076 advances in pulmonary imaging

Advances in Pulmonary Advances in Pulmonary Embolism ImagingEmbolism Imaging

Kelly MacLean; David Tso; Ferco Berger; Kelly MacLean; David Tso; Ferco Berger; Anja Reimann; Chris Davison; Joao Inacio; Anja Reimann; Chris Davison; Joao Inacio;

Ahmed Albuali; Savvas NicolaouAhmed Albuali; Savvas Nicolaou ASER 2010ASER 2010

ObjectivesObjectives Identify the importance of a proper clinical scoring Identify the importance of a proper clinical scoring

index exam in the ERindex exam in the ER Review of literature supporting CT for pulmonary Review of literature supporting CT for pulmonary

embolism versus V/Q scanningembolism versus V/Q scanning Appropriate imaging of pulmonary embolism for Appropriate imaging of pulmonary embolism for

pregnant patientspregnant patients Illustrate MDCT technique, findings, artifacts, and Illustrate MDCT technique, findings, artifacts, and

clinical correlationsclinical correlations Introduce new techniques and methods for Introduce new techniques and methods for

assessing pulmonary embolismassessing pulmonary embolism

OutlineOutline IntroductionIntroduction Pathophysiology and clinical presentationPathophysiology and clinical presentation Clinical prediction rules and D-dimer screeningClinical prediction rules and D-dimer screening Diagnostic imaging modalities Diagnostic imaging modalities Imaging in pregnancyImaging in pregnancy Clinical implications of MDCT findingsClinical implications of MDCT findings Diagnostic imaging algorithmDiagnostic imaging algorithm New imaging approachesNew imaging approaches

IntroductionIntroduction

Acute PE is common Acute PE is common High mortality rate if left untreatedHigh mortality rate if left untreated Clinical presentation is highly variable and non-Clinical presentation is highly variable and non-

specificspecific Diagnosis requires appropriate and accurate Diagnosis requires appropriate and accurate

imagingimaging Prompt diagnosis and treatment can reduce Prompt diagnosis and treatment can reduce

mortality from 30% to 2-8%mortality from 30% to 2-8%

Horlander KT; Mannino DM; Leeper KV. Arch Intern Med. 2003 Jul; Horlander KT; Mannino DM; Leeper KV. Arch Intern Med. 2003 Jul; 163(14):1711-7.163(14):1711-7.

Carson JL et al. N. Engl. J. Med. 1992 May 7; 326(19):1240-5.Carson JL et al. N. Engl. J. Med. 1992 May 7; 326(19):1240-5.

Pathophysiology Pathophysiology

PE most commonly arise from thrombi in PE most commonly arise from thrombi in deep venous system of lower extremitiesdeep venous system of lower extremities Iliofemoral vein thrombi most clinically Iliofemoral vein thrombi most clinically

recognized cause of PErecognized cause of PE50-80% of proximal vein thrombi originate distal to 50-80% of proximal vein thrombi originate distal to

popliteal veinpopliteal vein

Size of PE determines location:Size of PE determines location:Main pulmonary arteryMain pulmonary arteryLobar branchesLobar branchesSubsegmental emboliSubsegmental emboli

Moser, KM. Am. Rev. Respir. Dis. 1990; 141:235.Moser, KM. Am. Rev. Respir. Dis. 1990; 141:235.Weinmann, EE; Salzman, EW. N. Engl. J. Med. 1994; Weinmann, EE; Salzman, EW. N. Engl. J. Med. 1994;

331:1630.331:1630.

PathophysiologyPathophysiology Impaired gas exchange Impaired gas exchange

Ventilation/perfusion mismatchVentilation/perfusion mismatchRelease of inflammatory mediators leads to Release of inflammatory mediators leads to

surfactant dysfunction, atelectasis, alveolar surfactant dysfunction, atelectasis, alveolar hemorrhagehemorrhage

Intrapulmonary shuntingIntrapulmonary shuntingHypotensionHypotension

Results from increased PVR, RV dilatation, Results from increased PVR, RV dilatation, impaired LV filling, eventual impaired COimpaired LV filling, eventual impaired CO

Nakos G; Kitsiouli EI; Lekka ME. Am. J. Respir. Crit. Care Med. 1998 Nov; 158(5 Pt 1):1504-10.

Goldhaber Z; Elliot CG. Circulation 2003; 108:2726-2729.

Clinical Presentation - Clinical Presentation - SymptomsSymptoms

Dyspnea (73%) – usually acute onsetDyspnea (73%) – usually acute onsetPleuritic 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):1386-9.

Stein PD et al. Am. J. Med. 2007 Oct;120(10):871-9.

Clinical Presentation – SignsClinical 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- Signs and symptoms are highly variable, non- specific, and common in patients without PEspecific, and common in patients without PE

Goldhaber SZ; Visani L; De Rosa M. Lancet 1999 Apr 24;353(9162):1386-9.

Stein PD et al. Am. J. Med. 2007 Oct;120(10):871-9.

Work-up of patient with Work-up of patient with suspected PEsuspected PE

Stable patients should follow sequential Stable patients should follow sequential diagnostic workup including:diagnostic workup including:Clinical probability assessment i.e. Wells Clinical probability assessment i.e. Wells

ScoreScore+/- D-dimer+/- D-dimer+/- MDCT or V/Q scan +/- MDCT or V/Q scan

The Christopher Study JAMA 2006The Christopher Study JAMA 2006Prospective cohort study of 3306 patients Prospective cohort study of 3306 patients

with clinically suspected PEwith clinically suspected PE

Writing Group for the Christopher Study Investigators JAMA. 2006; 295:172-179.

The Christopher Study - OutcomesThe 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; 295:172-179.

Modified Wells CriteriaModified Wells Criteria

Clinical symptoms of DVT (leg swelling, pain with Clinical symptoms of DVT (leg swelling, pain with palpation)palpation)

3.03.0

Other diagnosis less likely than PEOther diagnosis less likely than PE 3.03.0

Heart rate >100Heart rate >100 1.51.5

Immobilization or surgery in previous 4 weeksImmobilization or surgery in previous 4 weeks 1.51.5

Previous DVT/PEPrevious DVT/PE 1.51.5

HemoptysisHemoptysis 1.01.0

MalignancyMalignancy 1.01.0

PE LikelyPE Likely >4>4

PE UnlikelyPE Unlikely </= 4</= 4

Wells PS et al. Thromb Haemost 2000 Mar; 83(3):416-20.

D-Dimer ScreeningD-Dimer Screening Poor specificity and positive predictive valuePoor specificity and positive predictive value Sensitivity generally good but varies with:Sensitivity generally good but varies with:

Type of assay usedType of assay used Location of PE Location of PE

Normal D-dimer sufficient to exclude PE if Normal D-dimer sufficient to exclude PE if low/moderate pretest probability (Wells Score)low/moderate pretest probability (Wells Score)

Cost-effectiveCost-effective Avoids unnecessary imagingAvoids unnecessary imaging

Stein PD et al. Ann Intern Med. 2004 Apr 20;140(8):589-602.Stein PD et al. Ann Intern Med. 2004 Apr 20;140(8):589-602.De Monye W et al. Am. J. Respir. Crit. Care Med. 2002 Feb

1;165(3):345-8. Perrier et al. Am. J. Respir. Crit. Care Med. 2003; 167:39-44.

The Christopher Study – Workup The Christopher Study – Workup AlgorithmAlgorithm

Patient with clinically suspected pulmonary embolism

Modified Wells Score

PE Unlikely

D-Dimer ELISA

PE Likely

MDCT-PA Indicated

Normal Abnormal

Writing Group for the Christopher Study Investigators JAMA. 2006; 295:172-179.

Lower extremity venous ultrasonographyLower extremity venous ultrasonography Compression U/S = B-mode imaging onlyCompression U/S = B-mode imaging only Duplex U/S = B-mode plus Doppler waveform analysisDuplex U/S = B-mode plus Doppler waveform analysis Limited vs.complete examLimited vs.complete exam

IIliac, common femoral, femoral, popliteal, greater saphenous, IIliac, common femoral, femoral, popliteal, greater saphenous, calf veinscalf veins

AdvantagesAdvantages CostCost PortabilityPortability May avoid further diagnostic imaging if positiveMay avoid further diagnostic imaging if positiveLimitationsLimitations Low sensitivity and risk of false positivesLow sensitivity and risk of false positives No consistent protocol for techniqueNo consistent protocol for technique Operator dependantOperator dependant

Turkstra F; Kuijer PM; van Beek EJ; Brandjes DP; ten Cate JW; Buller HR. Ann Intern Med. 1997 May 15;126(10):775-81.

Venous UltrasonographyVenous 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. 2008 Nov;38(6)412-7.

Multidetector helical CT pulmonary Multidetector helical CT pulmonary angiographyangiography

Increasingly the first-line imaging modalityIncreasingly the first-line imaging modalityPIOPED-II Study: 824 patients evaluated PIOPED-II Study: 824 patients evaluated

prospectively with multidetector CTA prospectively with multidetector CTA versus composite reference testversus composite reference testSensitivity 83%Sensitivity 83%Specificity 96%Specificity 96%PPV = 96% with concordant clinical PPV = 96% with concordant clinical

assessment assessment

Stein PD et al. N. Engl. J. Med. 2006 Jun 1;354(22):2317-27.

Multidetector helical CT pulmonary Multidetector helical CT pulmonary angiography – angiography – AdvantagesAdvantages

Diagnosis of alternative disease entitiesDiagnosis of alternative disease entitiesCoverage of entire chest with high spatial Coverage of entire chest with high spatial

resolution in one breath holdresolution in one breath holdHigh interobserver correlationHigh interobserver correlationAvailabilityAvailability Improved depiction of small peripheral Improved depiction of small peripheral

emboliemboli

Schoepf J; Costello P. Radiology. 2004 Feb; 230:329-337.

Multidetector helical CT pulmonary Multidetector helical CT pulmonary angiography – angiography – LimitationsLimitations

Reader expertise requiredReader expertise requiredExpenseExpenseRequires precise timing of contrast bolusRequires precise timing of contrast bolusRadiation exposureRadiation exposureNot portableNot portableContraindications to contrastContraindications to contrast

Renal insufficiencyRenal insufficiencyContrast allergyContrast allergy

Schoepf J; Costello P. Radiology. 2004 Feb; 230:329-337.

MRIMRI PIOPED III Trial PIOPED III Trial

Accuracy of gadolinium-Accuracy of gadolinium-enhanced MR enhanced MR angiography in angiography in combination with combination with venous phase venous phase venography in venography in diagnosing acute PEdiagnosing acute PE

Insufficient sensitivity Insufficient sensitivity High rate of technically High rate of technically

inadequate imagesinadequate images

Stein PD et al. Ann Intern Med. 2010;152:434-43.

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

MRIMRIAdvantagesAdvantages

Lack of ionizing radiationLack of ionizing radiation

LimitationsLimitations Respiratory and cardiac motion artifactRespiratory and cardiac motion artifact Suboptimal resolution for peripheral pulmonary arteriesSuboptimal resolution for peripheral pulmonary arteries Complicated blood flow patternsComplicated blood flow patterns

Experimental technology may have role in future Experimental technology may have role in future Real-time MR sequence without breath holdReal-time MR sequence without breath hold Molecular MRI with fibrin-specific contrast agentMolecular MRI with fibrin-specific contrast agent

Tapson, VF. N. Engl. J. Med. 1997; 336:1449.

Haage P et al. Am. J. Respir. Crit. Care Med. 2003 Mar 1;167(5):729-34. Epub 2002 Nov 21.Am. J. Respir. Crit. Care Med. 2003 Mar 1;167(5):729-34. Epub 2002 Nov 21. Spuentrup E et al. Am. J. Respir. Crit. Care Med. 2005 Aug 15;172(4):494-500. Epub 2005 Jun 3.

Ventilation-perfusion scintigraphyVentilation-perfusion scintigraphy

PIOPED Study: Accuracy of V/Q scan versus PIOPED Study: Accuracy of V/Q scan versus reference standard (pulmonary angiogram)reference standard (pulmonary angiogram)

Scan ProbabilityScan ProbabilityClinical Probability of Pulmonary EmboliClinical Probability of Pulmonary Emboli

HighHigh IntermediateIntermediate LowLow

HighHigh 9595 8686 5656IntermediateIntermediate 6666 2828 1515LowLow 4040 1515 44Normal or near Normal or near normal normal

00 66 22

The PIOPED Investigators. JAMA. 1990 May 23-30;263(20):2753-9.

Table: Likelihood of pulmonary embolism according to scan category and clinical probability in PIOPED study

V/Q ScanV/Q Scan

AdvantagesAdvantagesExcellent negative predictive value (97%)Excellent negative predictive value (97%)Can be used in patients with contraindication Can be used in patients with contraindication

to contrast mediumto contrast mediumLimitationsLimitations

30-50% of patients have non-diagnostic scan 30-50% of patients have non-diagnostic scan necessitating further investigationnecessitating further investigation

Sostman HD et al. Radiology. 2008;246:941-6.

CT-PA vs. V/Q scanCT-PA vs. V/Q scan

Directly compared in trial of 1417 patients with Directly compared in trial of 1417 patients with suspected PEsuspected PE

Randomized to CT-PA or V/Q scanRandomized to CT-PA or V/Q scan Main outcome measure was development of Main outcome measure was development of

symptomatic VTE post-negative testsymptomatic VTE post-negative test Result: CT-PA not inferior to V/Q scan for ruling Result: CT-PA not inferior to V/Q scan for ruling

out pulmonary embolismout pulmonary embolism

PIOPED IIPIOPED II higher rate of non-diagnostic tests with V/Q Scan vs. higher rate of non-diagnostic tests with V/Q Scan vs.

CT-PA (26.5% vs. 6.2%)CT-PA (26.5% vs. 6.2%)Anderson DR et al. JAMA. 2007 Dec 19;298(23):2743-53.Sostman DH et al. Radiology. 2008 Jan 14;246:941-946.

Imaging in PregnancyImaging in Pregnancy No validated clinical decision rulesNo validated clinical decision rules No consensus in evidence for diagnostic No consensus in evidence for diagnostic

imaging algorithmimaging algorithm Balance risk of radiation vs. risk of missed fatal Balance risk of radiation vs. risk of missed fatal

diagnosis or unnecessary anticoagulationdiagnosis or unnecessary anticoagulation MDCT delivers higher radiation dose to mother MDCT delivers higher radiation dose to mother

but lower dose to fetus than V/Q scanningbut lower dose to fetus than V/Q scanning Consider low-dose CT-PA or reduced-dose lung Consider low-dose CT-PA or reduced-dose lung

scintigraphyscintigraphy

Stein P et al. Radiology. 2007 Jan;242:15-21.Stein P et al. Radiology. 2007 Jan;242:15-21.

Marik PE; Plante LA. N. Engl. J. Med. 2008;359:2025-33.Marik PE; Plante LA. N. Engl. J. Med. 2008;359:2025-33.

Multidetector-CTMultidetector-CTTechniqueTechnique

Parameters vary by scanner equipmentParameters vary by scanner equipment Contrast material bolusContrast material bolus

Duration of injection should approximate duration of Duration of injection should approximate duration of scanscan

Desired flow rate 3-5ml/sDesired flow rate 3-5ml/s Usually 50-80mlUsually 50-80ml

Best results achieved if:Best results achieved if: Thin sectionsThin sections High and homogenous enhancement of pulmonary High and homogenous enhancement of pulmonary

vesselsvessels Data acquisition in single breath holdData acquisition in single breath hold

Schaefer-Prokop C; Prokop M. Eur. Radiol. Suppl. 2005;15(4):d37-d41.

Multidetector-CTMultidetector-CTFindingsFindings

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):271-231.

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

CD

MDCT FindingsMDCT Findings

Arrow indicating rim sign Arrow indicating tram-track sign

Multidetector-CT: ArtifactsMultidetector-CT: Artifacts

Pseudo-filling defects or “pseudo-emboli” caused by:Suboptimal contrast enhancementMotion artifact – respiratory and cardiacVolume averaging of obliquely oriented

vesselsNon-enhanced pulmonary veinsHilar lymph nodesAsymmetric pulmonary vascular resistance

Macdonald S; Mayo J. Semin. Ultrasound CT. 2003;24(4):231-271.

Clinical relevance of MDCT findingsClinical relevance of MDCT findingsI. Subsegmental EmboliI. Subsegmental Emboli

Natural history largely unknownNatural history largely unknown Lack of evidence to guide managementLack of evidence to guide management Some suggest isolated subsegmental PE may Some suggest isolated subsegmental PE may

not require treatment in appropriately selected not require treatment in appropriately selected subset of patientssubset of patients

Currently treat on case-by-base basisCurrently treat on case-by-base basis

Le Gal G et al. 2006;4(4):724-731.Goodman LR. Radiology. 2005;234(3)654-658.

Glassroth J. JAMA. 2007;298(23):2788-2789.

Patient with pneumonectomy

Lingular subsegmental pulmonary embolism (arrow)

Clinical Relevance of MDCT findingsClinical Relevance of MDCT findings II. RV StrainII. 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).

Contrast seen in IVC, indicating RV strain Bilateral mosaic attenuation

Clinical Relevance of MDCT findings Clinical Relevance of MDCT findings III. Clot BurdenIII. Clot Burden

Clot burden = pulmonary arterial obstruction indexClot burden = pulmonary arterial obstruction index Conflicting evidence re: clinical relevanceConflicting evidence re: clinical relevance Prospective study of 105 patients with PE found no Prospective study of 105 patients with PE found no

correlation between clot burden and all-cause correlation between clot burden and all-cause mortality at 12 monthsmortality at 12 monthsPossible selection bias – patients with large clot Possible selection bias – patients with large clot

burden may have died prior to CTPAburden may have died prior to CTPASingle-detector CTPA usedSingle-detector CTPA used

Clinical Relevance of MDCT findingsClinical Relevance of MDCT findingsiv. Mosaic Perfusioniv. 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)

Diagnostic Imaging AlgorithmDiagnostic Imaging Algorithm

Elevated D-Dimer or High clinical probability

MDCT-PA V/Q Scan if contraindication to contrast

Negative PE confirmed

May consider venous U/S but will be positive in

less than 1% of patients

Diagnostic Non-diagnostic

PE confirmed

PE ruled out

Venous U/S

Adapted from Agnelli G; Becattini C. N. Engl. J. Med. 2010;363:266-74.

New Imaging ApproachesNew Imaging Approaches Dual Energy Iodine Distribution MapsDual Energy Iodine Distribution Maps

Provides functional and anatomic Provides functional and anatomic lung imaginglung imaging

Demonstrates perfusion defects Demonstrates perfusion defects beyond obstructive and non-beyond obstructive and non-obstructive clotsobstructive clots

Diagnostic accuracy and Diagnostic accuracy and inter/intra-observer variability inter/intra-observer variability requires further researchrequires further research

AdvantagesAdvantages Indirect evaluation of Indirect evaluation of

peripheral pulmonary arterial peripheral pulmonary arterial bedbed

DisadvantagesDisadvantages Longer data acquisition time Longer data acquisition time Increased radiation exposureIncreased 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

New Imaging ApproachesNew 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

ConclusionConclusion

Proper use of clinical prediction rules aids in better Proper use of clinical prediction rules aids in better utilization of imaging studies and cost effectivenessutilization of imaging studies and cost effectiveness

MDCT-PA is preferred diagnostic techniqueMDCT-PA is preferred diagnostic technique V/Q scan for patients with contraindication to iodine V/Q scan for patients with contraindication to iodine

contrastcontrast Low-dose CT-PA or reduced-dose lung Low-dose CT-PA or reduced-dose lung

scintigraphy in pregnancyscintigraphy in pregnancy Dual energy CT can depict regional perfusion Dual energy CT can depict regional perfusion

status as well as intravascular embolistatus as well as intravascular emboli High pitch low dose technique can reduce motion High pitch low dose technique can reduce motion

artifactsartifacts

ReferencesReferences Agnelli GL Becattini C. Acute Pulmonary Embolism. N. Engl. J. Med. 2010;363:266-74. Anderson DR et al. Computed tomographic pulmonary angiography vs ventilation-perfusion lung scanning in patients with suspected pulmonary

embolism: a randomized controlled trial. JAMA. 2007 Dec 19;298(23):2743-53. Anderson DR; Barnes D. The use of leg venous ultrasonography for the diagnosis of pulmonary embolism. Semin. Nucl. Med. 2008

Nov;38(6)412-7. Carson JL; Kelly MA; Duff A, et al. The clinical course of pulmonary embolism. N Engl J Med 1992 May 7;326(19):1240-5. 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. 2002 Feb 1;165(3):345-8.

Glassroth J. Imaging of Pulmonary Embolism – Too much of a Good Thing? JAMA. 2007;298(23):2788-2789. 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):1386-9. Goldhaber Z; Elliot CG. Acute Pulmonary Embolism: Part I: Epidemiology, Pathophysiology, and Diagnosis. Circulation 2003;108;2726-2729. Goodman LR. Small pulmonary emboli: what do we know? Radiology. 2005;234(3)654-658. 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. 2003 Mar 1;167(5):729-34. Epub 2002 Nov 21.

Horlander KT; Mannino DM; Leeper KV. Pulmonary embolism mortality in the United States, 1979-1998: an analysis using multiple-cause mortality data. Arch Intern Med. 2003 Jul;163(14):1711-7.

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):724-731.

Macdonald S; Mayo J. Computed Tomography of Acute Pulmonary Embolism. Semin. Ultrasound CT. 2003;24(4):271-231. Marik PE; Plante LA. Venous thromboembolic disease and pregnancy. N. Engl. J. Med. 2008;359:2025-33. 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. 1998 Nov;158(5 Pt

1):1504-10. Perrier et al. Cost-Effectiveness Analysis of Diagnostic Strategies for Suspected Pulmonary Embolism Including Helical Computed Tomography.

Am. J. Respir. Crit. Care Med. 2003;167:39-44. 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.

References 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. 2004 Feb;230:329-337. Sostman DH et al. Acute Pulmonary Embolism: Sensitivity and Specificity of Ventilation-Perfusion Scintigraphy in PIOPED II Study. Radiology.

2008 Jan 14;246:941-946. 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;246:941-6. 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. 2005 Aug 15;172(4):494-500. 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. 2007 Jan;242:15-21.

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. 2007 Oct;120(10):871-9.

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;152:434-43.

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. 2006 Jun 1;354(22):2317-27.

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. 2004 Apr 20;140(8):589-602.

Subramaniam, RM et al. Pulmonary Embolism Outcome: A Prospective Evaluation of CT Pulmonary Angiographic Clot Burden Score and ECG Score. Am. J. Roentgenol. 2008;190:1599-1604.

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. 1990 May 23-30;263(20):2753-9. 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. 1997 May 15;126(10):775-81. 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):416-20. 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;295:172-179.