Respiration 14 Pulmonary Embolism

Pulmonary Venous Thromboembolism Pulmonary venous thromboembolism, often referred to as pulmonary embolism, is a common, serious, and potentially fatal complication of thrombus formation within the deep venous circulation

• Majority of cases are not recognized antemortem, and fewer than 10% of patients with fatal emboli have received specific treatment for the condition • Management demands a vigilant systematic approach to diagnosis and an understanding of risk factors so that appropriate preventive therapy can be given

Many substances can embolize to the pulmonary circulation, including ; • Air (during neurosurgery, from central venous catheters) • Amniotic fluid (during active labor) • Fat (long bone fractures) • Foreign bodies (talc in injection drug users) • Parasite eggs (schistosomiasis) • Septic emboli (acute infectious endocarditis) • Tumor cells (renal cell carcinoma)

• The most common embolus is thrombus, which may arise anywhere in the venous circulation or heart but most often originates in the deep veins of the major calf muscles • Thrombi confined to the calf rarely embolize to the pulmonary circulation. However, calf vein thrombi propagate proximally to the popliteal and ileofemoral veins, at which point they may break off and embolize to the pulmonary circulation

Risk factors • Pulmonary embolism and DVT are two manifestations of the same disease

• Venous stasis • Venous stasis increases with immobility (bed rest—especially postoperative—obesity, stroke), hyperviscosity (polycythemia), and increased central venous pressures (low cardiac output states, pregnancy).

• Injury to the vessel wall • Vessels may be damaged by prior episodes of thrombosis, orthopedic surgery, or trauma

Hypercoagulability (Virchow's triad) Hypercoagulability can be caused by • Medications (oral contraceptives, hormonal replacement therapy) • Disease (malignancy, surgery) • Inherited gene defects Most common inherited cause in white populations is resistance to activated protein C, also known as factor V Leiden • Other major risks for hypercoagulability include the following: deficiencies or dysfunction of protein C, protein S, and antithrombin III; prothrombin gene mutation; and the presence of antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibody).

Clinical Findings Symptoms and Signs • The clinical diagnosis of pulmonary thromboembolism is notoriously difficult for two reasons • First, the clinical findings depend on both the size of the embolus and the patient's preexisting cardiopulmonary status • Second, common symptoms and signs of pulmonary emboli are not specific to this disorder

Symptoms       • Dyspnea • Respirophasic chest pain • Cough • Legpain • Hemoptysis • Palpitations • Wheezing • Anginal pain

Signs • • • • • • • • • •

Respiratory rate >16-20/min Crackles (rales)    Heart rate > 100/min Fourth heart sound (S4) Accentuated pulmonary component of second heart sound (S2P)    T >37.5 °C - 38.5 °C Homans' sign Pleural friction rub Third heart sound (S3) Cyanosis

Indeed, no single symptom or sign or combination of clinical findings is specific to pulmonary thromboembolism

Laboratory Findings ECG • Abnormal in 70% of patients with pulmonary thromboembolism • Most common abnormalities are sinus tachycardia and nonspecific ST and T wave changes (S1 Q3 T3) • Few patients have P pulmonale, right ventricular hypertrophy, right axis deviation, and right bundle branch block

Arterial blood gases • Reveal acute respiratory alkalosis due to hyperventilation • The arterial PO2 and the alveolar-arterial oxygen difference (A–a– DO2) are most often abnormal in patients with pulmonary thromboembolism • Profound hypoxia with a normal chest radiograph in the absence of preexisting lung disease is highly suspicious for pulmonary thromboembolism.

Plasma levels of D-dimer • Plasma levels of D-dimer, a degradation product of cross-linked fibrin, are elevated in the presence of thrombus • Using a D-dimer threshold between 300 and 500 ng/mL, the quantitative enzyme-linked immunosorbent assay (ELISA) has shown a sensitivity for venous thromboembolism

Imaging and Special Examinations Chest radiography

• The chest radiograph is necessary to exclude other common lung diseases and to permit interpretation of the ventilation-perfusion ( V/ Q) scan, but it does not establish the diagnosis by itself • A prominent central pulmonary artery with local oligemia (Westermark's sign) or pleural-based areas of increased opacity that represent intraparenchymal hemorrhage (Hampton's hump) are uncommon • Paradoxically, the chest radiograph may be most helpful when normal in the setting of hypoxemia

Lung scanning • A perfusion scan is performed by injecting radiolabeled microaggregated albumin into the venous system, allowing the particles to embolize to the pulmonary capillary bed • To perform a ventilation scan, the patient breathes a radioactive gas or aerosol while the distribution of radioactivity in the lungs is recorded • A defect on perfusion scanning represents diminished blood flow to that region of the lung • Defects in the perfusion scan are interpreted in conjunction with the ventilation scan to give a high, low, or intermediate (indeterminate) probability that pulmonary thromboembolism is the cause of the abnormalities.

CT • Helical CT arteriography is rapidly supplanting V/Q scanning as the initial diagnostic study for suspected pulmonary thromboembolism • Helical CT arteriography requires administration of intravenous radiocontrast dye but is otherwise noninvasive

Venous thrombosis studies • Seventy percent of patients with pulmonary thromboembolism will have DVT on evaluation, and approximately half of patients with DVT will have pulmonary thromboembolism on angiography • Commonly available diagnostic techniques include venous ultrasonography, impedance plethysmography, and contrast venography

Pulmonary arteriography • Pulmonary arteriography remains the reference standard for the diagnosis of pulmonary thromboembolism • An intraluminal filling defect in more than one projection establishes a definitive diagnosis • Pulmonary arteriography is a safe but invasive procedure with well-defined morbidity and mortality data

MRI • The test is noninvasive and avoids the use of potentially nephrotoxic radiocontrast dye • Expensive and not widely available

Integrated approach for diagnosis of Pulmonary embolism

Treatment Anticoagulation • The standard regimen of heparin followed by 6 months of oral warfarin

• Heparin

• Heparin binds to and accelerates the ability of antithrombin III to inactivate thrombin, factor Xa, and factor IXa. It thus retards additional thrombus formation, allowing endogenous fibrinolytic mechanisms to lyse existing clot • Heparin is administered in dosages determined by body weight • It is necessary to monitor the activated partial thromboplastin time (aPTT) and adjust dosing to maintain the aPTT 1.5–2.5 times control • Unfractionated Heparin • Low Molecular Weight Heparin

• LMW heparins are depolymerized preparations of heparin, they are administered once or twice daily without the need for coagulation monitoring, with subcutaneous route • Anticoagulation therapy for venous thromboembolism is continued for a minimum of 3 months, so oral anticoagulant therapy with warfarin is usually initiated concurrently with heparin

• Warfarin • Warfarin affects hepatic synthesis of vitamin K-dependent coagulant proteins • It usually requires 5–7 days to become therapeutic; therefore, heparin is generally continued for 5 days • Adequacy of therapy must be monitored by following the prothrombin time, The target INR is 2.5, with the acceptable range from 2.0 to 3.0; below 2.0, there is an increased risk of thrombosis; above 4.0, there is an increased risk of hemorrhage • Warfarin has interactions with many drugs • Warfarin is a pregnancy category X medication, indicating known fetopathic and teratogenic effects • When oral anticoagulation with warfarin is contraindicated, LMW heparin is a convenient alternative.

• It is reasonable to continue therapy for 6 months after a first episode when there is a reversible risk factor, 12 months after a first-episode idiopathic thrombus, and 6–12 months to indefinitely in patients with nonreversible risk factors or recurrent disease • The major complication of anticoagulation is hemorrhage

Thrombolytic Therapy • Streptokinase, urokinase, and recombinant tissue plasminogen activator (rt-PA; alteplase) increase plasmin levels and thereby directly lyse intravascular thrombi • In patients with established pulmonary thromboembolism, thrombolytic therapy accelerates resolution of emboli within the first 24 hours compared with standard heparin therapy • Current evidence supports thrombolytic therapy for pulmonary thromboembolism in patients at high risk for death in whom the more rapid resolution of thrombus may be lifesaving. Such patients are usually hemodynamically unstable despite heparin therapy

Additional Measures • Inferior vena cava filter

• Interruption of the inferior vena cava may be indicated in patients with a major contraindication to anticoagulation who have or are at high risk for development of proximal DVT or pulmonary embolus • It is also recommended for recurrent thromboembolism despite adequate anticoagulation amd for chronic recurrent embolism with pulmonary hypertension

• Mechanical or surgical extraction of thrombus • In rare critically ill patients for whom thrombolytic therapy is contraindicated or unsuccessful, mechanical or surgical extraction of thrombus may be indicated • Pulmonary embolectomy is an emergency procedure of last resort with a very high mortality rate.

Prevention • Early ambulation • Low-dose unfractionated heparin • Low-molecular-weight heparin (LMWH)