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Advances in Pulmonary Embolism Imaging Kelly MacLean; David Tso; Ferco Berger; Anja Reimann; Chris Davison; Joao Inacio; Ahmed Albuali; Savvas Nicolaou.

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Presentation on theme: "Advances in Pulmonary Embolism Imaging Kelly MacLean; David Tso; Ferco Berger; Anja Reimann; Chris Davison; Joao Inacio; Ahmed Albuali; Savvas Nicolaou."— Presentation transcript:

1 Advances in Pulmonary Embolism Imaging Kelly MacLean; David Tso; Ferco Berger; Anja Reimann; Chris Davison; Joao Inacio; Ahmed Albuali; Savvas Nicolaou ASER 2010

2 Objectives Identify the importance of a proper clinical scoring index exam in the ER Identify the importance of a proper clinical scoring index exam in the ER Review of literature supporting CT for pulmonary embolism versus V/Q scanning Review of literature supporting CT for pulmonary embolism versus V/Q scanning Appropriate imaging of pulmonary embolism for pregnant patients Appropriate imaging of pulmonary embolism for pregnant patients Illustrate MDCT technique, findings, artifacts, and clinical correlations Illustrate MDCT technique, findings, artifacts, and clinical correlations Introduce new techniques and methods for assessing pulmonary embolism Introduce new techniques and methods for assessing pulmonary embolism

3 Outline Introduction Introduction Pathophysiology and clinical presentation Pathophysiology and clinical presentation Clinical prediction rules and D-dimer screening Clinical prediction rules and D-dimer screening Diagnostic imaging modalities Diagnostic imaging modalities Imaging in pregnancy Imaging in pregnancy Clinical implications of MDCT findings Clinical implications of MDCT findings Diagnostic imaging algorithm Diagnostic imaging algorithm New imaging approaches New imaging approaches

4 Introduction Acute PE is common Acute PE is common High mortality rate if left untreated High mortality rate if left untreated Clinical presentation is highly variable and non- specific Clinical presentation is highly variable and non- specific Diagnosis requires appropriate and accurate imaging Diagnosis requires appropriate and accurate imaging Prompt diagnosis and treatment can reduce mortality from 30% to 2-8% Prompt diagnosis and treatment can reduce mortality from 30% to 2-8% Horlander KT; Mannino DM; Leeper KV. Arch Intern Med Jul; 163(14): Carson JL et al. N. Engl. J. Med May 7; 326(19):

5 Pathophysiology PE most commonly arise from thrombi in deep venous system of lower extremities PE most commonly arise from thrombi in deep venous system of lower extremities Iliofemoral vein thrombi most clinically recognized cause of PE Iliofemoral vein thrombi most clinically recognized cause of PE 50-80% of proximal vein thrombi originate distal to popliteal vein 50-80% of proximal vein thrombi originate distal to popliteal vein Size of PE determines location: Size of PE determines location: Main pulmonary artery Main pulmonary artery Lobar branches Lobar branches Subsegmental emboli Subsegmental emboli Moser, KM. Am. Rev. Respir. Dis. 1990; 141:235. Weinmann, EE; Salzman, EW. N. Engl. J. Med. 1994; 331:1630.

6 Pathophysiology Impaired gas exchange Impaired gas exchange Ventilation/perfusion mismatch Ventilation/perfusion mismatch Release of inflammatory mediators leads to surfactant dysfunction, atelectasis, alveolar hemorrhage Release of inflammatory mediators leads to surfactant dysfunction, atelectasis, alveolar hemorrhage Intrapulmonary shunting Intrapulmonary shunting Hypotension Hypotension Results from increased PVR, RV dilatation, impaired LV filling, eventual impaired CO Results from increased PVR, RV dilatation, impaired LV filling, eventual impaired CO Nakos G; Kitsiouli EI; Lekka ME. Am. J. Respir. Crit. Care Med Nov; 158(5 Pt 1): Goldhaber Z; Elliot CG. Circulation 2003; 108:

7 Clinical Presentation - Symptoms Dyspnea (73%) – usually acute onset Dyspnea (73%) – usually acute onset Pleuritic chest pain (44%) Pleuritic chest pain (44%) Calf pain/swelling (41-44%) Calf pain/swelling (41-44%) Orthopnea (28%) Orthopnea (28%) Wheezing (21%) Wheezing (21%) Cough (20%) Cough (20%) Syncope (14%) Syncope (14%) Hemoptysis (7%) Hemoptysis (7%) Goldhaber SZ; Visani L; De Rosa M. Lancet 1999 Apr 24; 353(9162): Stein PD et al. Am. J. Med Oct;120(10):871-9.

8 Clinical Presentation – Signs Tachypnea (53%) Tachypnea (53%) Tachycardia (24%) Tachycardia (24%) Rales (18%) Rales (18%) Decreased breath sounds (17%) Decreased breath sounds (17%) Accentuated P2 (15%) Accentuated P2 (15%) JV distension (14%) JV distension (14%) Signs and symptoms are highly variable, non- specific, and common in patients without PE Goldhaber SZ; Visani L; De Rosa M. Lancet 1999 Apr 24;353(9162): Stein PD et al. Am. J. Med Oct;120(10):871-9.

9 Work-up of patient with suspected PE Stable patients should follow sequential diagnostic workup including: Stable patients should follow sequential diagnostic workup including: Clinical probability assessment i.e. Wells Score Clinical probability assessment i.e. Wells Score +/- D-dimer +/- D-dimer +/- MDCT or V/Q scan +/- MDCT or V/Q scan The Christopher Study JAMA 2006 The Christopher Study JAMA 2006 Prospective cohort study of 3306 patients with clinically suspected PE Prospective cohort study of 3306 patients with clinically suspected PE Writing Group for the Christopher Study Investigators JAMA. 2006; 295:

10 The Christopher Study - Outcomes Low risk of VTE when low clinical probability and normal D-dimer testing CT-PA effectively rules out PE without need for other imaging studies First study to validate safety of dichotomized (modified) Wells Score vs. original Wells Score Writing Group for the Christopher Study Investigators JAMA. 2006; 295:

11 Modified Wells Criteria Clinical symptoms of DVT (leg swelling, pain with palpation) 3.0 Other diagnosis less likely than PE 3.0 Heart rate > Immobilization or surgery in previous 4 weeks 1.5 Previous DVT/PE 1.5 Hemoptysis1.0 Malignancy1.0 PE Likely >4 PE Unlikely

12 D-Dimer Screening Poor specificity and positive predictive value Poor specificity and positive predictive value Sensitivity generally good but varies with: Sensitivity generally good but varies with: Type of assay used Type of assay used Location of PE Location of PE Normal D-dimer sufficient to exclude PE if low/moderate pretest probability (Wells Score) Normal D-dimer sufficient to exclude PE if low/moderate pretest probability (Wells Score) Cost-effective Cost-effective Avoids unnecessary imaging Avoids unnecessary imaging Stein PD et al. Ann Intern Med Apr 20;140(8): De Monye W et al. Am. J. Respir. Crit. Care Med Feb 1;165(3): Perrier et al. Am. J. Respir. Crit. Care Med. 2003; 167:39-44.

13 The Christopher Study – Workup Algorithm Patient with clinically suspected pulmonary embolism Modified Wells Score PE Unlikely D-Dimer ELISA NormalAbnormal PE Likely MDCT-PA Indicated Writing Group for the Christopher Study Investigators JAMA. 2006; 295:

14 Overview of Imaging Modalities for Pulmonary Embolism Lower extremity venous ultrasonography Lower extremity venous ultrasonography Multidetector helical CT pulmonary angiography Multidetector helical CT pulmonary angiography MRI MRI Ventilation-perfusion scintigraphy (V/Q scan) Ventilation-perfusion scintigraphy (V/Q scan)

15 Lower extremity venous ultrasonography Compression U/S = B-mode imaging only Compression U/S = B-mode imaging only Duplex U/S = B-mode plus Doppler waveform analysis Duplex U/S = B-mode plus Doppler waveform analysis Limited vs.complete exam Limited vs.complete exam IIliac, common femoral, femoral, popliteal, greater saphenous, calf veins IIliac, common femoral, femoral, popliteal, greater saphenous, calf veinsAdvantages Cost Cost Portability Portability May avoid further diagnostic imaging if positive May avoid further diagnostic imaging if positiveLimitations Low sensitivity and risk of false positives Low sensitivity and risk of false positives No consistent protocol for technique No consistent protocol for technique Operator dependant Operator dependant Turkstra F; Kuijer PM; van Beek EJ; Brandjes DP; ten Cate JW; Buller HR. Ann Intern Med May 15;126(10):

16 Venous Ultrasonography Recommendations of Use First-line if radiographic imaging contraindicated or not readily available Not likely required in patient with negative CT- PA Helpful to rule out DVT in patient with non- diagnostic V/Q scan Anderson DR; Barnes D. Semin. Nucl. Med Nov;38(6)412-7.

17 Multidetector helical CT pulmonary angiography Increasingly the first-line imaging modality Increasingly the first-line imaging modality PIOPED-II Study: 824 patients evaluated prospectively with multidetector CTA versus composite reference test PIOPED-II Study: 824 patients evaluated prospectively with multidetector CTA versus composite reference test Sensitivity 83% Sensitivity 83% Specificity 96% Specificity 96% PPV = 96% with concordant clinical assessment PPV = 96% with concordant clinical assessment Stein PD et al. N. Engl. J. Med Jun 1;354(22):

18 Multidetector helical CT pulmonary angiography – Advantages Diagnosis of alternative disease entities Diagnosis of alternative disease entities Coverage of entire chest with high spatial resolution in one breath hold Coverage of entire chest with high spatial resolution in one breath hold High interobserver correlation High interobserver correlation Availability Availability Improved depiction of small peripheral emboli Improved depiction of small peripheral emboli Schoepf J; Costello P. Radiology Feb; 230:

19 Multidetector helical CT pulmonary angiography – Limitations Reader expertise required Reader expertise required Expense Expense Requires precise timing of contrast bolus Requires precise timing of contrast bolus Radiation exposure Radiation exposure Not portable Not portable Contraindications to contrast Contraindications to contrast Renal insufficiency Renal insufficiency Contrast allergy Contrast allergy Schoepf J; Costello P. Radiology Feb; 230:

20 MRI PIOPED III Trial PIOPED III Trial Accuracy of gadolinium- enhanced MR angiography in combination with venous phase venography in diagnosing acute PE Accuracy of gadolinium- enhanced MR angiography in combination with venous phase venography in diagnosing acute PE Insufficient sensitivity Insufficient sensitivity High rate of technically inadequate images High rate of technically inadequate images Stein PD et al. Ann Intern Med. 2010;152: Image: 59 y.o. male with severe dyspnea MR angiogram depicts large amounts of embolic material (arrowheads) in right pulmonary artery, in right upper and lower lobes, and in left lingual pulmonary artery. Nonenhancing masses (arrow) are present in liver. Kluge, A. et al. Am. J. Roentgenol. 2006;187:W7-W14

21 MRI Advantages Lack of ionizing radiation Lack of ionizing radiationLimitations Respiratory and cardiac motion artifact Respiratory and cardiac motion artifact Suboptimal resolution for peripheral pulmonary arteries Suboptimal resolution for peripheral pulmonary arteries Complicated blood flow patterns Complicated blood flow patterns Experimental technology may have role in future Experimental technology may have role in future Real-time MR sequence without breath hold Real-time MR sequence without breath hold Molecular MRI with fibrin-specific contrast agent Molecular MRI with fibrin-specific contrast agent Tapson, VF. N. Engl. J. Med. 1997; 336:1449. Am. J. Respir. Crit. Care Med Mar 1;167(5): Epub 2002 Nov 21. Haage P et al. Am. J. Respir. Crit. Care Med Mar 1;167(5): Epub 2002 Nov 21. Spuentrup E et al. Am. J. Respir. Crit. Care Med Aug 15;172(4): Epub 2005 Jun 3.

22 Ventilation-perfusion scintigraphy PIOPED Study: Accuracy of V/Q scan versus reference standard (pulmonary angiogram) PIOPED Study: Accuracy of V/Q scan versus reference standard (pulmonary angiogram) Scan Probability Clinical Probability of Pulmonary Emboli HighIntermediateLow High Intermediate Low40154 Normal or near normal 062 The PIOPED Investigators. JAMA May 23-30;263(20): Table: Likelihood of pulmonary embolism according to scan category and clinical probability in PIOPED study

23 V/Q Scan Advantages Advantages Excellent negative predictive value (97%) Excellent negative predictive value (97%) Can be used in patients with contraindication to contrast medium Can be used in patients with contraindication to contrast medium Limitations Limitations 30-50% of patients have non-diagnostic scan necessitating further investigation 30-50% of patients have non-diagnostic scan necessitating further investigation Sostman HD et al. Radiology. 2008;246:941-6.

24 CT-PA vs. V/Q scan Directly compared in trial of 1417 patients with suspected PE Directly compared in trial of 1417 patients with suspected PE Randomized to CT-PA or V/Q scan Randomized to CT-PA or V/Q scan Main outcome measure was development of symptomatic VTE post-negative test Main outcome measure was development of symptomatic VTE post-negative test Result: CT-PA not inferior to V/Q scan for ruling out pulmonary embolism Result: CT-PA not inferior to V/Q scan for ruling out pulmonary embolism PIOPED II PIOPED II higher rate of non-diagnostic tests with V/Q Scan vs. CT-PA (26.5% vs. 6.2%) higher rate of non-diagnostic tests with V/Q Scan vs. CT-PA (26.5% vs. 6.2%) Anderson DR et al. JAMA Dec 19;298(23): Sostman DH et al. Radiology Jan 14;246:

25 Imaging in Pregnancy No validated clinical decision rules No validated clinical decision rules No consensus in evidence for diagnostic imaging algorithm No consensus in evidence for diagnostic imaging algorithm Balance risk of radiation vs. risk of missed fatal diagnosis or unnecessary anticoagulation Balance risk of radiation vs. risk of missed fatal diagnosis or unnecessary anticoagulation MDCT delivers higher radiation dose to mother but lower dose to fetus than V/Q scanning MDCT delivers higher radiation dose to mother but lower dose to fetus than V/Q scanning Consider low-dose CT-PA or reduced-dose lung scintigraphy Consider low-dose CT-PA or reduced-dose lung scintigraphy Stein P et al. Radiology Jan;242: Marik PE; Plante LA. N. Engl. J. Med. 2008;359:

26 Multidetector-CT Technique Parameters vary by scanner equipment Parameters vary by scanner equipment Contrast material bolus Contrast material bolus Duration of injection should approximate duration of scan Desired flow rate 3-5ml/s Usually 50-80ml Best results achieved if: Best results achieved if: Thin sections High and homogenous enhancement of pulmonary vessels Data acquisition in single breath hold Schaefer-Prokop C; Prokop M. Eur. Radiol. Suppl. 2005;15(4):d37-d41.

27 Multidetector-CT Findings Partial or complete filling defects in lumen of pulmonary arteries Most reliable sign is filling defect forming acute angle with vessel wall with defect outlined by contrast material Tram-track sign Parallel lines of contrast surrounding thrombus in vessel that travels in transverse plane Rim sign Contrast surrounding thrombus in vessel that travels orthogonal to transverse plane RV strain indicated by straightening or leftward bowing of interventricular septum Macdonald S; Mayo J. Semin. Ultrasound CT. 2003;24(4):

28 Large saddle thrombus with extensive clot burden. Arrows demonstrating tram-track sign (A), rim sign (B), complete filling defect (C), and a fully non-contrasted vessel (D) A B C D MDCT Findings

29 Arrow indicating rim sign Arrow indicating tram-track sign

30 Multidetector-CT: Artifacts Pseudo-filling defects or pseudo-emboli caused by: Suboptimal contrast enhancement Motion artifact – respiratory and cardiac Volume averaging of obliquely oriented vessels Non-enhanced pulmonary veins Hilar lymph nodes Asymmetric pulmonary vascular resistance Macdonald S; Mayo J. Semin. Ultrasound CT. 2003;24(4):

31 Clinical relevance of MDCT findings I. Subsegmental Emboli Natural history largely unknown Natural history largely unknown Lack of evidence to guide management Lack of evidence to guide management Some suggest isolated subsegmental PE may not require treatment in appropriately selected subset of patients Some suggest isolated subsegmental PE may not require treatment in appropriately selected subset of patients Currently treat on case-by-base basis Currently treat on case-by-base basis Le Gal G et al. 2006;4(4): Goodman LR. Radiology. 2005;234(3) Glassroth J. JAMA. 2007;298(23):

32 Patient with pneumonectomy Lingular subsegmental pulmonary embolism (arrow)

33 Clinical Relevance of MDCT findings II. RV Strain Increased RV:LV ratio correlated with increased thrombus load Increased RV diastolic dimensions on axial CT correlate with worse outcome in acute PE Sanchez O et al. Eur. Heart J. 2008;29:1569–77. Massive bilateral PE with signs of RV strain. Dilated RV with visible thrombus (arrow).

34 Contrast seen in IVC, indicating RV strainBilateral mosaic attenuation

35 Clinical Relevance of MDCT findings III. Clot Burden Clot burden = pulmonary arterial obstruction index Clot burden = pulmonary arterial obstruction index Conflicting evidence re: clinical relevance Conflicting evidence re: clinical relevance Prospective study of 105 patients with PE found no correlation between clot burden and all-cause mortality at 12 months Prospective study of 105 patients with PE found no correlation between clot burden and all-cause mortality at 12 months Possible selection bias – patients with large clot burden may have died prior to CTPA Single-detector CTPA used

36 Clinical Relevance of MDCT findings iv. Mosaic Perfusion Mosaic perfusion is an indirect sign of nonuniform pulmonary arterial perfusion Non-specific for acute PE DDx = chronic PE, emphysema, infection, compression/invasion of pulmonary artery, atelectasis, pleuritis, and pulmonary venous hypertension No evidence demonstrating clinical relevance Wittram C et al. AJR 2006;186:S421-S429. Massive PE with RV strain and mosaic attenuation (arrow)

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38 Diagnostic Imaging Algorithm Elevated D-Dimer or High clinical probability MDCT-PA Negative May consider venous U/S but will be positive in less than 1% of patients PE confirmed V/Q Scan if contraindication to contrast Diagnostic PE confirmed PE ruled out Non-diagnostic Venous U/S Adapted from Agnelli G; Becattini C. N. Engl. J. Med. 2010;363:

39 New Imaging Approaches Dual Energy Iodine Distribution Maps Dual Energy Iodine Distribution Maps Provides functional and anatomic lung imaging Provides functional and anatomic lung imaging Demonstrates perfusion defects beyond obstructive and non- obstructive clots Demonstrates perfusion defects beyond obstructive and non- obstructive clots Diagnostic accuracy and inter/intra-observer variability requires further research Diagnostic accuracy and inter/intra-observer variability requires further research Advantages Advantages Indirect evaluation of peripheral pulmonary arterial bed Indirect evaluation of peripheral pulmonary arterial bed Disadvantages Disadvantages Longer data acquisition time Longer data acquisition time Increased radiation exposure Increased radiation exposure Pontana F et al. Acad. Radiol. 2008;15(12):1494. Multiple thrombi in main PA with extensive clot burden. Perfusion defects seen on iodine mapping

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41 New Imaging Approaches Low dose MDCT using ultra high pitch technique Useful in patients who are unable to hold their breath Timing of contrast bolus even more critical Left lower lobe subsegmental embolism (arrow) with associated atelectasis using high-pitch technique

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43 Conclusion Proper use of clinical prediction rules aids in better utilization of imaging studies and cost effectiveness Proper use of clinical prediction rules aids in better utilization of imaging studies and cost effectiveness MDCT-PA is preferred diagnostic technique MDCT-PA is preferred diagnostic technique V/Q scan for patients with contraindication to iodine contrast V/Q scan for patients with contraindication to iodine contrast Low-dose CT-PA or reduced-dose lung scintigraphy in pregnancy Low-dose CT-PA or reduced-dose lung scintigraphy in pregnancy Dual energy CT can depict regional perfusion status as well as intravascular emboli Dual energy CT can depict regional perfusion status as well as intravascular emboli High pitch low dose technique can reduce motion artifacts High pitch low dose technique can reduce motion artifacts

44 References Agnelli GL Becattini C. Acute Pulmonary Embolism. N. Engl. J. Med. 2010;363: Anderson DR et al. Computed tomographic pulmonary angiography vs ventilation-perfusion lung scanning in patients with suspected pulmonary embolism: a randomized controlled trial. JAMA Dec 19;298(23): Anderson DR; Barnes D. The use of leg venous ultrasonography for the diagnosis of pulmonary embolism. Semin. Nucl. Med Nov;38(6) Carson JL; Kelly MA; Duff A, et al. The clinical course of pulmonary embolism. N Engl J Med 1992 May 7;326(19): Chatellier G et al. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. Eur. Heart J. 2008;29:1569–77. De Monye W; Sanson BJ; Mac Gillavry MR; Pattynama PM; Buller HR; van den Berg-Huysmans AA; Huisman MV. Embolus location affects the sensitivity of a rapid quantitative D-dimer assay in the diagnosis of pulmonary embolism Am. J. Respir. Crit. Care Med Feb 1;165(3): Glassroth J. Imaging of Pulmonary Embolism – Too much of a Good Thing? JAMA. 2007;298(23): Goldhaber SZ; Visani L; De Rosa M. Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER). Lancet 1999 Apr 24;353(9162): Goldhaber Z; Elliot CG. Acute Pulmonary Embolism: Part I: Epidemiology, Pathophysiology, and Diagnosis. Circulation 2003;108; Goodman LR. Small pulmonary emboli: what do we know? Radiology. 2005;234(3) Haage P; Piroth W; Krombach G; Karaagac S; Schaffter T; Gunther RW; Bucker A. Pulmonary embolism: comparison of angiography with spiral computed tomography, magnetic resonance angiography, and real-time magnetic resonance imaging. Am. J. Respir. Crit. Care Med Mar 1;167(5): Epub 2002 Nov 21. Horlander KT; Mannino DM; Leeper KV. Pulmonary embolism mortality in the United States, : an analysis using multiple-cause mortality data. Arch Intern Med Jul;163(14): Kluge, A. et al. Acute Pulmonary Embolism to the Subsegmental Level: Diagnostic Accuracy of Three MRI Techniques Compared with 16-MDCT. Am. J. Roentgenol. 2006;187:W7-W14. Le Gal G; Righini M; Parent F: Van Strijens M; Couturaud F. Diagnosis and management of subsegmental pulmonary embolism. J. Thromb Haemost 2006;4(4): Macdonald S; Mayo J. Computed Tomography of Acute Pulmonary Embolism. Semin. Ultrasound CT. 2003;24(4): Marik PE; Plante LA. Venous thromboembolic disease and pregnancy. N. Engl. J. Med. 2008;359: Moser KM. Venous thromboembolism. Am. Rev. Respir. Dis. 1990;141:235. Nakos G; Kitsiouli EI; Lekka ME. Bronchoalveolar lavage alterations in pulmonary embolism. Am. J. Respir. Crit. Care Med Nov;158(5 Pt 1): Perrier et al. Cost-Effectiveness Analysis of Diagnostic Strategies for Suspected Pulmonary Embolism Including Helical Computed Tomography. Am. J. Respir. Crit. Care Med. 2003;167: Pontana F; Faivre BP; Remy-Jardin M et al. Lung Perfusion with Dual-energy Multidetector-row CT (MDCT): Feasibility for the Evaluation of Acute Pulmonary Embolism in 117 Consecutive Patients. Acad. Radiol. 2008;15(12):1494.

45 References Sanchez O; Trinquart L; Colombet I; Duriex P; Huisman MV. Schaefer-Prokop C; Prokop M. MDCT for the diagnosis of acute pulmonary embolism. Eur. Radiol. Suppl. 2005;15(4):d37-d41. Schoepf J; Costello P. CT Angiography for Diagnosis of Pulmonary Embolism: State of the Art. Radiology Feb;230: Sostman DH et al. Acute Pulmonary Embolism: Sensitivity and Specificity of Ventilation-Perfusion Scintigraphy in PIOPED II Study. Radiology Jan 14;246: Sostman HD; Stein PD; Gottschalk A; Matta F; Hull R; Goodman L. Acute pulmonary embolism: sensitivity and specificity of ventilation- perfusion scintigraphy in PIOPED II study. Radiology. 2008;246: Spuentrup E; Katoh M; Wiethoff AJ; Parsons EC Jr; Botnar RM; Mahnken AH; Gunther RW; Buecker A. Molecular Magnetic Resonance Imaging of Pulmonary Emboli with a Fibrin-specific Contrast Agent. Am. J. Respir. Crit. Care Med Aug 15;172(4): Epub 2005 Jun 3. Stein P; Woodard P; Weg J, et al. Diagnostic Pathways in Acute Pulmonary Embolism: Recommendations of The PIOPED II Investigators. Radiology Jan;242: Stein PD; Beemath A; Matta F; Weg JG; Yusen RD; Hales CA; Hull RD; Leeper KV Jr; Sostman HD; Tapson VF; Buckley JD; Gottschalk A; Goodman LR; Wakefied TW; Woodard PK. Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Am. J. Med Oct;120(10): Stein PD; Chenevert TL; Folwer Se et al. Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism: a multicenter prospective study (PIOPED III). Ann Intern Med. 2010;152: Stein PD; Fowler SE; Goodman LR; Gottschalk A; Hales CA; Hull RD; Leeper KV Jr; Popovich J Jr; Quinn DA; Sos TA; Sostman HD; Tapson VF; Wakefield TW; Weg JG; Woodard PK. Multidetector computed tomography for acute pulmonary embolism. N. Engl. J. Med Jun 1;354(22): Stein PD; Hull RD; Patel KC; Olson RE; Ghali WA; Brant R; Biel RK; Bharadia V; Kalra NK. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med Apr 20;140(8): Subramaniam, RM et al. Pulmonary Embolism Outcome: A Prospective Evaluation of CT Pulmonary Angiographic Clot Burden Score and ECG Score. Am. J. Roentgenol. 2008;190: Tapson VF. Pulmonary embolism new diagnostic approaches. N. Engl. J. Med. 1997;336:1449. The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA May 23-30;263(20): Turkstra F; Kuijer PM; van Beek EJ; Brandjes DP; ten Cate JW; Buller HR. Diagnostic utility of ultrasonography of leg veins in patients suspected of having pulmonary embolism. Ann Intern Med May 15;126(10): Weinmann EE; Salzman EW. Deep-vein thrombosis. N. Engl. J. Med. 1994;331:1630. Wells PS; Anderson DR; Rodger M et al. Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000 Mar;83(3): Wittram C et al. Acute and Chronic Pulmonary Emboli: Angiography–CT Correlation. AJR 2006;186:S421-S429. Writing Group for the Christopher Study Investigators. Effectiveness of Managing Suspected Pulmonary Embolism Using an Algorithm Combining Clinical Probability, D-Dimer Testing, and Computed Tomography. JAMA. 2006;295:


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