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pulmonary embolism (PE)

Etiology: 1) source a) majority of clinically significant pulmonary emboli arise from deep venous thromboses (DVT) in the iliac artery - femoral artery system b) post surgically, the pelvic venous complex is a source of pulmonary emboli 2) predisposing factors a) venous disease of the lower extremities - deep vein thrombosis - varicosities b) carcinoma d) heart failure e) postoperative risk of PE elevated for >= 12 weeks after any surgery - risk of PE 6-12 weeks after surgery markedly < 1-6 weeks - risk highest for orthopedic & vascular surgery [90] - recent pelvic or lower abdominal surgery f) prolonged immobilization, includes sitting [24] g) pregnancy h) estrogen therapy i) fracture of hip or leg j) chronic lung disease k) hypercoagulable states l) atrial fibrillation m) beta-thalassemia n) trauma o) hospitalization for autoimmune disease (HR=10) [25] Epidemiology: 1) cause of death in 5-15% of hospitalized patients in US 2) detected in 25-30% of routine autopsies 3) prevalence of 1% in hospitalized patients Pathology: - venous thromboembolism - pulmonary vascular occlusion - right heart failure - hypotension - cerebrovascular ischemia [56] Diagnostic criteria: - use Wells score first prior to PERC (MKSAP19) [4] - use Wells score first prior to PERC (MKSAP19) - if Wells score indicates moderate probability of pulmonary embolism. do not use Pulmonary Embolism Rule-Out Criteria [4] - Pulmonary Embolism Rule-Out Criteria (PERC) for low risk: [68] - oxygen saturation > 94% - heart rate < 100 beats/minute - age < 50 years - no unilateral leg swelling - no hemoptysis - no recent trauma or surgery - no prior PE or deep venous thrombosis - no exogenous estrogen use - Intermediate risk: right ventricular dysfunction [91] - High risk: intensive care & reperfusion therapy [91] Clinical manifestations: 1) pulmonary embolism is generally asymptomatic 2) dyspnea (clinical predictor of delayed diagnosis) [77] - exertional dyspnea [97] 3) pleuritic chest pain or chest pressure 4) apprehension 5) cough 6) lower extremity edema, leg pain 7) tachypnea 8) tachycardia 9) hemoptysis (clinical predictor of delayed diagnosis) [77] 10) accentuation of the pulmonic component of the 2nd heart sound (P2) 11) monophonic wheeze, inspiratory & expiratory wheeze 12) crackles 13) lungs may be clear to auscultation 14) fever 15) cyanosis 16) S4 heart sound 17) syncope [8] 9-35% [56,57] - presentation with syncope or presycope increases risk of 30-day mortality (43% vs 6%) [70] 18) hypotension [26] Laboratory: 1) if Pulmonary Embolism Rule-Out Criteria (PERC) of zero, no further testing [4] - use Wells score first prior to PERC (MKSAP19) [4] - if Wells score indicates moderate probability of pulmonary embolism, do not use Pulmonary Embolism Rule-Out Criteria [4] 2) pulse oximetry*: low SaO2 (hypoxia) 3) arterial blood gas (ABG)* if needed a) hypoxia b) increased P(A-a)O2 gradient correlates with severity c) 20% of patients with PE show normal P(A-a)O2 gradient d) pCO2 is generally diminished 4) plasma D-dimer# may be elevated in pulmonary embolism a) increased D-dimers have no positive predictive value b) normal D-dimer excludes PE in < 30% of suspected cases c) negative D-dimer & low clinical probability excludes pulmonary embolism [10,14,17,32] d) elevated plasma D-dimer has very low specificity (11%) in hospitalized patients [67] e) Wells score in combination with plasma d-dimer testing can rule out pulmonary embolism in hemodynamically stable patients who present several days after onset of symptoms suggestive of PE [35] f) Wells score outperforms Geneva scores in ruling out pulmonary embolism in the primary care setting [49] g) YEARS clinical decision rule with plasma d-dimer can eliminate need for computed-tomography pulmonary angiography in 48% of patients vs 34% of patients using Wells score with a fixed cutoff plasma d-dimer of 500 ng/mL [62] - meta-analysis recommends adjusted D-dimer or YEARS criteria to rule out pulmonary embolism [93] h) D-dimer 3-4 weeks after cessation of warfarin is predictive of thromboembolic recurrence [4] - > 4-fold increased risk of elevated D-dimer relative to a normal value [4,30] - 5-year risk for recurrence ~30% in men with unprovoked VTE, despite negative D-dimer testing [82] i) -D-dimer adjusted for clinical probability [85] - < 1000 ng/mL for low-risk patients 5) serum chemistries a) serum LDH: increased b) serum bilirubin: increased (normal with MI) c) serum AST may be normal (elevated with MI) d) prostate-specific antigen (PSA) unprovoked PE in men e) serum Ca+2 & serum albumin f) troponin I in serum - positive troponin identifies moderately high 30-day risk [75] g) N-terminal pro-BNP in serum 6) complete blood count (CBC) leukocytosis 7) serum troponin I: - increase suggests right ventricular strain 8) Pap Smear vs HPV DNA for unprovoked venous thromboembolism in women [45] 9) most patients with venous thromboembolism do not require - thrombophilia testing, since results will not affect management [4,65] - extensive screening for cancer [4] 10) see ARUP consult [86] * a normal pO2 or SaO2 does not rule out PE # a low pretest probability & Pulmonary Embolism Rule-Out Criteria (PERC) rules out pulmonary embolism, plasma D-dimer & imaging not needed; with a high pretest probability, omit plasma D-dimer, go direct to pulmonary CT angiography or ventilation-perfusion scan if contraindicated or unavailable [50] Special laboratory: 1) electrocardiogram a) sinus tachycardia b) infrequent changes: (15%) - S in lead I - Q in lead III &/or aVF - ST segment elevation in leads III &/or aVF [4] - T wave inversion in lead III, aVF c) right axis deviation d) incomplete right bundle branch block e) inverted T waves in right precordial leads (40%) - T wave inversions in V2 & V3 more likely unstable angina [87] 2) consider use of Pulmonary Embolism Severity Index (PESI) to estimate risk [79] Radiology: 1) obtain imaging if D-dimer is positive or Wells score >4 [4] - do not delay treatment for diagnostic testing in symptomatic patients with high pretest probability (Wells score >6) - infuse unfractionated heparin in symptomatic patients with high test probability of pulmonary embolism [100] 2) chest X-ray: PA & lateral a) normal in 30% of patients b) Hampton's hump on lateral view c) elevated hemidiaphragm may be seen (40%) d) enlarged pulmonary artery (20%) e) pulmonary embolism unlikely if multifocal pulmonary opacities on chest X-ray [104] *** 3) evaluation for DVT by Doppler ultrasonography - 1st diagnostic imaging test in pregnancy [4] - combined thoracic, cardiac, & lower-extremity ultrasound may reduce need for CT angiography [39] - point-of-care (bedside) lung & venous ultrasound increases diagnostic performance of Wells criteria for PE [58] - pulmonary CT angiography unnecessary if DVT has been diagnosed because treatments are the same [4] 4) ventilation-perfusion scan (VQ scan) showing VQ mismatch [23] a) administer unfractionated heparin prior to VQ scan (see above) b) method of choice in the evaluation of chronic thromboembolic pulmonary hypertension [4,34] c) preferred method in patients with risk of acute kidney injury - preexisting kidney disease (chronic renal failure) - diabetes mellitus - hypovolemia - free urinary light chains of multiple myeloma [4] c) method of choice in pregnant patients because of lower radiation exposure than CT angiography [4] 5) pulmonary CT angiography (spiral CT) detects emboli [12] a) preferred method of diagnosis in patients with intermediate (moderate) to high-probability pulmonary embolism [4,33] b) detects emboli in main, lobar or segmental arteries but not subsegmental arteries c) 2nd generation helical CT may be better [14]t d) indicated in patients with abnormal D-dimer &/or high clinical suspicion [17] e) pulmonary CT angiography 83% sensitivity [18] - false positives 26% [48] f) may preclude need for ultrasound of lower extremity to rule out DVT [20] g) more than twice as likely to find an incidental nodule or adenopathy as it is to find PE [21] h) reserve for patients with indeterminate findings on ventilation-perfusion scan (VQ scan) [21] i) can not rule out PE in patients with high pre-test probability [72] 6) pulmonary CT angiography for confirmation of abnormal VQ scan [4,15] 7) mammography for unprovoked venous thromboembolism in women [45] 8) echocardiography - may show non-collapsing inferior vena cava [100] - may show right ventricular dilation with septal bowing & preserved ejection fraction [100] - clot in right atrium (case report) [40] 9) CT of abdomen not helpful for detection of cancer in unprovoked venous thromboembolism [45] *** ARDS more likely if multifocal pulmonary opacities on chest X-ray [104] Differential diagnosis: 1) asthma 2) bronchopneumonia 3) pleurisy 4) pericarditis 5) pneumothorax 6) myocardial infarction 7) acute pancreatitis 8) perforated peptic ulcer 9) fat embolism following long-bone fracture [4] 10) pulmonary hypertension* - chronic thromboembolic pulmonary hypertension * if chronic, echocardiography is the first diagnostic test to confirm pulmonary hypertension [100] Complications: 1) pulmonary infarction (< 10%) 2) recurrent pulmonary embolism (8%) - for subsegmental pulmonary embolism, recurrent venous thromboembolism within 90 days if not anticoagulated is 3.1% (1.8% if < 65 & 5.5% if > 65 years) [92] 3) secondary pulmonary hypertension (0.5-4%) occurs within 2 years [13] - chronic thromboembolic pulmonary hypertension 4) acute cor pulmonale with obstructive shock occurs when > 65% of vasculature is obstructed by pulmonary embolism - otherwise unlikely to result in congestive heart failure 5) occult malignancy (8% over two years) 6) mortality a) 7% when diagnosed at presentation b) highest in first 24 hours c) 30-day mortality 1.7% low-risk, 5.0% submassive, 23% massive PE [99] 7) heparin-induced thrombocytopenia 8) risk factors [25] a) oxygen saturation <90% on room air b) systolic blood pressure <100 mm Hg c) chest pain requiring opioids d) active bleeding, or were at high risk for hemorrhage 1] recent stroke 2] gastrointestinal bleeding 3] platelet count >75,000/mm3 e) older age f) malignant neoplasm (cancer) g) elevated N-terminal pro-BNP in serum h) elevated serum troponin 9) hemodynamic instability, serum troponin elevation, & right ventricular dysfunction more common with saddle emboli than with more distal thrombi, but outcomes are similar [66] 10) presence of patent foramen ovale may increase risk of embolic stroke in patients with pulmonary embolism [81] 11) diagnostic delays worsen prognosis [77] 12) 1/3 of patients with initial unprovoked venous thromboembolism who discontinue anticoagulation may experience recurrence within 10 years [84] Management: - also see clinical decision rules for pulmonary embolism === Unstable patients === 1) infuse unfractionated heparin if - symptomatic patient with high test probability of pulmonary embolism [100] - high risk of bleeding [100] - emergent surgery - pulmomary embolectomy or thrombolytic therapy is likely (diagnostic imaging pending)[4] 2) systemic thrombolytic therapy a) indications: 1] massive or submassive pulmonary emboli [29] - diagnosis confirmed by imaging (see radiology) 2] hemodynamically unstable [36] 3] low risk of bleeding b) contraindications: high risk of bleeding c) thrombolytic agent 1] streptokinase 2] urokinase 3] recombinant tissue plasminogen activator (Alteplase) a] 50 mg total dose (max) b] 10 ug bolus followed by 40 mg infusion over 2 hours c] 0.5 mg/kg total dose for patients weighing <50 kg 3) pulmonary embolectomy (clot extraction) a) indications - patients with angiographically-proven pulmonary emboli - patients who remain in shock despite thrombolytic therapy & supportive care, or - patients in whom thrombolytic therapy is contraindicated b) use unfractionated heparin if high risk of bleeding [100] c) case fatality rate is not age-dependent [37] d) may improve outcomes relative to anticoagulation [95] 4) intravenous catheter-directed thrombolysis for intermediate & high-risk pulmonary embolism [101] - lower mortality than systemic thrombolytic therapy or anticoagulation alone - not recommended [100] without mention of ref [101] 5) vena cava filter (see below) - associated with a reduced in-hospital all-cause case fatality rate in unstable adults with pulmonary embolism, regardless of age [38] - benefit &/or optimal use unclear [55] 6) follow with anticoagulation [89] === Stable patients === 1) supportive therapy - subsegmental pulmonary embolism may not need anticoagulation [74] - chronic thromboembolic pulmonary hypertension with proximal thromboembolism may benefit from pulmonary thromboendarterectomy - Pulmonary Embolism Severity Index (PESI) score < 86, low risk echocardiography & negative lower extremity ultrasound may be treated as outpatient [76,105] 2) anticoagulation a) therapeutic anticoagulation within 24 hours to prevent progression [4] - do not delay treatment for diagnostic testing in symptomatic patients with high pretest probability (Wells score >6) b) unfractionated heparin IV to maintain aPTT 60-90 sec 1] preferred if reversal of anticoagulation is needed - high risk of bleeding [100] - emergent surgery - pulmomary embolectomy or thrombolytic therapy is likely [4] 2] preferred if patient with brain tumor [4] 3] easier to dose in patients with renal insufficiency [4] c) LMW heparin for intermediate-risk pulmonary embolism (PE) 1] patients with metastatic cancer should receive long-term treatment with LMW heparin vs LMW heparin with transition to direct oral anticoagulant (avoid warfarin with metastatic cancer) 2] duration prior to oral anticoagulation: - 5-10 days [5]; 3 days [91] 3] enoxaparin a] 1.5 mg/kg QD or b] 1 mg/kg BID) 4] dalteparin 200 units/kg SQ QD 5] tinzaparin 175 units/kg SQ QD 6] fondaparinux a] < 50 kg (< 110 lbs) 5 mg SQ QD b] 50-100 kg (110-220 lbs) 7.5 mg SQ QD c] > 100 kg (> 220 lbs) 10 mg SQ QD [5] d) warfarin (begin concurrently with heparin or LMW heparin) 1] bolus, 10 mg QD for 1-2 days 2] begin at 2.5 mg QD 3] adjust dose to achieve INR of 2.0-3.0 (>= 5 days) 4] overlap continued heparin >= 5 days with INR > 2 for 24 hours [4] 5] maintain INR 2.0-3.0 for at least 3 months [4,19] 6] if INR becomes subtherapeutic in the 1st month following pulmonary embolism, add LMW heparin until INR is stable in the therapeutic range [4] 7] use LMW heparin rather than warfarin in patients with underlying malignancy (had been "generally accepted") [52,63], but warfarin & 8] direct-acting oral anticoagulants equally effective [42] - hemorrhage may be more common with rivaroxaban than with dalteparin [73] - see special case of antiphospholipid antibody syndrome e) American College of Chest Physicians recommends use of newer anticoagulants vs warfarin in patients with or without cancer [42,52,96] - see special case of antiphospholipid antibody syndrome - rivaroxaban may be an option [27] a] no need for bridging LMW heparin [4,61] b] NICE confirms rivaroxaban is an option for initial treatment of pulomonary embolism c] low risk of recurrent PE or bleeding while treated with rivaroxaban [47] (low = 0 in study) - apixaban may be an option - no need for bridging LMW heparin [4] - rivaroxaban & apixaban probably confer the lowest risks for major bleeding [41] - dabigatran is an option [NGC (NICE)] - requires bridging with LMW heparin [4] - edoxaban is an option - requires bridging with LMW heparin [4] - direct oral anticoagulants comparable to warfarin in patients with cancer-related venous thromboembolism [42] f) empiric anticoagulation prior to confirmation if high-probability of PE [4] g) duration of anticoagulation 1] 1st episode of thromboembolism with reversible risk factors: 3 months - 6 weeks if < 21 years [94] 2] 1st episode of idiopathic thromboembolism a] life-long therapy [4,40,46] b] continued anticoagulation reduces composite outcome of recurrent recurrent venous thrombosis & serious bleeding [46] 3] recurrent episodes of thromboembolism or 1st episode with hypercoagulable state: 12 months to life-long therapy [4] 4] HERDOO2 score may be useful in women to assess need for long-term anticoagulation h) American College of Chest Physicians recommends use aspirin after stopping anticoagulation [52] - rivaroxaban 10 or 20 mg QD more effective in preventing recurrent thromboembolism than aspirin with no difference in bleeding (RR= 1.5%, 1.2%, & 4.4%, respectively) [59] i) no clear evidence of benefit for anticoagulation in subsegmental pulmonary embolism [69] 3) inferior vena cava interruption, i.e. Greenfield filter should be considered in the following settings: a) anticoagulation is contraindicated - major bleeding from arteriovenous malformation or other cause - unless contraindicated, heparin therapy should be continued to prevent extension of a pre-existing clot - no benefit over anticoagulation alone [44] b) documented recurrent thromboembolic events in patients who are adequately anticoagulated c) massive or submassive pulmonary emboli with hemodynamic compromise, especially if the is evidence of residual thrombus in a lower extremity [88] d) patients with compromised cardiac or pulmonary function who might not survive a recurrent event e) patients undergoing pulmonary embolectomy f) patients with paradoxic emboli via a patent foramen ovale g) septic pulmonary emboli from lower extremities or pelvic veins 4) graduated compression stockings only if post-thrombotic syndrome [52] 5) routine screening for potentially treatable carcinomas [64] a) breast examination & mammography b) Pap Smear c) sigmoidoscopy d) prostate-specific antigen (PSA) e) chest X-ray 6) low risk patients may be treated as outpatient [4,25,28,71,89] a) no cardiopulmonary distress b) supplemental oxygen not needed c) intravenous medications not needed d) no cormobidities that require inpatient management [4] e) low risk of recurrence f) supportive/sufficient home environment === Prognosis === - after 1 year, exercise limitation due to deconditioning - not due to persistent physiological abnormalities [60] - good prognosis = age < 80 years, no significant comorbidity, stable vital signs - can be managed as outpatient [4] - cardiopulmonary rehabilitation improves exercise capacity & quality of life [103] . === Prevention === - see venous thromboembolism

Interactions

disease interactions

Related

clinical decision rules for pulmonary embolism deep vein thrombosis (DVT) Greenfield filter; umbrella; inferior vena cava filter; IVC filter hypercoagulability Prospective Investigation Of Pulmonary Embolism Diagnosis (PIOPED) study thrombolysis for pulmonary embolism

Specific

chronic thromboembolic pulmonary hypertension (CTEPH)

General

pulmonary vascular disease venous thromboembolism (VTE)

References

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