Non-massive acute pulmonary embolus

William Atchley, MD, PhDPGY–2

Internal MedicineUAMS

Discussion overview

• Acute PE– Risk factors– Signs and symptoms– Diagnostic algorithms– Imaging studies– Treatment

• Journal Discussion– Multidetector computed tomography for acute pulmonary

embolism. New England Journal of Medicine, 354(22), 2317–2327.

• A 56-year-old woman is evaluated in the emergency department for a 4-hour history of nonproductive cough and shortness of breath. She does not have chest pain, hemoptysis, or other localizing signs. She underwent laparoscopic cholecystectomy under general anesthesia 6 weeks ago. Her medical history is notable for a childhood history of asthma, but she has not had asthma symptoms as an adult. Her sister and daughter both have asthma. She currently takes no medications.

• On physical examination, temperature is 37.0 °C (98.6 °F), blood pressure is 140/86 mm Hg in both arms, pulse rate is 72/min and regular, and respiration rate is 18/min; BMI is 33. Mild injection of the pharynx is noted. Cardiac examination is normal. Pulmonary examination reveals rare scattered wheezes bilaterally over the chest with no tenderness to palpation. Surgical incisions are healing well. The abdomen is minimally tender, and bowel sounds are normal. There is no swelling or tenderness of the legs.

• Laboratory studies reveal a D-dimer level of less than 0.5 µg/mL (0.5 mg/L) and a leukocyte count of 4,900/µL (4.9 × 109/L). Pulse oximetry is 93% breathing ambient air. Electrocardiogram and chest radiograph are normal.

Which of the following is the most appropriate next step in management?

a. Abdominal CTb. CT angiographyc. Duplex US of the legsd. Peak flow measurement

D. Peak flow measurement

• She has wheezing and pharyngeal injection on examination, which could reflect a viral respiratory infection or reflux triggering bronchospasm as the cause of her dyspnea. Thus, assessment for airflow obstruction is appropriate.

• Despite a history of recent surgery and symptoms of acute onset of dyspnea, this patient's pulmonary embolism (PE) risk score determined by either the Wells or Revised Geneva scoring systems suggests a low probability of PE.

• Immunologic D-dimer assays are particularly sensitive for detecting the presence of intravascular thrombosis. In this patient with a low PE risk score, the normal D-dimer level effectively excludes PE; therefore, further testing for PE, either by CT angiography or by duplex ultrasound of the legs (to identify deep venous thrombosis as a source for PE), is not indicated.

Acute PE

• Range of clinical severity of symptoms:– No combination of signs/symptoms/risk factors

likelihood can rule in/out PE• Can be used to estimate pre-test probability and utilize

clinical decision rules (e.g., wells score, geneva score)

– Clinical decision rules matter:• Wells and geneva scores well-validated• NOT Using CDRs is associated with inappropriate

management and worse outcomes for pts with suspected PE

Acute PE• Risk factors:

– Surgery/trauma within 3 months– OCP use, hormone therapy– Lower limb fractures/joint replacements– Neurologic injury: Stroke, paresis, paralysis– DVT

• Occurs >50% cases of confirmed DVT– Immobilization– Malignancy (highest risk with lung, hematopoietic, GI/pancreatic, and brain)– Chronic heart disease– Autoimmune diseases– Personal history of venous thromboembolism– Women, heavy smoking, obesity

Acute PE

• Symptoms:• Dyspnea/DOE (77%)

– Typically acute onset• Pleuritic/typical chest pain (44%)• Calf/thigh pain (44%)• Calf/thigh swelling (41%)• Cough (34%)• Asymptomatic (32%) • Orthopnea (28%)• Wheezing (21%)• Hemoptysis (18%)• Syncope (6%)

• Signs:• Tachypnea (54%)• Signs of DVT (25-47%)

– Edema, tenderness, erythema, palpable cord

• Hypoxia (~40% on ABG)• Tachycardia (24%)• 4th heart sound (24%)• Rales (18%)• Reduced breath sounds (17%)• JVD (14%)• Fever (10%)• Hypotension (8%)

Diagnosis of PE• H&P:– Signs/symptoms are important but non-specific– Clinical impression alone• ~85% sensitive and 51% specific for acute PE

– Additional diagnostic studies and algorithms required whenever PE is suspected• Use a clinical decision prediction rule!

– Over and underdiagnosis associated significant morbidity and mortality

Classification

Clinical decision rules

• The use of evidence-based pre-test probability rules to guide diagnostic testing. – Key step in all diagnostic algorithms for acute PE. • Wells score• Modified Geneva score

Wells scoreCriteria Points

Clinical signs/symptoms of DVT 3

PE is most likely diagnosis 3

Tachycardia (>100 bpm) 1.5

Immobilization/surgery in previous 4 weeks 1.5

Prior DVT/PE 1.5

Hemoptysis 1

Active malignancy (trt w/in 6 month) 1

Low Risk< 2 points

Intermediate risk2-6 points

High risk>6 points

PE unlikely0-4 points

PE Likely>4 points

Revised Geneva scoreCriteria Points

Age >65 1

Previous DVT/PE 3

Surgery/lower limb fracture (past month) 2

Active malignancy 2

Unilateral limb pain 3

Hemoptysis 2

HR 75-94 3

HR >94 5

Low Risk< 4 points

Intermediate risk4-10 points

High risk>10 points

Prevalence of PE by risk score

Stein, P. D., Woodard, P. K., Weg, J. G., Wakefield, T. W., Tapson, V. F., Sostman, H. D., et al. (2006). Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II investigators. The American Journal of Medicine, 119(12), 1048–1055.

Clinical decision pathways

D-dimer• Fibrin degradation product, elevated in acute thrombotic disorders

• High sensitivity: – In select populations, has high negative predictive value. i.e., can exclude the diagnosis

• Populations LOW/INTERMEDIATE pre-test probability

– Post-test probability of having a PE is < 1-3%

• Low specificity:– False positives: elderly, malignancy, hospitalization, prior VTE

• Populations where D-dimer testing not useful – > 14 days since symptom onset– HOSPITALIZED pts– Pts already on heparin or oral anticoagulants – Specificity decreases steadily with increasing age

• Age-corrected cut-offs? May be useful.

Other diagnostic studies• ABG/pulse ox:

– Limited diagnostic utility– Hypoxemia, respiratory alkalosis typical– Massive PE w/hypotension: hypercapenia, mixed acidosis

• Troponin: – Elevated in 30-50% of cases with mod -> large PE– Due to acute R-sided overload/strain– Associated with worse prognosis

• ECG:– Common: non-specific ST and T-wave changes (70%)– S1Q3T3 - R-ventricular strain– New incomplete RBBB

• Chest radiography:– Very non-specific– Atelectasis or parenchymal abnormalities common– Less than 20% have a “normal” chest radiograph

Compression ultrasonography• Relatively Inexpensive, non-invasive, low risk

• Sensitivity (90-95%), specificity (94-99%) for DVT in symptomatic pts

• Positive result establishes VTE - TREAT!

• Consider in unstable or pregnant patients and in those with signs/sxs of DVT.

• Useful as adjunctive test for indeterminant V/Q scans

• Cannot be used alone to exclude PE. – >50% pts with acute PE have no DVT on US

V/Q scan• Nuclear medicine study. Avoids contrast, less radiation exposure

– Utilized technetium-99 labeled albumin particles and an inhaled particle– Assess ventilation/perfusion mismatches.

• A well-validated tool, but now supplanted by CTPA– Not available 24 hrs/day (technologist not always available)– CTPA provides increased cardiopulmonary diagnostic yields– Lower volume of studies = less skilled interpreters

• Interpretation: – Normal result: rules out PE.

• NPV ~100%

– Positive (high probability) result in moderate to high risk pts• PPV ~90%

– Indeterminant results:• Depending on study population, only ~50% pts get definitive dx• Can improve diagnostic yield by excluding pts with underlying cardiopulmonary dz or abnormal CXR

• Clinical utility increased in renal failure, contrast allergy, pregnancy, young women• Some consider it first line in young patients with normal CXR

Computed Tomography Pulmonary Angiography (CTPA)

• Method of choice for suspected PE

• PIOPED II study established sensitivity/specificity (more on that later)– Many studies supporting CTPA use in conjunction

with clinical decision rules

• Most experts agree, CTPA is effective at ruling OUT PE in pts with low-moderate pre-test probability

CTPA• Controversies:

• Management after a negative CTPA in setting of HIGH pre-test probability– LOW Negative predictive value

• Management after a positive CTPA in setting of LOW pre-test probability– LOW Positive predictive value

• Clinical significance of isolated sub-segmental PE is questionable. – Inter-observer variation HIGH– Many recommend f/up with compression US and address risk/benefits for each

patient individually.

• Incidental PE discovered on chest CT:– ~1-2% of studies find PE when ordered for other reason. – Address size, risk factors, and clinical significance for each patient individually

Pulmonary angiography

• Historically, THE Gold standard• Higher radiation and contrast exposure• Invasive• Costly

• A 62-year-old woman is admitted to the hospital for a 4-hour history of moderate dyspnea and right-sided pleuritic chest pain following an extended automobile trip. Her medical history is significant for long-standing type 2 diabetes mellitus for which she takes glipizide. She had transient hypotension on initial presentation that was corrected with a 500-mL bolus of normal saline.

• On physical examination, she appears alert but anxious. Temperature is 37.8 °C (100.0 °F), blood pressure is 118/70 mm Hg, pulse rate is 108/min and regular, and respiration rate is 22/min. Oxygen saturation is 82% on ambient air and improves to 94% on 5 L/min of oxygen by nasal prongs. Pulmonary examination reveals no focal findings. Cardiac examination discloses sinus tachycardia with a prominent S2; there are no murmurs or rubs.

• Laboratory studies reveal a serum creatinine level of 2.5 mg/dL (221 µmol/L) and a B-type natriuretic peptide level of 500 pg/mL. Ventilation-perfusion lung scanning shows multiple bilateral segmental filling defects consistent with a high probability of pulmonary embolism. An echocardiogram shows normal left and right ventricular systolic function with right ventricular dilatation; mean pulmonary artery pressure is estimated to be 20 mm Hg.

Which of the following is the most appropriate next step in management?

a. Alteplaseb. Low molecular weight heparinc. Thrombus extractiond. Unfractionated heparin

D. Unfractionated heparin

• There is right ventricular dilatation, borderline pulmonary hypertension, and an elevated B-type natriuretic peptide level, suggesting she is at risk for hemodynamic complications. Thus, anticoagulation with unfractionated heparin is indicated at this time.

• The primary indication for thrombolysis with agents such as alteplase in pulmonary embolism is persistent hypotension and hemodynamic instability. Similar indications as thrombus extraction.

Acute PE Treatment

• Consider pre-test likelihood of disease and clinical setting

• In all unstable patients, and in those who have high pre-test probability, anticoagulation should be instituted barring any contraindications.

• Early treatment with anticoagulation is associated with a reduced inpatient and 30-day mortality in pts with acute PE

Anticoagulation

• Goal to prevent early death and recurrent VTE

• Acute phase:– LMWH, UFH, fondaparinux

• UFH recommended only if reperfusion is considered and/or when Creatinine clearance < 30

– Overlap with institution of vitamin K antagonist• Goal INR 2-3

– New agents: dabigatran, rivaroxaban, abixaban

European society of Cardiology 2014 guidelines

• Duration of anticoagulant therapy

Journal Discussion

• Multidetector Computed Tomography for Acute Pulmonary Embolism – Stein, P. D., Fowler, S. E., Goodman, L. R.,

Gottschalk, A., Hales, C. A., Hull, R. D., et al. (2006). New England Journal of Medicine, 354(22), 2317–2327.

PIOPED II

• The Prospective Investigation of Pulmonary Embolism Diagnosis II trial

• Designed to assess the utility of contrast-enhanced spiral CT (multidetector CTA) to detect and exclude the diagnosis of acute PE. – Also compared CTA alone vs combined CTA-CTV– Also assessed whether the Well’s score improves detection (PPV) or

exclusion (NPV) of acute PE (using either CTA or CTA-CTV)

• Funded by the NIH - National Heart, Lung, and Blood Institute.

PIOPED II

• Study design:– Prospective, multi-center (8 centers), 2001-2003– Utilized institutional IRBs and a data safety monitoring

board

• Study Population:– 18yrs or older– Clinically suspected acute PE– Willing to have several diagnostic studies performed to

diagnose/exclude PE

PIOPED II

• Exclusion criteria:• Prisoners• Pregnant women• Allergy to intravenous contrast• Renal failure• Chronic pulmonary hypertension• Chronic anticoagulant therapy or planned thrombolytic

therapy• Inferior vena cava filter• Major ventricular arrhythmias in the preceding 24 hours;• Myocardial infarction in the preceding month; and• Critically ill or ventilated patients.

PIOPED II• Diagnostic work-up:

– Wells score determined for each patient– All patients underwent:

• CTA-CTV• V/Q scan• Venous compression US• Chest radiograph• Pulmonary-digital subtraction angiography (DSA) (IF NEEDED)

– Only used if PE could not be diagnosed/excluded with other studies.

– All studies to be completed within 36 hr period.

– All studies were interpreted by two independent radiologists at outside institutions. • If disagreement, additional radiologist asked to read and majority ruled. • Radiologists were blinded and had no additional imaging

Criteria for diagnosis• Composite reference standard:

– To diagnose PE:• Required ONE of the following:

– High probability of PE on V/Q scan in pt w/no hx of PE– DVT found on compression US in pt with no prior DVT and non-diagnostic V/Q scan (Surrogate of

acute PE in this case). – Abnormal pulmonary DSA findings

– To exclude PE:• Required ONE of the following

– Normal findings on V/Q scan– Normal findings on DSA– V/Q scan showing low/very-low probability PE

» AND Wells score < 2» AND normal venous US of lower extremities

• IF PE was excluded by the reference standard, they had 3 and 6 month follow up to assess for death and VTE

Study demographics

PIOPED II Results

23% (192/824) diagnosed with acute PE based on reference standard

Key interpretative terms• Population Independent measures:

– Sensitivity: (true positive rate) • Number with the condition who test positive for it• Higher sensitivity = lower false negative• TP / (TP + FN)

– Specificity: (true negative rate)• Number without the condition who test negative for it• Higher specificity = lower false positive• TN / (TN + FP)

• Population-dependent measures– PPV:

• Probability that pts with POS screening test truly have the disease• TP / TP + FP

– NPV: • Probability that pts with NEG screening test truly do NOT have the disease• TN / TN + FN

CTA:- 51 of the CTA studies were non-interpretable by the radiologist- Sensitivity: 83% (150/181) PPV: 86% (150/175)- Specificity: 96% (567/592) NPV: 95% (567/598)

True positive True negativeTest positiveTest negative

CTA-CTV:- 87 of the studies were non-interpretable by the radiologist- Sensitivity: 90% (164/183) PPV: 85% (164/194)- Specificity: 95% (524/554) NPV: 97% (524/543)

True positive True negativeTest positiveTest negative

Wells score and CT prediction

• In patients with LOW wells scores and a “positive” CTA, only 58% truly have a PE• High FALSE POSITIVE rate (42% FP)

Wells score and CT prediction

• In patients with HIGH wells scores and a “negative” CTA, only 60% truly DON’T have a PE• High FALSE NEGATIVE rate (40% FN)

Key findings

• Both CTA and CTA-CTV require additional testing to rule out/in PE if Wells score and CT results are incongruent

• CTA alone has an overall false negative rate of 17%, which suggests need additional studies/info to rule out PE.

Recommendations from PIOPED II

• Patients with suspected pulmonary embolism should have an objective clinical assessment.

• Obtain a D-dimer rapid ELISA if clinical assessment is low or intermediate probability.

• CT angiography/CT venography is recommended by most PIOPED II investigators as the first imaging tests.

• With discordant findings of clinical assessment and CT angiograms or CT angiograms/CT venograms, further evaluation may be necessary.

• In pregnant women and women of reproductive age, pulmonary scintigraphy may be the imaging test of choice.

Recommendations from PIOPED II

Stein, P. D., Woodard, P. K., Weg, J. G., Wakefield, T. W., Tapson, V. F., Sostman, H. D., et al. (2006). Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II investigators. The American Journal of Medicine, 119(12), 1048–1055.

Recommendations from PIOPED II

Stein, P. D., Woodard, P. K., Weg, J. G., Wakefield, T. W., Tapson, V. F., Sostman, H. D., et al. (2006). Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II investigators. The American Journal of Medicine, 119(12), 1048–1055.

Recommendations from PIOPED II

Stein, P. D., Woodard, P. K., Weg, J. G., Wakefield, T. W., Tapson, V. F., Sostman, H. D., et al. (2006). Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II investigators. The American Journal of Medicine, 119(12), 1048–1055.

References• Stein, P. D., Fowler, S. E., Goodman, L. R., Gottschalk, A., Hales, C. A., Hull, R. D., et al. (2006). Multidetector

computed tomography for acute pulmonary embolism. New England Journal of Medicine, 354(22), 2317–2327.

• Roy, P.-M. (2006). Appropriateness of Diagnostic Management and Outcomes of Suspected Pulmonary Embolism. Annals of Internal Medicine, 144(3), 157–164.

• Ceriani, E., Combescure, C., Le Gal, G., Nendaz, M., Perneger, T., Bounameaux, H., et al. (2010). Clinical prediction rules for pulmonary embolism: a systematic review and meta analysis. ‐ Journal of Thrombosis and Haemostasis, 8(5), 957–970.

• Moores, L. K., King, C. S., & Holley, A. B. (2011). Current Approach to the Diagnosis of Acute Nonmassive Pulmonary Embolism. CHEST Journal, 140(2), 509–518. doi:10.1378/chest.10-2468

• Authors/Task Force Members, Konstantinides, S. V., Torbicki, A., Agnelli, G., Danchin, N., Fitzmaurice, D., et al. (2014). 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) Endorsed by the European Respiratory Society (ERS). European Heart Journal.

• Stein, P. D., Woodard, P. K., Weg, J. G., Wakefield, T. W., Tapson, V. F., Sostman, H. D., et al. (2006). Diagnostic pathways in acute pulmonary embolism: recommendations of the PIOPED II investigators. The American Journal of Medicine, 119(12), 1048–1055.

Questions?

Hemodynamic compromise

NPV of D-dimer

Konstantinides, S. V., Torbicki, A., Agnelli, G., Danchin, N., Fitzmaurice, D., et al. (2014). 2014 ESC Guidelines on the diagnosis and management of acute pulmonary embolism: The Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC) Endorsed by the European Respiratory Society (ERS). European Heart Journal. doi:10.1093/eurheartj/ehu283

European society of Cardiology 2014 guidelines

• Non-massive PE:

European society of Cardiology 2014 guidelines

• Non-massive PE:

CTA results

• PPV adjusted for location of PE:– Main/lobar PE: • PPV 97% (116/120)

– Segmental vessel PE:• PPV 68% (32/47)

– Sub-segmental vessel PE:• PPV 25% (2/8)

Sensitivity, Specificity, Positive Predictive Value, & Negative

Predictive Value

Test Disease

Yes No

Positive True Positives False Positives(Type II Error)

Negative False Negatives(Type I Error)

True Negatives

 

Summary

Sensitivity- How many cases of a disease a positive test identifies

Specificity- How many non-cases of a disease a negative test identifies

Positive Predictive Value- How many times a positive test is correct

Negative Predictive Value- How many times a negative test is correct

Test Disease

Yes No Total Positive  150  25  175 PPV

150/175=86%

Negative  31  567  598 NPV567/598=95%

Total  181  592  773

Sensitivity150/181=83%

Specificity567/59=96%

Test Disease  

Yes No Total

Positive  81  1  82 PPV81/82=99%

Negative  9  9  18 NPV9/18=50%

Total  90 10 100  

 

Sensitivity=90%

Specificity=90%

 

High Prevalence

Test Disease  

Yes No Total

Positive  9  9  18 PPV9/18=50%

Negative  1  81  82 NPV81/82=99%

Total  10 90 100  

 

Sensitivity=90%

Specificity=90%  

Low Prevalence

Perfect Test 100% Sensitivity 100% Specificity

Sensitivity = Specificity

High Sensitivity, Low Specificity

High Specificity, Low Sensitivity

Resources

http://www.youtube.com/watch?v=vtYDyGGeQyohttp://www.youtube.com/watch?v=Z5TtopYX1Gchttp://www.youtube.com/watch?v=zIn6d3umPGo