PULMONARY EMBOLISM

1. PULMONARY EMBOLISM Edward Hamaty D.O., FACCP, FACOI

2. Epidemiology • Third most common acute cardiovascular disease • After coronary ischemia and stroke • Rate is 98 (nonfatal) and 107 (fatal) events per 100,000 persons in USA • Over 300,000 hospitalizations and 50,000 deaths per year • Mortality increases with age and male sex • 40% (idiopathic / primary PE's) have increased incidence of developing overt cancer (9.1%-11.5% will HAVE occult cancer at time of PE diagnosis) • 10-20% of persons with PE have genetic thrombophilic disorders • Patients with PE are at increased risk (>1.5X) of death within 6 months of diagnosis

3. Predisposing Factors • History of DVT, Concurrent DVT >95% of patients with PE; PE occurs in >50% of cases with phlebographically confirmed DVT [31]     • Obesity ~40% (of cases) - risk is 1.7-3.2X versus non-obesity (Primarily women with BMI ≥29 kg/m2) • Cancer ~30% • Heart Failure ~35% • Surgery - perioperative and up to 30 days post surgery, ~20% • Fracture ~20% • Smoking (> 25 cigarettes/day) • Shock • Air Travel - particularly >3100 miles (5000 km) [51]

4. Predisposing Factors- con’t. • Intake of (high doses of) Estrogen        • Especially in smokers, mainly on birth control pills (oral contraceptives, OCP) • Third generation OCP have ~2X increased risk of thromboembolism versus 2nd generation • Estrogen replacement therapy (ERT): increase risk ~1.2-2X in current users [6,8] • Factor V Leiden patients on OCPs may have >30X increased risk of thromboembolism [30] • Trauma • Pregnancy: peri- and post-partum • Tumor Microembolization

5. Predisposing Factors- con’t. • Hypercoagulable States        • Factor V Leiden - Resistance to Activated Protein C (~12% of PE cases) [44] • Factor II (Prothrombin) 20210A mutation - (~10% of PE cases) [44] It was discovered in 1996 that a specific change in the geneticcode causes the body to produce an excess of the prothrombinprotein. • Protein C, S or Antithrombin III Deficiency • Acquired - antiphospholipid antibodies, paraneoplastic syndromes • Low levels of tissue factor pathway inhibitor (TFPI) Elevated clotting factors and homocysteine likely contribute • Hypertension - at least in women [5] • Thrombosis of axillarysubclavian vein (Paget-Shroetter syndrome) [55]

6. Clotting Cascade 20210A mutation ↑ F II F5L

7. RISK FACTORS FOR VENOUS THROMBOEMBOLISM

8. THROMBOPHILIAS AND PE/DVT

9. THROMBOPHILIAS AND PE/DVT

10. High Risk for Fatal Outcome • Cancer • ~15% of underlying cancer if >1 independent episode of PE • Low yield for finding occult malignancy if second event is induced (for example, by surgery) • Congestive Heart Failure (CHF) • Chronic underlying lung disease • Recurrent PE • Elevated troponin (T or I) levels in setting of PE was associated with an increased risk of short-term mortality (OR 5.24, 95% CI 3.28-8.38) or death due to PE (OR 9.44, 95% CI 4.14-21.49) [32].

11. High Risk for Fatal Outcome • Pulmonary Hypertension (P-HTN) [55,64] • Chronic recurrent PE with progression to P-HTN • Overall incidence of P-HTN ~4% within 2 years of initial PE [64] • Persistent right ventricular (RV) dysfunction after PE increases risk for recurrent DVT by 2.4X [31] • BNP: An elevated brain natriuretic peptide (BNP) or N-terminal pro-brain natriuretic peptide (NT-proBNP) predicts RV dysfunction and mortality [15,16]. This was illustrated by two meta-analyses: • A meta-analysis of 16 studies found that short-term mortality was increased 6-fold among patients with a BNP >100 pg/mL and 16-fold among patients with an NT-proBNP >600 ng/L [16]. • A meta-analysis of 13 studies (1132 patients) found that 30-day mortality was increased among patients with an elevated BNP or NT-proBNP (odds ratio 7.6, 95% CI 3.4-17) [17].

12. High Risk for Fatal Outcome • BNP and NT-proBNP may predict other adverse outcomes. • In an observational study of 73 consecutive patients diagnosed with acute PE, serum BNP levels >90 pg/mL (drawn within four hours of presentation) were associated with cardiopulmonary resuscitation, mechanical ventilation, vasopressor therapy, thrombolysis, and embolectomy, as well as death. • Serum BNP levels <50 pg/mL identified 95 percent of patients with a benign clinical course. • Troponin T > 0.07 mcg/L plus NT-proBNP ≥ 600ng/L had higher 40 day mortality vs Trop T > 0.07 and NT-proBNP < 600 (33 vs 0 %) • RV thrombus — Patients with PE and a right ventricular (RV) thrombus have a higher 14-day mortality (21 versus 11 percent) and three-month mortality (29 versus 16 percent) than patients without an RV thrombus. • Overall, few patients have recurrent emboli, particularly after initiation of therapy

13. Pathogenesis    • Clot forms at distal site, usually in distal veins in the leg or in pelvic veins • Clots usually initiated by hypercoagulable state, risk factors above, usually combination • Clots migrate to pulmonary vasculature • Most clots lodge in pulmonary arterioles or segmental arteries • Lodging at pulmonary artery bifurcation leads to "saddle" embolism • Lodged thrombi release vasoconstrictors        • Serotonin • Thrombin • Endothelin • Others

14. Pathogenesis – con’t. • Release of these vasoconstrictors causes diffuse pulmonary vascular constriction • P-HTN follows        • Severe, particularly acute, P-HTN can cause right heart failure • In addition, can cause cardiac arrest (likely due to acute P-HTN) [11,43] • Jugular venous distension on clinical exam has poor sensitivity for severe P-HTN [55] • Alveolar Dead Space • Vascular blockade (full or partial) leads to unperfused areas of lung • These areas are called dead space (ventilated but not perfused) • Alveolar dead space increases in PE in proportion to severity of vascular blockade • Alveolar dead space can be estimated from difference of exhaled and arterial CO2 levels

15. Pathogenesis – con’t. • Loss of gas exchange surface also occurs (reduced diffusion limit of carbon monoxide) • Pulmonary Tumor Embolism [62] • Presentation similar to more common thromboembolic PE • Incidence ~15% amongst patients with solid tumors • Breast, stomach, lung, liver cancers most often reported • Consider in any patient with cancer who presents with acute dyspnea

16. Pathology

17. Cardiac Consequences of Acute PE

18. Symptoms [13] • Symptoms are non-specific, not very sensitive; high suspicion must be maintained • Dyspnea 77% (A-a gradient) • Tachypnea 70% • Chest Pain 55% (usually pleuritic) • Tachycardia 43% • Cyanosis 18% • Hemoptysis 13% • Syncope 10% • Systemic embolism may occur in patients with L-R shunts [1] • Pleuritic chest pain in absence of dyspnea is common first presentation [10] • Sudden cardiac arrest with pulseless electrical activity [43]

19. Symptoms – con’t. • Cough 43% • Leg Swelling 33% • Leg Pain 30% • Palpitations 12% • Wheezing 10% • Angina-like pain 5%

20. Differential Diagnosis • Myocardial Infarction [13]        • Pneumonia        • Pulmonary Edema / Congestive Heart Failure        • Asthma, COPD Exacerbation        • Intrathoracic Cancer • Pericardial Tamponade        • Pneumothorax • Rib Fracture • Musculoskeletal Pain, Costochondritis • Sarcoma of the pulmonary artery (rare) [41] • Dissecting Thoracic Aneurysm        • Primary Pulmonary Hypertension       • Anxiety / Panic Attack

21. PE Prediction Rules "Evaluation for Pulmonary Embolism" • Suspicion should be high if ANY risk factors or symptoms/signs are present • >70% of patients who die of PE are not suspected of having it • Only ~35% of patients suspected of having PE actually have it • Pre-test probability is very important for making clinical (diagnostic) judgements • PE testing is less reliable in older persons than in younger persons [42] • Age is a major risk factor, particularly with underlying predisposing conditions

22. Clinical Probability Calculation [3,10] • Risk factors are assigned points – Modified Well’s Score • Low (<2.0), Intermediate (2.0-6.0) High (>6.0) clinical probability assigned • Clinical signs and symptoms of DVT: 3.0 points • Alternative diagnosis deemed less likely than PE: 3.0 points • Heart rate >100 beats per minute: 1.5 points • Immobilization or surgery in previous 4 weeks: 1.5 points • Previous DVT or PE: 1.5 points • Hemoptysis: 1.0 points • Cancer: 1.0 points • Clinical probabilities are used to determine evaluation • Clinical suspicion in experienced physicians likely as good as quantitative evaluation [27] • More complex clinical prediction rules have been created with similar accuracy as above

23. Wells Clinical Prediction Rule for PE

24. Evaluation Scheme Based on Clinical Probability [10,63] • Low clinical probability: high sensitivity D-dimer (level <500µg/L) to rule out PE • Lower extremity venous ultrasound (US) to rule in DVT • Helical CT angiography or V/Q scanning can also be used to rule out PE in low probability • Intermediate probability: CT angiography or V/Q scanning • High clinical probability: CT angiography or V/Q scanning • Helical CT scan may substitute for V/Q scan when combined with lower extremity US [1] • Helical CT scan can be used safely as primary diagnostic test to rule out PE [57,58] • Negative CT angiography results effectively rule out PE as well as standard angiography [] • Additional testing is done following results of initial test

25. Evaluation Scheme Based on Clinical Probability [10,63]

30. V/Q Scans • VQ scan results correlated reasonably well with positive pulmonary angiograms in PIOPED [15] • Goal is to limit pulmonary angiography to a minimum number of patients • Helical CT angiography is generally preferred over V/Q scanning • Computerized tomographic (CT) pulmonary angiography is as effective as standard pulmonary angiography and safer for ruling out PE [9] • Percentages are % of patients with positive pulmonary angiograms in PIOPED Study [15]: • V/Q Scan High PTP Intermediate Low • High probability 95% 86% 56% • Intermediate 66% 28% 15% • Low probability 40% 15% 4% • Quantitative prediction tools recommended for initial pre-test probability prediction [27]

31. V/Q Scan AND Clinical Probability

32. Specific Evaluation [32,42,63] • Routine Laboratory Tests in Suspected PE • Electrolytes, complete blood count, coagulation parameters (PT, aPTT) • ECG (standard) and ECG with right sided leads on all patients • All patients should have an Arterial Blood Gas (ABG, preferably on room air) • A PaO2 between 85 and 105 mmHg exists in approximately 18 percent of patients with PE • Normal A-a gradient found in <6% of patients with PE (see below) • High Sensitivity D-Dimer Test • Lower extremity venous US with doppler measurements

33. ECG Changes • Most common ECG is normal sinus rhythm: 23% of submassive, 6% of massive PE • Sinus Tachycardia extremely common • Right Axis Deviation; S in I, Q in III, inverted T in III "classic changes" but uncommon • If classic changes are present, anticoagulation should be started, pursue evaluation • Right sided leads should be evaluated       

34. High Sensitivity D-Dimer [17,33] • High negative predictive value for PE (based on pulmonary angiography) • For D-dimer <500ng/mL, negative predictive value (NPV) 91-99% [36] • For D-dimer >500ng/mL, sens=93%, spec=25%, and positive predictive value (PPV) = 30% • Test is also useful for DVT rule out (<500ng/mL): NPV 92% • For indeterminant V/Q scans, combination of D-Dimer and ultrasonography gave a definitive diagnosis in 62% of patients (others underwent angiography) [16] • SimpliRED bedside D-dimer test + alveolar dead space [ADS] calculation can be used in place of V/Q scans to rule out PE [36,46] Most patients with a normal ADF and a negative D-dimer do not have PE (98 percent) • Use of D-dimer test alone to rule out PE may not appropriate [39,40,46] • D-Dimer testing has reduced specificity in older persons (~10%) versus <40 years (67%) [42] • Patients with normal D-Dimer combined with low pretest clinical probability of PE could be safely discharged without further evaluation (NPV >99.5%) [33,49,50] • D-Dimer testing should be included in evaluation of PE in nearly all ambulatory patients • D-Dimer less helpful for hospital inpatients (elevations common and unrelated to PE)

35. Hi Sensitivity D-Dimer • High negative predictive value for PE (based on pulmonary angiography) • For D-dimer <500ng/mL, negative predictive value (NPV) 91-99% • For D-dimer >500ng/mL, sens=93%, spec=25%, and positive predictive value (PPV) = 30% • PPV and NPV are affected by prevalence. • Test is also useful for DVT rule out (<500ng/mL): NPV 92% • If pretest probability is intermediate (27.8) you are supposed to image, but if you order a D-Dimer what do the results mean?

36. Prevalence of 27.8% (Well’s Intermediate), Sensitivity of 93%, Specificity of 25% Sensitivity = 93% Disease +ve 80 people test positive………. of whom 26 have the disease So, chance of disease is 26/80 about 32.5% (PPV quoted at 30%) 26 28 100 Testing +ve 54 72 Disease -ve False positive rate = 75% (1-Sp)

37. Incidence of PE in the General Population • 650,000 to 900,000/year • Current US Population = 307,085,301Incidence Ranges : • From 650,000/307,085,301 = 0.0021 or 2/1000 • To 900,000/307,085,301 = 0.00293 or 3/1000 • Admittedly this includes newborns, children, etc. but is being used for illustrative purposes.

38. Prevalence of 0.003%, Sensitivity of 93%, Specificity of 25% Sensitivity = 93% Disease +ve 751 people test positive………. of whom 3 have the disease So, chance of disease is with a + test is 3/751 or about 0.4% (The lower the prevalence, the more false positives) 3 3 1000 Testing +ve 748 997 Disease -ve False positive rate = 75% (1-Sp)

39. Sensitivity and specificity don’t vary with prevalence • Test performance can vary in different settings/ patient groups, etc. • Occasionally attributed to differences in disease prevalence, but more likely is due to differences in diseased and non-diseased spectrums

40. D-Dimer

41. D-Dimer • False Positive D-Dimer • Pregnancy • Trauma • Postoperative Recovery • Inflammation • Cancer • Rheumatoid Factor • Older Age • False Negative D-Dimer • Heparin

42. D-Dimer

43. CXR

44. CXR Atelectasis Hampton’s Hump Prominent PA Westermark’s Sign

45. Ventilation-Perfusion (V/Q) Scans [15]        • High probability scans identify only ~50% of patients with PE overall • Abnormal (high + intermediate + low prob) scans detect 98% of PE's, but low specificity • About 60% of V/Q scans will be indeterminant (intermediate + low probability) • Of intermediate probability scans, ~33% occur with angiographically proven PE • Test results not affected by presence of pre-existing cardiac or pulmonary disease • Conclude: normal test rules out PE in ~98% of cases • Note that low probability test still has ~15-25% chance of PE • However, there were no deaths due to PE within 6 months in a study of 536 patients with low probability scans [35] • Further evaluation is clearly required for intermediate probability scans • For low probability scan with normal D-dimer level, no additional workup needed • Consider helical CT in patients with non-diagnostic V/Q scan [45] • NPV of helical CT with nondiagnostic V/Q is 96% [45]

46. Ventilation-Perfusion (V/Q) Scans

47. V/Q with Large Defect

48. V/Q with Multiple Defects

49. V/Q with Subsegmental Defects

50. Lower Extremity Doppler US [18,19,34] • To evaluate for DVT as possible cause of PE or to help rule in PE • Up to 40% of patients with DVT without PE symptoms will HAVE a PE by angiography • Serial US should be probably be performed in patients with abnormal (or non-diagnostic) V/Q scans and positive D-Dimers [34] • These US should be carried out on days 1, 3, 7, and 14 [32] • A positive US on any of these days with abnormal V/Q rules IN a PE [32] • Negative serial US scans reduce likelihood of PE to <2% [20]