to 30% higher in men than in women. African American men have the highest reported mortality from PE, at 6.0 deaths per 100,000 persons, followed by African American women at 4.8 deaths per 100,000 persons. The mortality for PE in white males is 2.4 deaths per 100,000 persons and is the lowest in white females at 2.3 deaths per 100,000 persons. The incidence of PE also is age-dependent, with increasing incidence of death with advancing age. From 1979 to 1998, accounting for both gender and race, age-specific mortality rates doubled for each 10-year age group after 15 to 24 years.

In recent decades, the overall mortality rate from PE has decreased dramatically. From 1998 to 2009, the annual in-hospital mortality decreased by approximately 30%. The decline has been observed across gender and ethnic groups and has been attributed to improved risk factor modification, including improved prophylaxis of DVT, better detection and treatment of DVT, and/or enhanced PE diagnostic techniques, which has led to a decrease in disease misclassification.

Risk Factors

The etiopathogenesis of VTE, which includes PE and DVT, is a dynamic process resulting from synergistic interaction between acquired and genetic risk factors. Historically, Rudolph Virchow is credited with describing the classic triad of vascular endothelial injury, hypercoagulability, and venous stasis as the combination of host factors that predispose to VTE. VTE risk factors traditionally are categorized as either genetic (inherited thrombophilia) or acquired.

Inherited Thrombophilia

Inherited thrombophilias may result from qualitative or quantitative defects in coagulation factor inhibitors (antithrombin, protein C, protein S), increased levels or function of coagulation factors (activated protein C resistance, factor V Leiden mutation, prothrombin gene mutation, elevated factor VIII levels), hyperhomocysteinemia, defects in fibrolysis, or altered platelet function. Epidemiologic features of the common inherited thrombophilias are shown in Table 57-1.

Table 57-1 Inherited Thrombophilias

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Antithrombin Deficiency

Formerly termed antithrombin III, antithrombin (AT) is a single-chain vitamin K–independent glycoprotein belonging to the serine protease inhibitor superfamily. AT functions as a natural anticoagulant by binding and inactivating thrombin and the activated coagulation factors IXa, Xa, XIa, and XIIa. The AT molecule also has an active heparin-binding site, which, when heparin-bound, has marked affinity and function for binding and inactivating coagulation factors such as thrombin. The augmentation of the inhibitory activity of AT by heparin is the basis for the clinical use of heparin therapy. Mutations in AT lead to decreased ability of the molecule to inhibit the coagulation cascade, thereby leading to increased risk for thrombosis. AT deficiency is inherited as an autosomal dominant trait affecting males and females equally. Most affected persons are heterozygotic for AT deficiency, because homozygotic inheritance typically is fetal-lethal. Heterozygote AT-deficient people have AT levels that are 40% to 70% of normal. Two different types of AT deficiency caused by more than 250 mutations have been described: Type I AT deficiency is characterized by a quantitative reduction in normally functioning AT. Type II AT deficiency is characterized by both quantitative and qualitative defects, with three different subtypes classified on the basis of the type of receptor defect: (1) abnormality of active thrombin binding site, (2) abnormality of heparin-binding site, and (3) abnormalities of both thrombin- and heparin-binding sites. These classification categories are clinically relevant in that defects in the active thrombin-binding site confer a higher risk for VTE than defects that involve only the heparin-binding site or that are strictly quantitative.

Despite a low prevalence, AT deficiency is considered the most severe inherited thrombophilia, with increased risk of thrombosis as much as 20-fold over that in the absence of such deficiency. In patients with AT deficiency, VTE typically develops during the latter part of the second or third decade of life. The most common sites of thrombosis include the lower extremity and iliofemoral veins. However, other sites including the upper extremities, mesenteric veins, vena cava, renal veins, and retinal veins have been reported. Thrombotic events in AT-deficient persons often are precipitated by acquired thrombophilic risk factors such as surgery, trauma, pregnancy, drugs, or infection. Approximately 60% of affected persons experience recurrent thrombotic events, and clinical signs of PE are evident in up to 40% of these patients.

The diagnosis of AT deficiency should be determined by a functional assay of heparin cofactor activity, which is able to detect all cases of AT deficiency of clinical relevance. AT levels usually are not influenced by warfarin therapy but can be decreased during the acute phase of a thrombotic event, in disseminated intravascular coagulation, or with the concomitant use of heparin. Heparin therapy can lower AT levels by as much as 30%. Screening for AT deficiency is recommended within at least 2 weeks of an acute thrombotic event or at least 5 days after discontinuation of heparin therapy.

Protein C Deficiency

Protein C is a vitamin K–dependent glycoprotein synthesized in the liver. Protein C is activated by the thrombin-thrombomodulin complex. Protein C circulates as an inactive precursor and exerts its anticoagulant function after activation to the serine protease, activated protein C. Once activated, protein C proteolytically degrades activated coagulation factors Va and VIIIa. More than 160 qualitative or quantitative mutations in protein C have been described. Protein C is inherited as an autosomal dominant trait affecting both males and females equally. Homozygous persons typically have more severe and earlier-onset thrombophilia.

Two different subtypes of inherited protein C deficiency have been identified. Type I deficiency is a quantitative disorder characterized by parallel reductions in functional and antigenic levels of protein C to 50% of normal levels. Type II deficiency is a qualitative defect with reductions in functional levels of protein C but preserved antigenic function.

The prevalence of protein C deficiency is estimated at 0.2% to 0.4% in the general population and 3% to 5% in people with VTE. Three clinical syndromes are associated with protein C deficiency: (1) VTE in teenagers and adults, (2) neonatal purpura fulminans in homozygous or doubly heterozygous newborns, or (3) warfarin-induced skin necrosis. Acquired protein C deficiency occurs in a variety of clinical settings, including liver disease, infection, septic shock, disseminated intravascular coagulation, acute respiratory distress syndrome, and postoperative states, and in association with chemotherapeutic drugs.

The diagnosis of protein C deficiency should be made by means of functional testing based on activation with thrombin-thrombomodulin or snake venom. Pregnancy and oral contraceptive use can increase plasma protein C levels. Protein C levels are decreased in acute thrombotic events and during therapy with warfarin. In the absence of warfarin therapy and known medical conditions that result in acquired protein C deficiency, patients with a protein C level less than 55% of normal are very likely to have a genetic abnormality, whereas levels from 55% to 65% normal are consistent with either a deficient state or low normal values. Thus, repeat testing and/or genetic testing is recommended in most populations.

Protein S Deficiency

Protein S is a vitamin K–dependent glycoprotein synthesized by hepatocytes, megakaryocytes, and endothelial cells. Protein S functions as a cofactor of activated protein C for the degradation of activated factors Va and VIIIa. Protein S circulates in plasma in equilibrium as a free functionally active form and an inactive form bound to a carrier protein (C4BP). The bioavailability of protein S is closely linked to the concentration of C4BP. C4BP functions as an important regulator in the protein C–protein S inhibitor pathway.

Three subtypes of protein S deficiency have been defined on the basis of total protein S concentrations, free protein S concentrations, and activated protein C cofactor activity. Type I protein S deficiency is associated with approximately 50% of normal protein S levels, more marked decrease in free protein S concentrations, and decreased functional activity. Type II deficiency is characterized by normal total and free protein S levels but decreased functional activity. Type III deficiency, also known as type IIa, is characterized by normal total protein levels but decreased free protein concentrations and decreased functional activity. Conditions that result in reductions in protein C levels, as mentioned in the preceding section, can similarly influence protein S levels. The prevalence of protein S deficiency is estimated to be 0.03% to 0.1% in the general population and 1% to 5% in patients with VTE. The clinical presentation of VTE in patients with protein S deficiency is similar to that in those with protein C deficiency. Warfarin-induced skin necrosis has been reported with protein S deficiency.

Measurement of the free protein S concentration is the preferred screening test for protein S deficiency. As with protein C, acute thrombosis, pregnancy, oral contraceptive use, comorbid disease, or use of warfarin can alter assay results. Heparin does not alter plasma protein S or protein C concentrations and thus is an acceptable antithrombotic agent for use during diagnostic workup. In patients on warfarin therapy, recommendations support waiting at least 2 weeks after discontinuation to investigate for suspected protein S deficiency.

Factor V Leiden and Activated Protein C Resistance

Factor V Leiden is the most common recognized cause of inherited thrombophilia, accounting for 20% to 50% of new VTE cases. Factor V circulates in the plasma as an inactive cofactor. After activation by thrombin, factor Va serves as a cofactor in the conversion of prothrombin to thrombin. In 1993, investigators in Leiden, The Netherlands, identified a single point mutation in the factor V gene in a cohort of patients with unexplained VTE. The molecular defect is a single amino acid change (arginine506 to glutamine) at one of the activated protein C (APC) cleavage sites, making the factor V molecule resistant to activated protein C at this site. The result of this genetic defect, termed factor V Leiden, is the most common cause of inherited APC resistance, although other mutations have been identified. Factor V Leiden is a common mutation. The prevalence of factor V Leiden in the general population is estimated at 5%. People who are heterozygous for the factor C Leiden mutation have approximately a five-fold increase in VTE risk over that in the general population. People who are homozygous for the mutation are estimated to have an 80-fold increase in VTE risk over that in the general population.

The major clinical manifestation of thrombosis in people with factor V Leiden is venous. Thrombosis in the deep veins of the lower extremities is common, whereas involvement of superficial, portal, and cerebral veins is less common. As might be expected with the high frequency of this mutation in the general population, a synergistic effect with other inherited or acquired VTE risk factors has been observed. In addition to inherited APC resistance, acquired APC resistance has been reported. Users of third-generation oral contraceptives, patients with malignancy, and persons with connective tissue disease—in particular, systemic lupus erythematosus and the antiphospholipid antibody syndrome—have APC resistance.

Activated partial thromboplastin time (aPTT)–based assays serve as the screening test for APC resistance. The aPTT is performed in the presence and then absence of a standardized amount of APC, and the two clotting times are expressed as an APC ratio (aPTT in the presence to aPTT in the absence of APC). APC resistance is associated with a reduced APC ratio. Results of the standard aPTT screening test may be influenced by a variety of factors, including inflammatory states, pregnancy, oral contraceptives, antiphospholipid antibodies, and anticoagulation. Genetic testing for the factor V Leiden mutation also is available.

Prothrombin Gene Mutation

Prothrombin (factor II), the precursor of thrombin, is a vitamin K–dependent protein synthesized in the liver. In 1996, researchers identified a single nucleotide change (guanine to adenine) at nucleotide position 20210 in the prothrombin gene as a risk factor for thrombosis. The prevalence of this mutation is 6% to 18% in people with VTE and 2% to 5% in the general population. Heterozygote carriers of this mutation have 30% higher plasma prothrombin levels than normal, which corresponds to a three-fold higher risk of thrombosis over that in the general population. In view of the relatively low thrombotic risk, controversy remains as to whether this mutation confers an increased risk for recurrent VTE. Studies have shown that the estimated risk of thrombosis associated with the prothrombin G20210A mutation is significantly increased only in those persons with additional thrombotic risk factors. Moreover, studies have demonstrated that the prothrombin G20210A mutation often is co-inherited with factor V Leiden mutation. Approximately 1% to 10% of symptomatic factor V Leiden carriers also have the prothrombin G20210A gene mutation. Diagnostic evaluation for the prothrombin G20210A gene mutation is best completed by direct genomic DNA analysis.

Elevated Factor VIII Levels

High levels of factor VIII are a strong independent risk factor for VTE. The prevalence of increased factor VIII levels in the general population is approximately 11%. In up to 25% of people presenting with VTE, factor VIII levels are higher than normal. Research has demonstrated that for each 10% increase in factor VIII levels, the risk of single-episode and recurrent VTE increases by 10% and 24%, respectively. Elevation in factor VIII level has been shown to remain an independent risk factor for VTE with institution of appropriate controls for inflammation, blood group antigens, and von Willebrand factor levels.

Hyperhomocysteinemia

Homocysteine is an intermediary amino acid formed by the conversion of methionine to cysteine. Hyperhomocysteinemia may result from either acquired or heritable factors. Homocysteine is metabolized by means of two pathways. The first involves the cystathionine B-synthase (CBS) enzyme and requires vitamin B6 as a cofactor. The second involves the enzyme methionine synthase and requires both vitamin B12 and methyltetrahydrofolate reductase (MTHFR). Acquired forms of hyperhomocysteinemia may result from dietary deficiencies in vitamin B12 or B6 or folate. Inherited forms may result from genetic defects in the CBS or MTHFR enzymes.

Evidence suggests that hyperhomocysteinemia is a risk factor for VTE. In people with homocysteine levels higher than two standard deviations above normal, the odds ratio for VTE is two to three times greater than in the control groups. Elevated homocysteine levels also have been associated with premature coronary artery disease and cerebrovascular disease, although debate regarding the strength of these associations continues.

Screening for hyperhomocysteinemia is suggested in patients with unexplained VTE. Sensitive laboratory assays are available for the quantification of total plasma homocysteine concentrations. If elevated plasma homocysteine levels are identified, additional laboratory evaluation may be warranted. Treatment varies with the underlying cause but typically involves supplementation with folate and vitamins B12 and B6.

Hypercoagulability Testing

Ongoing research continues to identify new and increasingly prevalent inherited thrombophilic defects in patients with VTE. Thus, which patients to screen, which tests to perform, and when to initiate hypercoagulability testing constitute important questions. Despite the high prevalence of inherited defects, only limited evidence or expert opinion indicates that the identification of an inherited thrombophilia influences either the duration of therapy or risk of recurrence. Arguments for screening acknowledge the increasing prevalence of identified inherited thrombophilias and, with the increase in the discovery of new mutations, the identification of persons with multiple prothrombotic defects. Multiple defects are now found in 1% to 2% of patients with initial-episode idiopathic VTE. Thus, the identification of patients with multiple defects may affect the risk of VTE recurrence, duration of anticoagulation therapy, and/or alteration of management when additional risk factors for the acquired form of VTE are present, such as surgery, pregnancy, or hormonal therapy. Arguments against screening cite the lack of available evidence supporting alteration in anticoagulation management in the presence of hereditary thrombophilia. The 2008 American College of Chest Physicians (ACCP) Antithrombotic and Thrombolytic Therapy Evidence-Based Clinical Practice Guidelines state that “the presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation in VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinates of risk of recurrence.” A 2009 Cochrane database study failed to identify a single randomized controlled trial evaluating the benefit of testing for inherited thrombophilia after VTE in relation to risk of recurrent VTE.

Given the lack of available evidence that testing and identifying inherited thrombophilia influences the duration of therapy, VTE outcomes from screening of asymptomatic relatives, or risk of recurrent VTE, current recommendations for screening are based primarily on clinical judgment and expert opinion. Key points to recognize regarding first-episode VTE are that (1) the strongest risk factor for recurrent VTE is a history of VTE—of particular importance if the first VTE event was idiopathic—and (2) all patients with VTE are at increased risk for recurrence for several years after the initial event. In view of current limitations in medical evidence regarding the impact of inherited thrombophilia with respect to duration of therapy and risk of recurrence, consultation with a hematologic expert is recommended regarding individual patient management decisions.

Screening for Inherited Thrombophilia

In general, the following patient groups may be considered for screening: (1) those with a first VTE before the age of 50 years without an identifiable risk factor such as recent surgery, (2) those with a history of recurrent VTE, and (3) those with a first-degree relative with recurrent VTE. All such patients should be considered “strongly thrombophilic” on the basis of thrombotic history and are appropriate candidates for hereditary thrombophilia testing. The standard testing approach to screening for inherited thrombophilias includes appropriate studies to detect activated protein C resistance/factor V Leiden mutation, prothrombin gene mutation, antiphospholipid antibodies, antithrombin deficiency, protein C deficiency, and protein S deficiency.

Several factors must be considered in decisions regarding screening for inherited thrombophilia in patients presenting with VTE. First, acute VTE can transiently reduce plasma levels of antithrombin, protein C, and protein S, resulting in erroneously low levels. Second, treatment with heparin can result in up to a 30% decrease in antithrombin levels over the first several days of therapy. Third, warfarin reduces the functional activity of protein C and protein S and can rarely elevate levels of antithrombin, potentially resulting in falsely normal levels of antithrombin in deficient patients. To sidestep the effects of therapy on measured levels, it is recommended to test for these defects at least 2 weeks after cessation of anticoagulation therapy. If levels are obtained at time of presentation and are within normal limits, then a deficiency generally is excluded. If levels are low at time of presentation, then repeat testing is recommended on cessation of initial therapy. Screening tests for factor V Leiden mutation, prothrombin gene mutation, anticardiolipin antibodies, or antiphospholipid antibodies are not affected by concurrent use of heparin or warfarin therapy. If an inherited thrombophilia is identified, it is recommended to screen all first-degree relatives of the patient.

Management of Inherited Thrombophilia

The initial management of VTE in patients with inherited thrombophilia does not differ from that in other patients. The long-term management of patients with VTE and inherited thrombophilia remains an area of question. Because no randomized controlled trials have evaluated the optimal duration of anticoagulation therapy in inherited thrombophilia, therapy must be tailored to the individual patient. General guidelines suggest indefinite anticoagulation in patients with a history of (1) a single episode of idiopathic VTE in the presence of more than one allelic abnormality (e.g., homozygosity for factor V Leiden, heterozygosity for factor V Leiden and prothrombin mutation), (2) one spontaneous life-threatening thrombosis such as near-fatal PE or cerebral, mesenteric, or portal vein thrombosis associated with a heritable risk factor, or (3) one episode of spontaneous thrombosis in association with antiphospholipid antibody syndrome or antithrombin deficiency. In patients with heterozygosity for inherited thrombophilia and a single episode of idiopathic VTE, the recommended duration of anticoagulation therapy remains in question. Expert consultation is advised to determine the optimum duration of anticoagulation.

Acquired Risk Factors

Acquired risk factors for VTE are far more prevalent than inherited thrombophilias. Box 57-1 lists common risk factors for acquired VTE.

Box 57-1

Acquired Risk Factors for Venous Thromboembolism

Age >40 years

Smoking

Obesity (body weight >120 kg)

Malignancy

Chemotherapy

Oral contraceptive use or hormone replacement therapy

Prolonged immobilization

Hospitalization
Prolonged air travel

Surgery/trauma

Acute inflammatory states

Acute infection
Inflammatory bowel disease
Connective tissuedisease

Intravascular devices

Pacemaker or implantable cardioverter-defibrillator leads
Indwelling venous catheters

Pregnancy/postpartum period

Atherosclerotic cardiovascular disease

Congestive heart failure

Cerebrovascular accident

Previous venous thromboembolism

Varicose veins/venous stasis

Acquired hypercoagulability

Nephrotic syndrome
Lupus anticoagulant
Antiphospholipid antibody syndrome
Hyperhomocysteinemia
Heparin-induced thrombocytopenia

Surgery and Trauma

The risk of VTE among surgical patients can be stratified by patient age, type of surgery, and comorbid conditions. The incidence of VTE in surgical patients is highest for those aged 65 years or older. High-risk procedures include orthopedic surgery; neurosurgery; thoracic, abdominal, or pelvic surgery for malignancy; renal transplantation; and cardiovascular surgery. The risks from surgery may be less with neuraxial anesthesia than with general anesthesia.

The association between trauma and VTE has long been recognized. As with surgical risks, the risk of VTE after trauma is related to predisposing host factors; the location, nature, and extent of injuries; and the use of prophylaxis. The risk of VTE in trauma victims is highest with advancing age. Injuries involving the lower extremities or pelvis confer the highest VTE risk. Other VTE risk factors associated with trauma include spinal cord injuries with paralysis, head injuries, vascular injuries, circulatory shock on hospital admission, requirement for mechanical ventilation for longer than 3 days, and the need for a major surgical procedure.

Age

The incidence of VTE increases significantly with advancing age for both idiopathic and secondary forms of the condition, suggesting that the biology of aging and not simply an increased accumulation of VTE risk factors may be involved. In one study, the annual incidence rates for VTE increased from 17 per 100,000 persons for patients 40 to 49 years of age to 232 per 100,000 persons for patients 70 to 79 years of age.

Pregnancy

Pregnancy is associated with increased risk for VTE as a consequence of the hypercoagulability associated with this condition, as well as the increased resistance to venous return by compression from the gravid uterus. VTE will develop in approximately 1 in 2000 women during pregnancy. Age-adjusted estimates of the risk of VTE range from 5 to 50 times higher in pregnant than in nonpregnant women. The risk in the postpartum period is approximately five times higher than during pregnancy. Previous superficial vein thrombosis is an independent risk factor for the occurrence of venous thrombosis during pregnancy and in the postpartum period.

Hormone Replacement Therapy

Hormone therapy is associated with a two- to four-fold increased risk of VTE. The risk of thrombosis increases within 4 months of the initiation of therapy and is unaffected by the duration of use. The VTE risk decreases to baseline levels within 3 months of discontinuation of hormone therapy. First- and third-generation oral contraceptives carry a higher risk for VTE than that reported with second-generation agents. Therapy with selective estrogen receptor modulators, including tamoxifen and raloxifene, has been associated with increased rates of VTE.

Cancer

Malignancy accounts for approximately 20% of cases of incident VTE in the community. Many primary malignancies are associated with VTE. Risk for VTE in patients with cancer seems highest among those with pancreatic cancer, lymphoma, malignant brain tumors, hepatocellular carcinoma, leukemia, colorectalcarcinoma, and other digestive cancers. Furthermore, the use of certain chemotherapy regimens in patients with cancer, including thalidomide, tamoxifen, and L-asparaginase, is associated with higher VTE risk.

Obesity

Emerging evidence supports obesity as an independent risk factor for VTE. The relative risk of VTE for obese people is greater in women than in men, with the greatest effect being noted before the age of 40 years. In addition to its role as an independent risk factor in the context of VTE, obesity is a common contributing factor for VTE occurring in people undergoing long-duration air travel and in women concomitantly taking oral contraceptives or hormone replacement agents.

Previous Venous Thromboembolism

Previous VTE is a major risk factor for recurrence. The magnitude of the risk depends on host factors. Persons with reversible risk factors such as immobility or surgery exhibit a lower rate of recurrence than that noted for those with nonmodifiable risk factors, such as malignancy or inherited thrombophilia.

Heparin-Induced Thrombocytopenia

Heparin-induced thrombocytopenia (HIT) is a life-threatening disorder that follows exposure to unfractionated (UF) or, less commonly, low-molecular-weight heparin (LMWH). HIT classically manifests with a low platelet count (less than 150,000/μL) or a relative decrease in platelet count by 50% from baseline typically within 5 to 10 days of the initiation of heparin or LMWH therapy. The incidence of HIT among patients treated with UF heparin is 10 times higher than among those receiving LMWH. In patients with HIT, the risk of thrombosis is more than 30 times that in the control population. The risk of thrombosis remains high for days to weeks after discontinuation of heparin, even after the platelet counts return to normal.

HIT is caused by antibodies against complexes of platelet factor 4 (PF4) and heparin. The heparin-PF4–antibody complex binds to the platelet surface, where it is recognized by circulating IgA, IgG, and IgM antibodies. Immunoglobulin recognition leads to further platelet activation and release of PF4, thus creating a positive feedback loop. The activated platelets aggregate, resulting in thrombocytopenia and thrombosis. Early-onset HIT, defined as that with onset within hours after initiation of heparin therapy, may be seen in approximately 30% of patients with persistent antibodies to heparin if such therapy is given within the previous 3 months. Diagnosis of HIT is based on recognition of the clinical syndrome and specific serologic testing. Serologic assays can detect circulating IgG, IgA, and IgM heparin-dependent antibodies with high sensitivity (97%) but modest specificity (74% to 86%). Therefore, positive results on serologic assays must be confirmed by more specific tests, including serotonin release assays, heparin-induced platelet aggregation assays, or solid phase immunoassays.

The first intervention in a patient with suspected HIT is immediate cessation of all exposure to heparin, including heparin-bonded catheters and heparin flushes. LMWH should be avoided, because it may cross-react with heparin-induced antibodies. In addition to heparin cessation, patients with suspected HIT should be started on alternative anticoagulation because of high risk of thrombosis. In patients with suspected HIT and/or the need for alternative anticoagulation, direct thrombin inhibitors such as lepirudin or argatroban may be used. The duration of alternative anticoagulant therapy and the subsequent use of oral anticoagulants will depend on whether the patient has had a thrombotic event or requires continued anticoagulation. For patients with HIT without evidence of thrombus, therapeutic doses of alternative anticoagulation should be continued until the platelet counts return to normal. Consideration should be given to continuing anticoagulation therapy with alternative anticoagulation or warfarin for 2 to 4 weeks after the diagnosis of HIT, because of persistent high risks of thrombosis over this period. For a patient with HIT and thrombosis, therapeutic doses of alternative anticoagulation should be continued until the platelet count has normalized; then the patient should be transferred to warfarin therapy with at least a 5-day overlap until the international normalized ratio (INR) is in the therapeutic range for at least 48 hours. Skin necrosis and warfarin-induced venous gangrene of the limbs have been reported during shorter periods of overlap or shorter duration of therapeutic INR.

Pathogenesis

Between 60% and 90% of pulmonary emboli arise from the deep veins of the lower extremity and pelvis. Other sources of thrombi include the renal veins, upper extremities, or right side of the heart. Iliofemoral thrombi are the most frequently clinically recognized causes of PE. Thrombi dislodge and embolize to the pulmonary arteries, where they cause hemodynamic abnormalities and impair gas exchange. The hemodynamic response to PE is determined by the embolic burden in association with the host’s hemodynamic reserve and compensatory adaptive response. After traveling through the right heart, large thrombi may lodge and obstruct the main pulmonary arteries or travel distally within the pulmonary vascular tree, leading to hemodynamic alterations. In addition to the physical obstruction to flow, acute PE triggers the release of vasoactive substances, resulting in further increase in pulmonary vascular resistance and right ventricular afterload. Because right ventricular afterload increases, increased right ventricular wall tension may lead to right ventricular dilatation and hypokinesis with further right ventricular dysfunction, tricuspid regurgitation, and right ventricular failure. Right ventricular pressure overload can lead to flattening or bowing of the interventricular septum toward the left ventricle with resulting impairment of left ventricular filling, systemic arterial hypotension, and cardiac arrest. Increased right ventricular wall stress caused by right ventricular pressure overload may also lead to right-sided stress-induced ischemia.

Impaired gas exchange may result from impaired ventilation-perfusion matching, increased alveolar dead space, or right-to-left shunting through a patent foramen ovale. Stimulation of pulmonary irritant receptors results in hyperventilation, contributing to the observed hypocapnia and respiratory alkalosis. The presence of hypercapnia in acute PE suggests a large amount of physiologic dead space and impaired minute ventilation, which can result from massive PE.

Clinical Features

The clinical consequences of PE range from incidental and clinically unimportant to circulatory collapse and sudden death. Equally challenging, the clinical signs and symptoms related to PE are diverse and nonspecific. Therefore, clinicians use a combination of history and examination findings in association with clinical prediction tools to determine appropriate diagnostic tests and the need for therapeutic interventions. Considerations in the differential diagnosis for acute PE are listed in Box 57-2.

Box 57-2

Differential Diagnosis for Acute Pulmonary Embolism

Pneumonia or bronchitis

Asthma or exacerbation of chronic obstructive lung disease

Pleuritis

Pericarditis/cardiac tamponade

Pneumothorax

Musculoskeletal pain

Costochondritis

Rib fracture

Pulmonary edema/congestive heart failure

Thoracic malignancy

Pulmonary hypertension

Myocardial infarction

Aortic dissection

Anxiety

Medical History

Patients with PE often have one or more identifiable risk factors for the development of VTE at the time of clinical presentation (see earlier, under “Risk Factors”). Details should be sought regarding the patient’s personal and family history of prior VTE, coexisting medical conditions, functional status, travel history, and current medications. Major risk factors for VTE include surgery or trauma within the preceding 30 days, prolonged immobility, advanced age, malignancy, previous VTE, known thrombophilia, recent myocardial infarction or stroke (cerebrovascular accident), or indwelling venous catheter. Moderate risk factors include obesity, use of estrogen or hormone replacement therapy, and family history of VTE. Scoring systems such as the Wells score and the Geneva score have been devised to help assess the patient’s probability of being diagnosed with a PE (see under “Diagnosis” later in the chapter).

Symptoms and Signs

Acute PE embolism may manifest with a wide spectrum of signs and symptoms. The most common symptom in angiographically confirmed acute PE is dyspnea (Table 57-2). Less frequently, patients with acute PE present with hemoptysis, wheezing, or chest pain. Frequent findings on physical examination include tachypnea (respiratory rate greater than 20 breaths/minute), tachycardia (heart rate greater than 100 beats/minute), and crackles on lung auscultation (see Table 57-2). The presence of syncope, cyanosis, jugular venous distention, pulsatile liver, or parasternal heave or auscultation of an accentuated pulmonic component of the second heart sound, right-sided third heart sound, and/or an audible systolic murmur at the left sternal border may reflect significant right ventricular dysfunction.

Table 57-2 Frequency of Signs and Symptoms in Acute Pulmonary Embolism

Manifestation Frequency (%)
Symptoms  
Dyspnea 73
Pleuritic chest pain 66
Cough 37
Leg swelling 33
Hemoptysis 13
Wheezing 9
Chest pain 4
Signs  
Respiratory rate ≥20 breaths/min 70
Crackles 51
Heart rate ≥100 beats/min 30
Third or fourth heart sound 26
Loud pulmonary component of second heart sound 23
Temperature >38.5° C 7
Pleural rub 3

Data from Stein PD, Terrin ML, Hales CA, et al: Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease, Chest 100:598–603, 1991.

Laboratory Tests

Standard laboratory tests do not significantly contribute to the evaluation of patients with suspected PE. Routine laboratory findings such as increased erythrocyte sedimentation rate and/or leukocytosis are nonspecific. Common laboratory tests performed as part of the evaluation for PE include arterial blood gas analysis and D-dimer, B-type natriuretic peptide (BNP), and troponin assays. Both troponin and BNP measurements have been suggested as prognostic indicators, differentiating between low risk and intermediate risk for PE-related complications, including hemodynamic collapse and death. Elevated levels of BNP and troponin have yet to become incorporated into formal PE guidelines for risk stratification and treatment, although this change is likely in the future. Normal levels of BNP and troponin have high negative predictive values that identify patients at low risk for adverse outcome related to PE. Alternatively, in hemodynamically stable patients with acute PE and elevated BNP and/or troponin levels, echocardiography is indicated to assess for right ventricular dysfunction, which is likely under these circumstances. Because of the short half-life of these markers and the characteristic delay between the acute event and their release into the circulation, if the duration of symptoms is less than 6 hours, a second laboratory measurement of both BNP and troponin levels is clinically warranted.

Arterial Blood Gas Analysis

Arterial blood gas analysis cannot accurately be used as a diagnostic tool to discriminate between patients with and without PE. Typically, patients with acute PE present with hypocapnia and respiratory alkalosis. The partial pressure of oxygen (PO2) may be increased, decreased, or normal in patients with PE. The alveolar-arterial oxygen gradient, PO2(A−a), typically is increased; however, this finding also lacks sufficient discriminatory characteristics to be useful as a screening test. Thus, a normal PO2 and PO2(A−a) do not obviate the need for further diagnostic investigation in patients with clinical findings suggestive of disease.

D-Dimer Assay

D-dimer is a plasmin-derived fibrin degradation product most commonly measured by a quantitative enzyme-linked immunosorbent assay (ELISA). D-dimer testing is characterized as highly sensitive with a high negative predictive value useful in the exclusion of VTE, particularly in the outpatient or emergency department setting. With most assays, a level higher than 500 ng/mL is considered abnormal. Used in combination with a low clinical probability of disease, a negative result on D-dimer assay (value lower than 500 ng/mL) has a 99% negative predictive value for PE. D-dimer assays lack specificity (30% to 75%). Elevated D-dimer levels are observed in persons with inflammatory states, infection, acute coronary syndromes, or malignancy or patients who have undergone recent surgery. Current evidence supports that a quantitative D-dimer level lower than 500 ng/mL measured by ELISA can exclude the diagnosis of VTE in patient with low/intermediate pretest probability of disease. At present, D-dimer testing should not be used as the sole modality to rule out VTE in patients with high pretest probability for disease. Clinicians should note that D-dimer assays vary in their sensitivities and specificities. Thus, it is important to be aware of the assay used for appropriate interpretation of results.

B-Type Natriuretic Peptide Assay

BNP is a hormone released by ventricular myocardial cells in response to volume overload and wall stretch. Because of its lack of sensitivity and specificity, BNP is not a useful diagnostic test for PE. In the absence of right ventricular dysfunction, BNP levels are typically normal in the setting of acute PE. However, increased levels of BNP seem to have prognostic significance in people with PE.

Elevation of BNP levels (to greater than 90 pg/mL) obtained within 4 hours of admission have a sensitivity of 85% and specificity of 75% for predicting PE-related clinical outcomes such as death, need for emergent thrombolysis, cardiopulmonary resuscitation, mechanical ventilation, vasopressor therapy, or emergency surgical embolectomy. Normal BNP values in the setting of acute PE have a 97% to 100% negative predictive value for in-hospital death.

Troponin Assay

Cardiac troponins are sensitive and specific markers of myocardial cell damage. Troponin elevation in acute PE is presumed to be related to acute right-sided heart strain with resulting myocyte ischemia and microinfarction. Troponin I and troponin T levels are elevated in 30% to 50% of people with large PE. However, these elevations are mild and short-lived compared with those observed in acute coronary syndromes. Like BNP, troponin levels correlate with right-sided heart dysfunction in acute PE. Normal troponin T values in the setting of acute PE have a 97% to 100% negative predictive value for in-hospital death.

Diagnosis

The diagnosis of pulmonary embolic disease can present a significant challenge. Typical presenting clinical signs of dyspnea and chest pain are nonspecific and can be confused as manifestations of other serious disease states such as acute myocardial infarction or pneumonia. Many patients with thromboembolic disease present with atypical symptoms, and the diagnosis of PE becomes even more difficult when comorbid conditions such as congestive heart failure (CHF) or chronic obstructive pulmonary disease (COPD) could otherwise explain their presenting complaints. Because of the high prevalence of VTE and the potentially serious consequences of misdiagnosis, it is essential to maintain a high degree of clinical suspicion for the possibility of PE.

Clinical Assessment

Typical clinical features of PE have already been described; here, it is important to stress that clinical judgment is an essential initial step in the evaluation of thromboembolic disease and figures prominently in diagnostic algorithms. The importance of the clinician’s assessment of the probability of PE initially was highlighted in the 1990 landmark Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study. Physicians in this study were asked to record their clinical impression (high, intermediate, or low probability) as to the likelihood of PE in patients they were treating before learning the results of the radiographic study (ventilation-perfusion scan or pulmonary arteriogram). The clinical impression was based on an agreed-on set of data but without standardized diagnostic algorithms. One very important finding of the PIOPED study was that diagnosis or exclusion of PE was possible only with clear and concordant clinical and radiographic findings. If the clinical impression did not match the findings on imaging (ventilation-perfusion scan in this study), pulmonary thromboembolic disease could not be confirmed or ruled out by that imaging study, and further investigation was necessary. Since the publication of PIOPED, numerous attempts have been made to standardize the definition of “clinical impression.” This has resulted in a variety of scoring systems, assigning points to historical, physical, and laboratory features of an individual patient. Patients receive scores on the basis of inherent risk factors and presenting signs that are then used to predict likelihood of disease. Currently, the two most commonly used scoring systems are the Wells criteria and the Geneva score (Table 57-3). These two scoring systems and subsequent modifications have been validated in a number of studies. By themselves, scoring systems lack adequate sensitivity or specificity to diagnose or exclude disease. Their true usefulness comes in conjunction with other laboratory or imaging studies, allowing the assessment of disease risk.

Table 57-3 Wells and Geneva Scoring Systems Used in Risk Assessment for the Diagnosis of Pulmonary Embolism (PE)*

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Electrocardiograms and Chest Radiographs

Electrocardiograms (ECG) and chest radiographs frequently are used in the evaluation of patients initially seen with dyspnea or chest pain. Although these studies are neither adequately sensitive nor specific to diagnose or exclude PE, they can suggest the diagnosis. ECG findings such as T wave inversions in the anterior leads, in particular V1 to V4, are typical of right ventricular strain and should raise suspicion for pulmonary thromboembolic disease (Figure 57-1). Other typical ECG changes include a deep S wave in lead I, a Q wave in lead III, and T wave inversions in lead III. Rhythm and conduction abnormalities such as new-onset atrial fibrillation or right bundle branch block occasionally are noted in association with acute PE.

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Figure 57-1 Electrocardiogram (ECG) in a patient with right ventricular (RV) strain secondary to thromboembolic disease. Note the right axis deviation, deep S wave in lead I, inverted T wave in lead III, and RV strain pattern in leads V1 to V4. The patient was diagnosed with chronic thromboembolic pulmonary hypertension secondary to multiple pulmonary emboli (PEs).

In the evaluation for PE, chest radiographs predominantly serve to exclude other potential explanations for the patient’s symptoms (e.g., a lobar infiltrate consistent with pneumonia). Occasionally, the chest radiograph will demonstrate changes suggestive of PE, such as focal oligemia (Westermark sign), a peripheral wedge-shaped density that indicates infarct (Hampton hump) (Figure 57-2), or an enlarged right descending pulmonary artery (Palla sign).

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Figure 57-2 Chest radiographs showing a wedge-shaped pulmonary infarct (Hampton hump) secondary to a pulmonary embolism. The infarct is located in the anterior segment of the right middle lobe (arrows on both left and right images).

D-Dimer Assay

Measurement of plasma D-dimer levels in peripheral blood has become an important screening tool to help exclude the presence of VTE. Plasma D-dimer is a degradation product of cross-linked fibrin. After a thrombotic event, endogenous fibrinolysis results in clot dissolution and a measurable increase in plasma D-dimer levels. An elevated D-dimer, however, is not specific for the presence of VTE. Numerous other conditions (e.g., trauma, inflammation, surgery) can raise plasma D-dimer levels; therefore, an abnormal laboratory result has a low positive predictive value for VTE.

Laboratory tests to measure D-dimer levels in peripheral blood have been available since the mid-1980s, but their acceptance as an early screening tool in the evaluation of VTE is relatively recent. Contributing to the initial confusion regarding the usefulness of D-dimer in the assessment of VTE was the presence of significant variability among the various D-dimer assays (ELISA, quantitative latex agglutination, semiquantitative agglutination latex, and whole blood agglutination assays) in both sensitivity and specificity. ELISAs have the highest sensitivity and are therefore superior in their ability to exclude the diagnosis of VTE. Numerous studies have validated the usefulness of D-dimer assays in the evaluation for this entity. A D-dimer ELISA level of less than 500 ng/mL is strong evidence against PE in patients with a low or intermediate clinical probability score. Van Belle and colleagues, reporting for the Christopher Study investigators, demonstrated that the incidence of PE was only 0.5% at 3 months in patients with a low clinical probability score (determined using a modified version of the Wells criteria) and a D-dimer plasma level of 500 ng/mL or less. Other VTE outcome studies have demonstrated similar results, showing the D-dimer assay to have a sensitivity of between 92% and 99% for the diagnosis of VTE. As previously noted, however, the specificity for this study has been reported to be as low as 25%.

Venous Compression Ultrasonography

Ultrasound evaluation of the deep venous system to search for thrombosis frequently is used to assist with the diagnosis of PE. This approach is pragmatic, because the treatments for both DVT and PE are similar, and the first disease process begets the second. Ultrasound imaging frequently is used when the initial tests for PE are nondiagnostic. A positive ultrasound test result confirms the need for anticoagulation and obviates the need for further diagnostic studies. A negative result, however, is more difficult to interpret and requires consideration of certain caveats in considering a treatment plan. In the presence of acute PE, DVT is detectable by compression ultrasound studies in only approximately 50% of cases (50% sensitivity). In patients with nondiagnostic chest imaging studies, compression ultrasound imaging of the proximal vein detects DVT in approximately 5% of cases. Normal findings on bilateral proximal venous ultrasound studies, therefore, do not rule out PE in patients with nondiagnostic lung scans. However, they do imply a reduced probability of this event (negative likelihood ratio of approximately 0.7). Negative results on ultrasound imaging therefore imply a lower short-term risk for development of thromboembolic disease or for a fatal thromboembolic event if anticoagulant therapy is withheld. Some studies have recommended a follow-up serial ultrasound study when anticoagulation therapy is withheld on the basis of initially negative ultrasound findings. These studies, examining a variety of time frames (2 days to 2 weeks), have reported that approximately 2% of patients with an initially negative venous ultrasound will be diagnosed with a DVT by serial testing. If ultrasound imaging continues to yield negative findings during serial examinations, the risk of subsequent symptomatic VTE is low, similar to that observed after a normal-appearing pulmonary angiogram (1% incidence at 6 months).

Contrast Venography

Venography was for many years the only reliable technique to confirm or exclude the possibility of a DVT but is now only of historical interest. Compression ultrasonography has all but replaced this more invasive approach for assessment of suspected DVT. Venography has a reported sensitivity ranging from 70% to 100% and specificity of 60% to 88% for the diagnosis of DVT. Potential complications of contrast venography include nephrotoxicity (secondary to contrast dye), bleeding complications from the venous puncture, and postprocedure phlebitis.

Ventilation-Perfusion Lung Scan

For many years, the ventilation-perfusion lung scan was considered the imaging study of choice to evaluate for PE (Figure 57-3). Recently, computed tomography angiography (CTA) has replaced the ventilation-perfusion lung scan as the predominant diagnostic test. However, the ventilation-perfusion scan maintains an important place in the evaluation of patients for thromboembolic disease who have contraindications to CTA such as renal insufficiency or contrast allergy. As mentioned previously, the PIOPED study correlated the clinical probability of a PE (high, intermediate, or low probability as assessed by history and clinical findings) with the interpretation of the ventilation-perfusion scan (high, intermediate, or low probability or normal perfusion). With concordance of the clinical assessment and the interpretation of the V/Q scan in the high or low probability range, PE can be diagnosed or excluded with reasonable certainty. When the clinical assessment and the interpretation of the ventilation-perfusion scan are discordant (i.e., high clinical probability but low-probability ventilation-perfusion scan, or vice versa), the possibility of PE cannot be adequately assessed, and other studies are required. A normal-appearing ventilation-perfusion scan (with a normal perfusion component) essentially excludes the diagnosis of PE.

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Figure 57-3 Ventilation-perfusion lung scan. Ventilation images are above their respective perfusion images. Significant heterogeneity is observed between the ventilation and perfusion images, with multiple unmatched defects in the perfusion images, consistent with thromboembolic disease.

Echocardiogram

Transthoracic and transesophageal echocardiography have limited use in the diagnosis of PE. The sensitivity and specificity of these tests are inadequate for diagnosis, because the offending emboli are rarely proximal enough to be visualized. Echocardiography can assist in acute care management decisions for those patients too unstable to be moved from a critical care setting for more definitive imaging studies. Although it is rare to visualize a thrombus within the pulmonary arteries by echocardiogram, changes in right ventricular size and function and increases in tricuspid regurgitation imply acute right heart strain. In the appropriate clinical scenario, these changes in the right ventricle can suggest the diagnosis of acute PE (Figure 57-4).

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Figure 57-4 Echocardiogram of a patient with markedly dilated right ventricle (RV) and right atrium (RA) secondary to pulmonary thromboembolic disease. The interventricular septum is bowing into and compressing the left ventricle (LV).

A more important role of echocardiography in the evaluation of patients with PE is that of risk stratification. Multiple studies have demonstrated that patients in whom right ventricular dysfunction develops in association with an acute PE have increased mortality compared with those with preserved right ventricular function. This observation is not surprising, because worsening right ventricular function relates directly to the degree the pulmonary vascular bed is affected by the thrombus and, therefore, the size of the embolic event. Some investigators have suggested that more aggressive therapy, such as thrombolysis, is indicated in patients with right ventricular dysfunction. This issue is discussed further in the section on treatment of PE.

Computed Tomography Angiography

CT pulmonary angiography (i.e., CTA) has become a favored study for the evaluation of PE over the past decade (Figure 57-5, B). CTA provides a number of potential advantages over other imaging modalities in the diagnosis of PE, including (1) direct visualization of the embolus, (2) the ability to assess for other potential causes for the patient’s complaints such as pneumonia, and (3) imaging algorithms that scan through the pelvis and lower extremities, as well as the chest, allowing simultaneous evaluation for PE and for DVT. The ability to evaluate for other thoracic disease is of no small consequence, because up to two thirds of patients initially suspected to have PE eventually receive another diagnosis for their symptoms. Many of these subsequently diagnosed disorders (i.e., pneumonia, thoracic aorta dissection, pneumothorax) are associated with lung changes that can be visualized on CT scan. The interobserver agreement for CT is better than that for ventilation-perfusion scan. The initial hardware used for assessment of PE was single-detector scanners that provided high specificity for the diagnosis of PE (greater than 90%), but their sensitivity was unacceptable (approximately 72%) for the exclusion of this potentially life-threatening diagnosis. Multidetector (40-, 64-, and 96-slice) scanners in current use, however, have significantly improved the sensitivity and specificity of CTA for the diagnosis of PE. The very high spatial resolution of these studies allows rapid evaluation of pulmonary vessels down to the sixth-order branches during a single breath hold, with consequent increased detection rate for segmental and subsegmental PEs.

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Figure 57-5 Pulmonary imaging for embolism. A, Pulmonary angiogram showing a filling defect in the right lower lobe pulmonary artery. B, A spiral (helical) computed tomography angiogram, obtained in another case, showing multiple filling defects (arrows).

A number of outcome studies have demonstrated that a technically adequate negative multidetector CTA study is sufficient to exclude PE (sensitivity and specificity greater than 95%). The Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) study initially raised some questions regarding the positive and negative predictive power of these studies. The investigators of PIOPED II sought to establish the sensitivity and specificity of multidetector CT scanners in the diagnosis of PE in the same fashion as that used by the original PIOPED for evaluation of ventilation-perfusion scans. These workers undertook a multicenter, prospective study assessing the accuracy of multidetector CTA alone and also of CTA combined with computed tomography venography (CTV) to include venous phase imaging (i.e., CTA-CTV) for the diagnosis of acute PE. However, in contrast with the original PIOPED study, which used pulmonary angiography as the reference test to which ventilation-perfusion lung scan was compared, PIOPED II used a composite reference test for VTE that was based on the ventilation-perfusion lung scan, venous compression ultrasound imaging of the lower extremities, and digital subtraction pulmonary angiography (performed in only a minority of cases). They reported the specificity of CTA for the diagnosis of PE to be 96%, but with a sensitivity of only 83%. Venous scanning of the pelvis and lower extremities improved the sensitivity of the study. The sensitivity of CTA-CTV for the diagnosis of PE was 90%, with a specificity of 95%.

PIOPED II also attempted to associate clinical probability with imaging studies to assess positive and negative predictive values. The results were reminiscent of the original PIOPED study in that the positive predictive value of the CT studies was 96% with a concordantly high or low clinical probability, 92% with an intermediate clinical probability, and nondiagnostic with a discordant clinical probability. As discussed earlier, however, a number of large outcome studies demonstrated the efficacy of CTA in the evaluation of PE and the safety of withholding anticoagulation in patients with negative CTA findings. CTA now plays the predominant role in diagnostic algorithms for the evaluation of PE (Figure 57-6).

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Figure 57-6 Diagnostic algorithm for evaluation of pulmonary embolism (PE). CTA (or CTA-CTV) is becoming the initial imaging study of choice. Ultrasound imaging and ventilation-perfusion (V/Q) scan can be used in patients in whom CTA is contraindicated (e.g., renal insufficiency) or when additional studies are needed to assist with the diagnosis. CTA, computed tomography angiography; CTV, computed tomography venography; ELISA, enzyme-linked immunosorbent assay; VTE, venous thromboembolism.

Pulmonary Arteriography

Pulmonary angiography or digital subtraction angiography (DSA) previously had been the “gold standard” modality for the diagnosis of PE (see Figure 57-5, A). Because of its invasive nature, it also is associated with the most inherent risk. Arrhythmias, hypotension, bleeding, and nephrotoxicity from contrast dye are potential complications. The mortality rate associated with pulmonary angiography has been estimated at 0.5%, with major nonfatal adverse events occurring with a frequency of 1%. Angiography also is more expensive than the noninvasive means of evaluating for PE and not always immediately available. As other imaging modalities, such as CTA, have gained popularity in the assessment of PE, angiography has become less used, so less experience with its application has been accrued. Approximately 1% of patients with a normal-appearing pulmonary angiogram will be diagnosed with a VTE at 6 months, implying that the result on angiography was falsely negative. Although large, segmental embolic events are readily appreciated, interobserver variability can be significant in evaluating smaller subsegmental emboli. The main role for DSA at present is for the evaluation of patients with chronic thromboembolic disease being considered for pulmonary endarterectomy (PEA) to assess surgical resectability.

Magnetic Resonance Imaging

Magnetic resonance angiography (MRA) and venography (MRV) were recently evaluated as diagnostic tests for VTE. The multicenter Prospective Investigation of Pulmonary Embolic Disease III (PIOPED III) study evaluated the sensitivity and specificity of MRA and then MRA in combination with MRV (i.e., MRA-MRV) in the assessment of PE. As in PIOPED II, the results were compared with a composite reference standard that included CTA and CTV, ventilation-perfusion scan, venous ultrasonography, D-dimer assay, and clinical assessment. MRA and MRA-MRV fared poorly in the diagnosis of PE. Of interest, the MRA study was technically inadequate in 25% of the 371 patients enrolled. When all enrolled patients were considered, MRA identified only 57% of patients with PE. If only patients with technically adequate studies were considered, the sensitivity of MRA for the diagnosis of PE was 78% and the specificity was 99%. In patients with a technically adequate MRA-MRV study, the sensitivity was 92% and the specificity was 96%; however, in only 52% of patients were both studies technically adequate. These poor results stem from the difficulty of capturing adequate images of the chest vasculature due to motion artifact as well as the difficulty of identifying abrupt termination of contrast in a vessel by MRA. With current MRA technology, the pulmonary vessel without contrast is lost in the background of the lung. In CTA, the same vessel remains visible making a cutoff from PE easier to visualize. The investigators recommended that MRA for evaluation of PE be done only in centers with significant experience in the performance of this study, and only when other tests for the evaluation of PE are contraindicated. Even in with these caveats, however, it is difficult to conceive of many clinical scenarios in which MRA-MRV would be used in the evaluation of PE.

Treatment

The basic approach to treatment of PE has not changed appreciably over the past half-century. More recently, however, refinements in recommendations regarding duration of therapy have evolved. In addition, some exciting recent additions of medications for anticoagulation are likely to alter selection and duration of therapy in the near future. The possibility of placement of mechanical barriers to prevent further embolization to the pulmonary vasculature also is now readily available, although data on the appropriate use of these devices are lacking. Thrombolysis remains an option for rapidly dissolving the offending thrombus but is associated with a higher incidence of bleeding complications. The discussion regarding treatment of PE can be divided into two distinct entities: (1) treatment for the acute event and (2) secondary prophylaxis against recurrent VTE.

Treatment of Acute Pulmonary Embolism

Anticoagulation

Heparin and Vitamin K Antagonists

The goal of the initial treatment of PE is to obtain adequate, rapid anticoagulation while minimizing bleeding complications. For many years the consensus has been that the initial treatment of acute nonmassive PE should include heparin for a period of at least 5 days overlapping with the initiation of a vitamin K antagonist (VKA). The VKA should be started on the first day of treatment if possible, but recommendations for 5 days of heparin therapy hold even if the desired level of VKA anticoagulation is achieved earlier. This recommendation stems from studies in patients with DVT that demonstrated a higher incidence of recurrence if heparin therapy was truncated.

The goal of therapy with use of UF heparin is an aPTT between 1.5 and 2.0 times the control level. An important development in the use of UF heparin in the treatment of VTE was the implementation of weight-based dosing to rapidly obtain appropriate levels of anticoagulation. This recommendation stemmed from the frequent observation of recurrent thromboembolism in subtherapeutic heparin dosing. UF heparin was the treatment of choice for initial therapy of VTE for decades. More recently, however, LMWH has replaced UF heparin for first-line therapy in most cases. LMWH has better bioavailability and a longer half-life than UF heparin. These features permit once- or twice-daily subcutaneous dosing without the need for coagulation monitoring in appropriate clinical populations (i.e., normal renal function). The ability to obtain a predictable and reliable level of anticoagulation through a subcutaneous route then allows for the possibility of outpatient therapy, significantly decreasing health care costs and increasing patient satisfaction. LMWH was first demonstrated efficacious in the treatment of DVT. In addition, the use of LMWH for at-home therapy of DVT was quickly shown to be both safe and effective. Its use has more recently been studied for initial treatment of acute submassive PE, for which it also was found to be efficacious and safe. These trials showed no difference in morbidity or mortality in patients treated with LMWH versus those treated with UF heparin. A small number of patients in these studies were treated at home or were allowed to go home early receiving subcutaneous LMWH. No difference in outcome was observed in the at-home population. Treatment with LMWH is less commonly associated with HIT than is UF heparin. Although heparin and VKA have played a central role in the treatment of VTE for years, innovations in other medications altering the coagulation cascade are advancing rapidly. Perhaps the most exciting therapeutic advances in the treatment of VTE involve the orally available direct factor Xa inhibitors.

Factor Xa inhibitors

Factor Xa is strategically positioned at the juncture of the intrinsic and extrinsic coagulation pathways proximal to thrombin. The new oral factor Xa inhibitors have excellent bioavailability and induce rapid, predictable systemic anticoagulation. A recent study comparing 3, 6, or 12 months of the oral Xa inhibitor rivaroxaban against 5 days of subcutaneous enoxaparin followed by 3, 6, or 12 months of an oral vitamin K antagonist demonstrated no significant differences in the primary end point of recurrent VTE (noninferiority). No differences were observed in the incidence of significant bleeding between groups. The investigators simultaneously reported the outcomes of a long-term continuation study in which patients with VTE (DVT or PE) who had already been treated with 6 to 12 months of oral vitamin K antagonists were then randomized to either an additional 6 to 12 months of oral rivaroxaban versus placebo. A significant decrease in the primary end point of recurrent VTE was noted in the patients treated with the oral Xa inhibitor. No statistically significant difference in bleeding events between groups was observed.

These medications have the potential to significantly alter the management of VTE. Their excellent bioavailability, rapid onset, predictable effect, and ease of use will greatly facilitate outpatient therapy. Close monitoring of coagulation levels, as is required with the vitamin K antagonists, is unnecessary, and the risk of over- or underanticoagulation is negligible. In the absence of unforeseen complications, use of these medications may be expected to rapidly become the standard of care in the management of VTE. One potential complicating factor regarding the use of the Xa inhibitors is the lack of a specific antidote for rapid reversal of anticoagulation. Rivaroxaban is cleared both hepatically and through the kidney, and unlike VKAs, it does not interact with food and has few drug-drug interactions. A third study by the same investigators comparing oral rivaroxaban to 5 days of subcutaneous enoxaparin and then 6 to 12 months of an oral vitamin K antagonist in patients with acute PE also demonstrated non-inferiority.

The subcutaneously administered Xa inhibitor fondaparinux also has been demonstrated to be efficacious in the treatment of VTE. Fondaparinux has a relatively long half-life (17 hours) and can be administered once daily. Another factor Xa inhibitor, idraparinux, also is being evaluated in the treatment of VTE. This agent has an even longer half-life (80 hours) than fondaparinux and could thus be administered on a weekly basis. Both fondaparinux and idraparinux are cleared by the kidney and must therefore be used with caution in patients with renal insufficiency.

Direct Thrombin Inhibitors

The direct thrombin inhibitors include hirudin, argatroban, and bivalirudin. Their potential advantage over heparin includes their ability to inactivate clot-bound thrombin and their resistance to circulating inhibitors released by activated platelets including PF4 and heparinase. Of importance, these agents do not cause HIT and are approved for the treatment of this dangerous condition, which is currently their primary role in the treatment of VTE.

Thrombolytics

For many years, significant interest has focused on the use of thrombolytic agents to rapidly dissolve pulmonary emboli in hopes of improving clinical outcomes. These agents have been successfully applied in acute coronary syndromes to help dissolve intracoronary thrombus, so their application to pulmonary vascular thrombus would seem reasonable. Although the use of these agents in the treatment of acute PE has been associated with earlier dissolution of clot, improved physiologic parameters, and resolution of imaging changes, most relevant studies did not show decreased patient mortality. As would be expected, however, an increase in significant bleeding complications was noted in patients receiving thrombolysis compared with those on anticoagulation alone. Attention has since been turned toward identifying subsets of patients with PE who might benefit from this therapy. Jerjes-Sanchez and associates evaluated the efficacy of thrombolytic therapy in patients with massive PE who presented in cardiogenic shock. The study was a small prospective, randomized controlled trial, enrolling a total of only 8 patients before it was terminated early (a total of 40 patients had been planned for enrollment). The 4 patients who received thrombolytics (streptokinase in this study) followed by heparin survived and at 2 years of follow-up demonstrated no evidence of pulmonary hypertension. The 4 who received heparin alone died within 1 to 3 hours of arrival in the emergency department. It is highly unlikely this study will be repeated, and by essentially uniform expert agreement, patients who develop cardiogenic shock related to PE should receive thrombolytics in the absence of major contraindications. A more controversial use of these medications is in patients with PE without hemodynamic compromise but with right ventricular dysfunction. A number of studies have demonstrated that patients with right ventricular dysfunction associated with PE have a significantly increased mortality. It would therefore seem reasonable to treat this group of patients more aggressively.

Two large studies have suggested a potential benefit of thrombolytics in patients with PE and right ventricular dysfunction or pulmonary hypertension, although both of these studies have received criticism regarding their design. The first study, the Management Strategies and Prognosis of Pulmonary Embolism Trial (MAPPET), demonstrated a survival benefit in patients with right ventricular dysfunction who received heparin and a thrombolytic (alteplase, streptokinase, and urokinase were the medications used) compared with heparin alone. The 30-day mortality rate for those who received thrombolysis was 4.7%, versus 11.1% for those receiving heparin alone. In addition, recurrent PE was significantly less frequent in those receiving thrombolytic therapy (7.7% versus 18.7%). This study was not randomized, however, and further inspection of the results reveals that the patients who received heparin alone were significantly older than those who received thrombolysis. This finding is relevant in that older age is a recognized risk factor for mortality in PE. The patients who received thrombolytics plus heparin also had less severe underlying cardiac and pulmonary disease than those receiving heparin alone, which also may have influenced the mortality outcomes.

The second study demonstrating an improvement in outcome for patients receiving thrombolytics was the Management Strategies and Prognosis of Pulmonary Embolism Trial-3 (MAPPET-3). This was a randomized prospective study examining the use of medical thrombolysis in PE associated with right ventricular dysfunction. The primary end point of this study was a combined end point of survival and escalation of therapy. A significant benefit in terms of this combined primary end point was reported in patients who received thrombolytics (alteplase) and heparin versus those who received heparin alone. Close review of this study, however, demonstrates no survival benefit between the two groups. Rather, the difference in the primary end point between groups was due to a difference in escalation of therapy, and in most patients this escalation of therapy related to later thrombolysis for PE. A number of experts have cited this article as evidence of benefit of thrombolytics in patients with PE and right ventricular dysfunction, although other workers are more skeptical of its use in this patient population. An interesting area of current exploration is the potential benefit of thrombolysis for submassive PE with right ventricular dysfunction in terms of long-term exercise tolerance and New York Heart Association (NYHA) functional class.

Prophylaxis Against Recurrent Venous Thromboembolism (Secondary Prevention)

Clear evidence has shown that “early” discontinuation of anticoagulation after an acute VTE results in a substantially increased risk for symptomatic extension of the thrombus, embolization, or recurrence of clot. The difficulty, however, is defining early. Most studies examining optimal duration of anticoagulation have found that the longer a person receives anticoagulation after a DVT or PE, the less likely they are to have a repeat VTE. Furthermore, when anticoagulation is discontinued, the risk of VTE increases substantially and is significantly above that in persons without a history of VTE. This elevation in risk is reflected in the clinical scoring systems (Wells score, Geneva score) discussed earlier. Of note, however, chronic anticoagulation presents its own inherent risks, cost, and requirements for lifestyle modification. The challenge then becomes balancing the inherent risk of anticoagulation with the individual patient’s risk of recurrent disease. The ACCP has published consensus statement recommendations regarding the duration of chronic anticoagulation to prevent recurrent VTE by considering patient risk factors and presentation (Table 57-4). These recommendations by necessity are directed at broad categories of patients. When applying these standards, therefore, clinicians must consider the individual patient’s risk of adverse outcomes with anticoagulation. As discussed earlier, however, the recent availability of the oral Xa inhibitors may change the risk-benefit ratio, resulting in longer periods of anticoagulation after VTE. The EINSTEIN investigators demonstrated that continuation of the oral Xa inhibitor rivaroxaban for an additional 6 to 12 months after completion of 6 to 12 months of anticoagulation resulted in significantly fewer episodes of recurrent VTE (1.3% versus 7.1%). Only a slight increase in nonfatal major bleeding (0.7%) was observed in the treatment cohort compared with the placebo cohort (0%).

Table 57-4 Recommendations for Duration of Anticoagulation in Patients Diagnosed With Venous Thromboembolism (VTE)

Indication for Anticoagulation Duration of Therapy
First VTE with reversible or transient risk factor Minimum of 3 months
First episode of idiopathic VTE Minimum of 6-12 months; consider use for indefinite period
VTE associated with malignancy LMWH for the first 3-6 months; then indefinitely or until the malignancy resolves
First episode of VTE associated with hypercoagulable state 12 months; suggest indefinitely
Two or more documented episodes of VTE Indefinite

LMWH, low-molecular-weight heparin.

Treating Pulmonary Embolism Associated with Malignancy

The pathophysiology of venous thrombosis in patients with cancer is complex and is influenced by a number of variables, including tumor type, stage, and overall tumor burden. Malignancies such as renal cell carcinoma are associated with a 43% incidence of VTE. Patients with DVT or PE related to cancer have increased 6-month mortality over patients with cancer not complicated by VTE. The CLOT (Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of VTE in Patients with Cancer) study demonstrated that LMWH (dalteparin) was more efficacious in the prevention of recurrent VTE in patients with malignancy than warfarin. Patients with cancer complicated by acute DVT, PE, or both were randomly assigned to receive 6 months of either warfarin or the LMWH dalteparin. Patients receiving dalteparin had less recurrent VTE than those receiving warfarin (9% versus 17%).

Treatment of Pulmonary Embolism in Pregnancy

Treatment of PE in pregnancy is complicated by risk to both the mother and the fetus. Warfarin is contraindicated in pregnancy because of its ability to cross the placenta and its association with both fetal hemorrhage and teratogenic effects such as central nervous system and neural developmental defects and nasal hypoplasia. Both UF heparin and LMWH can be used in the treatment of VTE in pregnancy, because neither crosses the placenta. Long-term use of UF heparin is associated with an increased risk for osteoporosis, but the risk is lower in patients treated with LMWH. Current recommendations for the treatment of VTE in pregnancy advocate the use of LMWH because of its favorable dosing and monitoring characteristics and its lower toxicity compared with other agents. An important consideration in this context, however, is that the maternal volume of distribution increases significantly during pregnancy, so the LMWH dose must be adjusted accordingly. Full-dose anticoagulation significantly increases the risk of hemorrhage at the time of delivery; therefore, LMWH and UF heparin should be discontinued 24 hours before planned induction of labor.

If spontaneous labor occurs, consideration should be given to reversal of anticoagulation with protamine. Anticoagulation can be restarted within 12 to 24 hours of delivery in the absence of ongoing bleeding. Warfarin, UF heparin, and LWMH are not excreted in breast milk, so these medications can be administered to breast-feeding women.

Pulmonary Embolectomy

Surgical resection of acute PE is a consideration in some patients. The operation is plagued by a high reported mortality (with rates as high as 30% in some series), in part because it typically is undertaken in already critically ill, hemodynamically unstable patients. Patients selected to undergo emergency embolectomy for this indication frequently have been found to have a large PE with resulting right ventricular dysfunction (a marker of increased mortality in itself). In such patients, anticoagulation or therapeutic thrombolysis often has failed to effect improvement or is contraindicated.

Treatment of Chronic Thromboembolic Disease

In most patients, the usual histopathologic and clinical course of PE eventuates in complete resolution of the thrombus and restoration of normal pulmonary artery pressures, usually within 30 days of the event. On the basis of a prospective incidence study, however, Pengo and colleagues reported that up to 4% of patients who survive a symptomatic PE may develop a condition termed chronic thromboembolic pulmonary hypertension (CTEPH). Most of these patients are seen late in the clinical course after significant pulmonary artery hypertension (PAH) develops; therefore, little is known about the natural history of this disease. In the currently accepted model for the pathogenesis of CTEPH, acute PE, either symptomatic or asymptomatic, serves as the initiating event, followed by disease progression. For reasons that are unknown, these emboli do not resolve but rather become coated by endothelial cells, a process referred to as endothelialization, making them inaccessible to endogenous or exogenous thrombolysis. This process eventually results in remodeling and obstruction of the pulmonary vascular bed and PAH.

What predisposes patients to CTEPH is unclear. Increased factor VIII levels have been detected in the peripheral blood of some of these patients, and an increased incidence of anticardiolipin antibodies also has been reported. The predicted 5-year survival rate for untreated severe CTEPH (i.e., mean pulmonary artery pressure greater than 50 mm Hg) is poor, with some estimates as low as 10%.

The treatment for CTEPH differs significantly from that for acute PE. Although these patients require anticoagulation to prevent further embolic events, the endothelialized clot is not accessible to these medications. Therapy, therefore, revolves around either removing the thrombus surgically or treating the elevation in pulmonary artery pressures medically. Surgical resection, termed pulmonary endarterectomy (PEA), is the treatment of choice in eligible patients (Figure 57-7). It is performed by dissecting away the endothelialized thrombus through careful separation of the thrombus from the pulmonary artery wall. This procedure is associated with significant operative and postoperative risk (as reflected by reported 5% to 10% mortality rates) and should be performed only in experienced centers. When PEA is successful, outcomes include significant improvement in pulmonary artery pressure, right-sided heart function, cardiac output, and functional class. A substantial number of patients (10% to 50%) with CTEPH referred for PEA, however, are deemed to be ineligible because of inaccessible distal thrombus or other serious comorbid conditions. Furthermore, persistent PH after successful PEA is frequent, with substantial small-vessel occlusion or arteriopathy. For these reasons, medical therapy for CTEPH has been applied. These treatments include nonspecific therapies such as administration of diuretics to improve fluid status, long-term oxygen therapy for hypoxemia, and digoxin to improve right ventricular contractility. More recently, however, novel therapies more specific for the treatment of PAH and approved for the treatment of idiopathic pulmonary artery hypertension (IPAH) have garnered attention as potentially useful in the medical management of CTEPH. Such therapies include use of the prostacyclin analogues (epoprostenol, treprostinil, and iloprost), endothelin receptor antagonists (bosentan), and the phosphodiesterase-5 (PDE-5) inhibitors (sildenafil). Evidence for the success of these medications, however, is limited to case series, retrospective studies, and prospective cohort studies. The only randomized controlled clinical trial to date that has included patients with CTEPH, as well as patients with other causes of PAH, is the Aerosolized Iloprost Randomized (AIR) study. Iloprost is an inhaled prostacyclin analogue approved for the treatment of PAH. This study did not demonstrate significant beneficial effects of inhaled iloprost in the CTEPH population, however.

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Figure 57-7 Thrombus removed from right and left pulmonary arteries in a patient with chronic thromboembolic pulmonary artery hypertension.

Prevention of Pulmonary Embolism

General Approach to Prophylaxis

VTE is a major cause of morbidity and mortality. Approximately 10% of in-hospital deaths are attributed to PE. Recognition of the prevalence and consequences associated with VTE has led to recommendations regarding primary prevention or thromboprophylaxis. Thromboprophylaxis has been demonstrated to be highly efficacious in a variety of patient populations and is associated with minimal risk. Recommendations for VTE prophylaxis advocate assessing the individual patient’s risk for thrombosis and adjusting the aggressiveness of the approach on the basis of that risk. Although means of assessing patient-specific risk have been described, these systems are cumbersome, have not been adequately validated, and are unlikely to be used routinely in clinical practice. An easier, more applicable method involves a “group-specific” approach applied routinely to all patients falling within a specific target group. A full discussion of these recommendations is reviewed in detail in the Seventh ACCP Conference consensus statement on the prevention of VTE. The statement divides patients into medical and surgical groups. The surgical patients are classified on the basis of individual risk factors, such as age, preexisting conditions, and the type of surgery planned. Recommendations are then made regarding the most appropriate type of thromboprophylaxis. A similar approach is used for medical patients. Of note, most medically managed patients admitted to the hospital in the current era will have at least one and probably multiple risk factors for VTE. Therefore, thromboprophylaxis is indicated in most hospitalized patients and is considered to be an essential component of optimal clinical care.

In most cases, the agents recommended for prophylaxis are anticoagulants. These anticoagulants include subcutaneous UF heparin or LMWH, with occasional recommendations for agents such as Xa inhibitors (fondaparinux) or oral vitamin K antagonists in high-risk groups such as postoperative patients recovering from hip or knee surgery. In a developing consensus, the use of mechanical compressive devices as the sole means of thromboprophylaxis against VTE is discouraged. The ACCP currently recommends that mechanical methods of thromboprophylaxis be used primarily in patients at high risk for bleeding or as an adjunct to anticoagulant-based prophylaxis. Currently, however, data supporting a role for such methods as adjunctive therapy are limited.

Inferior Vena Cava Filters

The concept of mechanically obstructing the vena cava to prevent embolization to the pulmonary vasculature is not new, being originally conceived by Trousseau in 1868. Techniques to insert this protective barrier have been refined substantially over the years, however, and now the placement of inferior vena cava (IVC) filters can be achieved safely and reliably. More recently, the development of retrievable IVC filters has expanded the number of patients considered for this procedure. The two most common scenarios in which IVC filters are used are (1) inability to anticoagulate and (2) failure of adequate anticoagulation in patients with known VTE. Other scenarios meriting consideration of IVC filter placement include high risk for PE despite use of recommended thromboprophylaxis, such as in trauma victims with lower extremity or pelvic fractures, high risk of death from pulmonary embolic disease in some patients, and/or those with severe pulmonary hypertension and a known DVT.

Only one randomized trial of IVC filters for the treatment of VTE has been published. This study demonstrated a decrease in the incidence of PE in the first 12 days after placement of the device (1.1% versus 4.8%) but an increase in the incidence of DVT at 2 years after placement (11.6% versus 20%). The incidence of PE at 2 years after filter placement was only slightly decreased (3.4% versus 6.2%). An 8-year follow-up study in the same cohort demonstrated a decrease in the recurrence of PE in the patients with IVC filters (6.2% versus 15.1%), but a significantly increased occurrence of DVTs was noted in the patients who received filters (35.7% versus 27.5%). No difference was found in the incidence of the postthrombotic syndrome or mortality between the cohorts. All patients in this study received anticoagulation for a minimum of 3 months, and many remained on anticoagulation indefinitely.

No randomized trials have been conducted to examine the incidence of PE in patients who received an IVC filter but did not receive anticoagulation. Retrievable filters are a potential option in patients who have only a transiently increased risk for VTE (Figure 57-8). The filters should be removed before endothelization of the struts occurs, which usually is within 7 to 21 days of placement. An increasing number of case reports and case series, however, have demonstrated the ability to remove retrievable filters months after their placement. The risk of complications rises with delayed removal. Randomized controlled trials demonstrating the efficacy of retrievable filters in terms of outcomes have yet to be performed.

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Figure 57-8 Inferior vena cava (IVC) retrievable filter. A, Gunter Tulip IVC filter. B, Filter is seen after deployment in the IVC. C, Preparation for retrieval of the filter. A snare is inserted percutaneously, which is used to engage the end of the filter. D, The filter is retracted and drawn into a sheath for percutaneous extraction.

Nonthrombotic Pulmonary Emboli

Although most pulmonary emboli arise from DVT, other clinically significant forms of emboli may have an impact on the lung vasculature, as summarized in Box 57-3.

Box 57-3

Causes of Nonthrombotic Pulmonary Emboli

Fat embolism

Air embolism

Venous
Arterial

Amniotic fluid embolism

Tumor embolism

Septic pulmonary embolism

Fat Embolism Syndrome

Fat embolism syndrome (FES) is a poorly understood complication of skeletal trauma. Although rare, FES most often occurs after fractures of long bones or other conditions resulting in bone marrow disruption. FES is characterized by the appearance of free fat and fatty acids in the blood, lungs, brain, kidneys, and other organs. The classic triad of respiratory insufficiency, neurologic abnormalities, and petechial rash occurs in 0.5% to 2.0% of solitary long bone fractures. The incidence increases to 5% to 10% in multiple fractures with pelvic involvement.

FES is a clinical diagnosis that typically manifests within 12 to 72 hours of initial injury. Respiratory impairment leads to hypoxemia in up to 30% of patients and, on occasion, to respiratory failure and the need for mechanical ventilation. The chest radiograph often shows diffuse infiltrates but can appear normal. Cerebral symptoms may occur in 60% of patients and tend to follow the pulmonary symptoms. Neurologic findings may range from restlessness, confusion, and altered sensorium to focal deficits, seizures, and coma. The characteristic petechial rash is observed in 50% of patients and usually is found on the neck, in the axillary region, or on the trunk, or petechiae may appear on the conjunctiva. The rash often is the last of the triad to develop and resolves within a range of hours to days.

Treatment of FES includes aggressive supportive care and early ventilatory support. Steroids have been demonstrated to be efficacious as prophylaxis for FES, although experience with steroids as specific treatment remains anecdotal.

Air Embolism

Air embolism is a consequence of entry of air into the vascular system, resulting in mechanical obstruction, end-organ ischemia, and/or hemodynamic compromise. Air can enter the venous system under two simultaneous conditions: (1) presence of a direct communication between the source of air and the venous system and (2) development of a pressure gradient favoring the passage of air into the venous system. Under high pressure, gas may be forced into the venous system such as with laparoscopic procedures, pressurized infusion sets, or mechanical ventilation. Conversely, generating high negative intrathoracic pressures (as in hyperventilation, exacerbation of underlying lung disease, hypovolemia, or upright positioning) may predispose patients to venous air embolism by increasing the pressure gradient between the atmosphere and the thorax.

In most instances, venous air embolism occurs in relation to placement of central venous catheters (zero to 2% incidence). The mortality rate for this entity associated with central venous catheters has been reported to be as high as 32%. In humans, the lethal volume of air is estimated to be 300 to 500 mL. With a pressure gradient of only 5 cm H2O (as with normal tidal breathing), air can pass through a 14 gauge catheter at a rate of 100 mL/second. The clinical symptoms of venous air embolism are nonspecific. Care providers must maintain a high index of suspicion to consider this diagnosis in patients who exhibit sudden cardiopulmonary and/or neurologic decompensation in the appropriate clinical setting. Patients may experience a gasping reflex, light-headedness, dizziness, chest pain, or sudden-onset dyspnea. If venous gas reaches the arterial circulation, myocardial or central nervous system injury may occur. Physical examination may reveal tachycardia, tachypnea, and elevated jugular venous pressure. A mill-wheel murmur, produced by movement of air bubbles in the right ventricle, is considered the only specific sign, but it is a rare, transient, and late finding. Wheezing or rales may occur secondary to induced bronchospasm.

Transthoracic or transesophageal echocardiography is the most sensitive method for detection of venous air and may show evidence of both acute right ventricular dilatation and pulmonary hypertension. Indwelling pulmonary artery catheters will show an acute increase in pulmonary artery pressure. Although this finding has a sensitivity of only 45%, the presence of a pulmonary artery catheter at the time of onset of venous air embolism can result in early therapeutic intervention. If venous air embolism is suspected, the patient should be placed left side down in Trendelenburg position, allowing air to migrate toward the right apex of the heart, thereby diminishing pulmonary outflow obstruction. Manual removal of air from an indwelling central line or pulmonary artery catheter may be attempted and is most effective at or above the right atrial junction, not in the right ventricular or pulmonary artery outflow tract. Closed-chest cardiac massage improves survival to the same extent as that achieved by proper positioning, presumably by mechanically forcing air out of the right ventricle and pulmonary outflow tract. Patients should be administered 100% inspired oxygen (FIO2) to increase the rate of bubble absorption. For patients with persistence of cardiopulmonary or cerebrovascular deficits despite application of these modalities, hyperbaric oxygen therapy should be initiated.

Amniotic Fluid Embolism Syndrome

Amniotic fluid embolism syndrome (AFES) is a rare complication of pregnancy with variable manifestations and high morbidity and mortality. The reported incidence of this catastrophic syndrome ranges from 1 in 8000 to 1 in 80,000 pregnancies. Amniotic fluid is a complex mixture of both maternal and fetal components, including particulate matter such as fetal squamous cells, lanugo hairs, and variably meconium. Amniotic fluid is postulated to enter the maternal circulation through endocervical veins, through the site of placental insertion, or through uterine trauma. Once in the circulation, amniotic fluid triggers an immunologically mediated systemic inflammatory response leading to cardiovascular compromise, respiratory failure, coagulopathy, and disseminated intravascular coagulation. AFES occurs during labor but before delivery in 70% of cases, after vaginal delivery in 11%, and during cesarean section in 19%. Of the patients in whom AFES developed after delivery, 69% experienced clinical onset within the first 5 minutes post partum. AFES also has been reported to occur as early as the second trimester and as late as 36 hours post partum. AFES may occur during therapeutic abortion, amniocentesis, and labor and delivery and in the setting of abdominal trauma. Factors historically associated with increased risk for AFES include advanced maternal age, multiparity, large fetal size, premature placental separation, fetal death, fetal male sex, meconium staining, and a history of allergy or atopy in the mother.

The clinical presentation of AFES often is dramatic, with sudden-onset respiratory distress, cyanosis, convulsions, and cardiovascular collapse classically occurring during labor and delivery. Rapid progression to asystole or pulseless electrical activity has been described. Among patients who survive the initial event, a major coagulopathy develops later on in 40% of the cases.

The diagnosis of AFES is clinical. Early aggressive support is imperative, because most maternal deaths occur within 1 hour of symptom onset. AFES is a life-threatening condition that necessitates prompt resuscitation, including airway and hemodynamic support in an intensive care setting. The maternal mortality rate for AFES ranges from 30% to 90%. The fetal survival rate is 40% when the fetus is in utero at the time of AFES onset. Furthermore, AFES is associated with significant morbidity, with neurologically intact survival observed in only 15% of maternal survivors in some reports.

Tumor Embolism

Pulmonary tumor embolism occurs when solid tumors seed the systemic circulation with individual cells, clusters of cells, or large tumor fragments. Emboli travel to the pulmonary vasculature, causing microvasculature obstruction. Furthermore, tumor emboli may activate the coagulation system, resulting in concomitant thrombotic obstruction. The pathologic spectrum of tumor embolism ranges from large tumor masses that may mimic PE, on one end, to the more common microvessel embolism in small arterioles and capillaries that cause a subacute clinical syndrome, on the other. The incidence of tumor embolism is estimated by autopsy series to be 3% to 26% in patients with solid tumors. Tumor embolism seems to be more common in patients with mucin-producing adenocarcinomas such as breast, gastric, and lung carcinoma; however, this observation may be explained by the higher prevalence of these tumors within the general population.

Controversies and Pitfalls

Although great progress has been made in expansion of the current understanding and approach to the clinical entity of PE, new developments frequently bring with them new questions and controversies. Some of these dilemmas are discussed next.

Isolated Subsegmental Pulmonary Emboli

The development of faster, multidetector scanners has improved the clinician’s ability to see the subsegments of the pulmonary vasculature on CTA. This ability, however, has raised an interesting conundrum: Are isolated small, subsegmental pulmonary emboli clinically meaningful? On one side of this argument are researchers who believe that any thrombus in the pulmonary vasculature is pathologic, and that even if a subsegmental thrombus does not have immediate clinical effects, it implies a risk for subsequent PE that therefore merits anticoagulation. The converse argument is that very small thrombi may intermittently occur in normal people, and that perhaps it is the lungs’ role to serve as a filter for these “microclots,” thereby preventing them from migrating into the arterial circulation. This possibility, although interesting to consider, has never been substantiated. At present, no consensus has been reached on the appropriate clinical approach toward an isolated subsegmental PE detected by multidetector CTA, and very little expert opinion on this topic has been published.

Outpatient Treatment of Pulmonary Embolism

As discussed earlier in this chapter, LMWH has been demonstrated to be safe and effective in the treatment of submassive PE. The oral Xa inhibitor rivaroxaban currently is being studied in the management of PE and was found to be effective for the treatment of DVT. Initial reports of success with these agents raise the possibility of treating patients with PE at home, thereby avoiding a hospital stay. This paradigm is well accepted in the treatment of DVT, for which it has been demonstrated to be safe and cost-effective, as well as popular from a patient perspective. Some of the studies examining the use of LMWH for the treatment of PE have permitted small percentages of the patients enrolled either to be treated entirely on an outpatient basis or to be discharged early from the hospital to complete home therapy. No increases in adverse events were found in patients managed as outpatients. This possibility of home therapy raises concern, however, because patients with PE have an increased mortality compared with patients with DVT. It is possible that treating them in a less monitored environment will carry an increased risk of death. Also, studies examining the use of LMWH in the treatment of PE have excluded patients with hemodynamically significant thromboembolic disease, a subgroup recognized to have even higher mortality. Realistically, however, more and more patients with PE are being treated as outpatients. This approach merits caution in patients known to have adverse hemodynamic changes or right ventricular dilatation or strain related to the thromboembolic event. This group of patients probably should be observed in an inpatient setting, at least initially in their treatment course.

Thrombolytic Therapy in Patients with Pulmonary Embolism without Hemodynamic Instability

Convincing evidence is lacking for a survival advantage in hemodynamically stable patients with pulmonary emboli who are treated with thrombolytics plus anticoagulation over that in those treated with anticoagulation alone. Two studies have suggested that thrombolytics improve outcomes in patients with pulmonary emboli and right ventricular dysfunction; however, both have been criticized for suboptimal design. Although it is currently agreed that patients with hemodynamic collapse secondary to PE should receive thrombolysis if possible, controversy exists regarding the use of this therapy in less severely affected patients. However, the use of thrombolytics in hemodynamically stable patients with evidence of right ventricular dysfunction is gaining support in a number of expert societies.

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