Pulmonary Embolism January 24, 2007 Henry L. Green, MD, FACC, FACP Incidence It is estimated that 600,000 episodes occur in the United States annually, 100,000 to 200,000 of them fatal. The majority of pulmonary emboli are probably not recognized clinically. Pulmonary emboli can range from small peripheral emboli to massive obstructive lesions producing shock or cardiac arrest. The mortality rate is greater than 15% in the first 3 months after diagnosis. About 25% of cases present with sudden death. Major risk factors: Acquired Old age Surgery Immobilization Oral contraceptives Acute infection Prior history of thromboembolism Hereditary Factor V Leiden mutation Protein C deficiency Protein S deficiency

Smoking Obesity Trauma Pregnancy Long-haul air travel Malignancy Hormone therapy Venous stasis Lupus anticoagulant Anticardiolipin antibody syndrome Pacemaker or other transvenous device

Antithrombin III deficiency Hyperhomocysteinemia Family history of thromboembolism

Source of embolus Rarely the source is in the upper extremity (central venous catheters, pacemaker wires, repetitive overuse of the upper extremity, as in certain athletic endeavors). Most of the emboli arise in the lower extremities. These usually begin in the venous sinuses of the calf muscles. These rarely embolize. However, 25% of them will propagate to the proximal veins. About 50% of proximal venous thrombi will result ion pulmonary emboli. Occasionally the source is in the pelvic veins. The clinical diagnosis is suggested by pain, swelling and tenderness, but often there are no appreciable signs. The differential diagnosis of deep vein thrombosis includes the following: Abscess Baker’s cyst Cellulitis Claudication Injury Venous stasis Lymphedema Vasculitis Postphlebitic syndrome Superficial thrombophlebitis

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Recognition of pulmonary embolism Atypical or subtle presentations are common. An underlying or coexisting disease, such as heart failure, emphysema, pneumonia or sepsis may further confuse the issue. For example, in patients with obstructive lung disease, as many as 25% of exacerbations appear to be due to pulmonary embolism in the absence of any other clinical sign and with low risk prediction by the various scoring systems. Symptoms: Dyspnea is the commonest presentation. There may be pleuritic pain, cough, or hemoptysis. Signs: There is often tachypnea, evidence of anxiety. With massive emboli, there can be hypotension shock, or cardiac arrest. Evidence of right heart failure may be present (neck vein distention, tricuspid regurgitation, accentuated pulmonic second sound). Differential diagnosis: Acute myocardial infarction Musculoskeletal disorders Costochondritis Rib fracture Pericardial disease

Aortic dissection Chest contusion Obstructive lung disease, asthma Pneumonia Pneumothorax

Laboratory: The D-dimer test is highly sensitive but not specific. It should be measured by the ELISA method. If negative, the diagnosis of pulmonary embolus is almost always excluded. Troponin and BNP levels are useful for risk stratification. Elevation of these markers indicates higher risk. One should not depend on blood gasees to exclude the diagnosis. Electrocardiogram: This is useful to exclude alternative diagnoses. However, the electrocardiogram is not a particularly strong diagnostic test for pulmonary embolism. It may be normal. Possible findings include new development of any of the following: Right ventricular strain pattern (T wave inversion in V1-V3) Right bundle branch block S in lead I with a Q wave and inverted T wave in lead III ST and T wave changes Sinus tachycardia Right axis deviation Clockwise rotation of the QRS (shift of transition zone to V5) P pulmonale Chest x-ray: This is often normal. There may be focal oligemia, a wedge-shaped peripheral opacity, or an enlarged descending right pulmonary artery. There may be cardiac enlargement, pleural effusion, atelectasis, or elevation of a hemidiaphragm.

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Chest CT angiography is the study of choice. It is at least as accurate as pulmonary angiography. Ventilation-perfusion scanning This can be used in patients in whom contrast dye and/or radiation should be avoided (e.g. renal insufficiency, pregnancy). If it is normal, it essentially excludes pulmonary embolism. If it is interpreted as “high probability,” the diagnosis is highly likely. Unfortunately, the majority of scans are “low” or “intermediate” probability. This is of little clinical value, as a significant number of these patients do have pulmonary emboli. Magnetic resonance angiography is also sometimes used if there is renal failure. Echocardiography This not a sensitive diagnostic tool for pulmonary embolism. A hypokinetic right ventricular free wall with preserved contraction of the right ventricular apex is said to be diagnostic. There may be right ventricular dysfunction, increased right ventricular end diastolic to left ventricular end-diastolic ratio, tricuspid regurgitation, congestion and reduced inspiratory collapse of the inferior vena cava. It may be possible to visualize a right atrial or main pulmonary artery thrombus. It is very helpful in risk stratification. High risk is implied if there is right ventricular dilatation and hypokinesis, paradoxical septal motion, tricuspid regurgitation and pulmonary hypertension. It also aids in the differential diagnosis (myocardial infarction, cardiac tamponade, aortic dissection). Venous ultrasonography of the lower extremities This study can effectively detect or exclude the diagnosis of proximal deep venous thrombosis. Thus, it may provide supporting evidence for pulmonary embolism. However, it is not uncommonly negative even in patients with proven pulmonary embolism. Pulmonary angiography This is general regarded as the gold-standard test. However, the complication rate is 4%, with a mortality of 0.2%. It is still used in unstable patients, those with suspected pulmonary hypertension, or when an operative intervention is planned. Point scoring systems can be used to determine the likelihood of a pulmonary embolus: Modified Wells criteria: Clinical signs and symptoms of DVT Alternative diagnosis less likely Heart rate ≥ 100 Recent immobilization or surgery Venous thromboembolism Hemoptysis Malignancy treatment within 6 months Pulmonary embolus unlikely: Pulmonary embolus likely:

3 points 3 points 1.5 points 1.5 points 1.5 points 1 point 1 point

≤ 4 points > 4 points

This can be used to determine which patients require a chest CT, unless the D-dimer is positive. 3

Revised Geneva Score: Age > 65 Previous DVT or PE Surgery under general anesthesia or leg fracture within 1 month Malignancy (active or within 1 year of cure) Unilateral leg pain Hemoptysis Heart rate 75-94 Heart rate > 94 Tenderness to deep venous palpation of leg and unilateral edema

1 point 3 points 2 points 2 points 3 points 2 points 3 points 5 points 4 points

Low probability: 0-3 points Intermediate: 4-10 points High: 11 points This score is a promising tool, but will require further validation. Risk stratification Patients with normal right ventricular function and blood pressure have a good prognosis. The following factors are associated with a worse prognosis: Age > 70 troponin elevation (microinfarction) heart failure Cancer BNP elevation (shear stress) right ventricular dysfunction on echo COPD chest CT -- RV:LV dimension > 0.9 systolic blood pressure < 90 Treatment Anticoagulation is used in all patients, unless there are major contraindications. This is initiated with either unfractionated heparin, low molecular weight heparin, or fondaparinux. Unfractionated heparin is the preferred drug when embolectomy or thrombolytic therapy is being considered, as it can be rapidly reversed. Treatment should be initiated with a weight-based bolus (e.g. 80 u/kg) followed by an infusion, usually started at 18 u/kg/hr. The activated partial thromboplastin time is maintained at 2 to 3 times the upper normal limit. Platelet counts should be ordered daily, to permit recognition of heparin-induced thrombocytopenia. If t-PA is given, heparin is held until the activated partial thromboplastin time falls to less than twice the upper normal limit. Low molecular weight heparins are as effective as unfractionated heparin. They are given subcutaneously, using a weight-based dose. No monitoring is required, unless the patient is pregnant, has chronic kidney disease, or is massively obese. In the latter cases, we usually monitor the anti-Xa levels. This is also done if the patient bleeds or has additional emboli while receiving a weight-based regimen. The usual dose for enoxaparin is 1 mg/kg every 12 hours and for dalteparin 120 u/kg every 12 hours. Fondaparinux is a third alternative that is as safe and effective as the others. It is a synthetic pentasaccharide. It is administered once daily subcutaneously. The daily dose is 5 mg for patients weighing under 50 kg, 7.5 mg for those weighing 50-100 kg., and 10 mg if the patient weighs over

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100 kg. It is contraindicated in severe renal disease. It does not cause heparin-induced thrombocytopenia, unlike the heparins. Monitoring is not required. Oral anticoagulation is started simultaneously with one of the above agents. No loading dose is given. Warfarin is started at 5 mg. daily. The target INR is 2 to 3. They are overlapped with heparin or fondaparinux for five days, even if the INR is in the therapeutic range before that time. The duration of anticoagulation is determined by risk of recurrence of pulmonary embolism. In patients with irreversible risk factors, anticoagulants are continued indefinitely. If the predisposing cause is not permanent (surgery, pregnancy, trauma, etc.) anticoagulation is maintained for six months. Longer duration of anticoagulation decreases the recurrence rate, but increases the risk of major bleeding. Thrombolytic therapy This is often used for massive or submassive pulmonary emboli when there is hemodynamic instability. The echocardiographic recognition of right ventricular dysfunction itself is considered to be an indication by some, but this is controversial. The approved drug is t-PA (alteplase) 100 mg, infused over 2 hours. There is significant risk to doing this, as intracranial hemorrhage may occur in as many as 3% of cases. The patient must be carefully screened for contraindications. There is no advantage to administration of the agent directly into the pulmonary artery. Surgical embolectomy This is used when thrombolytic therapy fails or is contraindicated. Additional indications include persistent right heart thrombi, paradoxical embolism, or the need for CPR due to respiratory or hemodynamic collapse. It is done using cardiopulmonary bypass with deep hypothermia. Catheter based embolectomy can be tried if surgery is contraindicated. Inferior vena cava filters These are employed if anticoagulants are contraindicated, if emboli recur during adequate anticoagulation, or if the patient undergoes surgical embolectomy. They increase the risk of deep vein thrombosis. Prognosis 90% resolve within 30 days with restoration of normal pulmonary hemodynamics. If the patient presents with hemodynamic impairment, the mortality is 20-30%. Clearly, the prognosis is worse if the diagnosis is missed. Paradoxical embolism can occur if a thrombus passes through a patent foramen ovale or other intracardiac shunt, and can result in a stroke. Chronic thromboembolic pulmonary hypertension Up to 4% of pulmonary emboli do not resolve. They become organized and obstruct the pulmonary vasculature. The patient may be asymptomatic for months or years, after which he develops dyspnea, syncope and angina. There is evidence of right heart failure with jugular venous distention, hepatomegaly, a right ventricular heave and dependant edema. The pulmonic second sound is exaggerated and may be widely split. There may be murmurs of tricuspid regurgitation and of pulmonic regurgitation.

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The chest x-ray may be normal, or may show enlargement of one or both pulmonary arteries and areas of hypoperfusion or hyperperfusion. Right atrial and/or right ventricular enlargement may be seen. Resting PO2 may be normal, but usually declines with exercise. The A-a gradient is usually widened. The ECG may show right atrial or right ventricular enlargement. Echocardiography reveals the pulmonary hypertension and a dilated right ventricle with reduced function. Helical CT demonstrates the thromboembolic material and helps in the differential diagnosis of pulmonary hypertension. Right heart catheterization and pulmonary angiography are the definitive studies. Coronary angiography should also be done if the patient is over 35. The treatment is surgical thromboendarterectomy, after placement of an inferior vena cava filter. Anticoagulation should be initiated after surgery. The surgical mortality is 7-24%. The postoperative course is often difficult. References Piazza G and Goldhaber SZ. Acute pulmonary embolism part I: epidemiology and diagnosis. Circulation 2006;114:28 Piazza G and Goldhaber SZ. Acute pulmonary embolism part II: treatment and prophylaxis. Circulation 2006;114:42 Stengel JW et al. Diagnostic imaging approach to pulmonary embolism. Cleveland Clinic J Med 2006;72:821 Kucher N and Goldhaber SZ. Recent advances in the diagnosis and treatment of pulmonary embolism. ACC Current Journal Review. Nov/Dec 2003 p. 28 Wells PS et al. Does This Patient Have Deep Vein Thrombosis? JAMA 2006;295:199 Fedullo PF and Tapson VF. The evaluation of suspected pulmonary embolism. New Eng J Med 2003;349:1247 Bhatia S et al. 56 year old man with progressive shortness of breath. Mayo Clin Proc;2003:491 (a case of chronic thromboembolic pulmonary hypertension) Legal G et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Int Med 2006;144:165 Lang I. Chronic thromboembolic pulmonary hypertension – not so rare after all. New Engl J Med 2004; 350:2236 Bates SM and Ginsberg JS. Treatment of deep vein thrombosis. New Engl J Med;2004 351:268 Perlroth DJ et al. Effectiveness and cost-effectiveness of thrombolysis in submassive pulmonary embolism. Arch Int Med; 2007 167:74 Tillie-Leblond I et al. Pulmonary embolism in patients with unexplained exacerbationl of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Int Med 2006; 144:390

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