The American Journal of Medicine
Volume 119, Issue 12 , Pages 1048-1055, December 2006

Diagnostic Pathways in Acute Pulmonary Embolism: Recommendations of The PIOPED II Investigators

  • Paul D. Stein, MD

      Affiliations

    • Department of Research, St. Joseph Mercy Oakland Hospital, Pontiac, Mich
    • Department of Medicine, Wayne State University, Detroit, Mich
    • Corresponding Author InformationRequests for reprints should be addressed to Paul Stein, MD, St. Joseph Mercy Oakland Hospital, 44405 Woodward Ave., Pontiac, MI 48341-5023.
    • ,
  • Pamela K. Woodard, MD

      Affiliations

    • Department of Radiology, Washington University, St. Louis, Mo
    • ,
  • John G. Weg, MD

      Affiliations

    • Department of Medicine, University of Michigan, Ann Arbor
    • ,
  • Thomas W. Wakefield, MD

      Affiliations

    • Department of Surgery, University of Michigan, Ann Arbor
    • ,
  • Victor F. Tapson, MD

      Affiliations

    • Department of Medicine, Duke University, Durham, NC
    • ,
  • H. Dirk Sostman, MD

      Affiliations

    • Office of the Dean, Weill Cornell Medical College, New York, NY
    • Office of the Executive Vice President, Methodist Hospital, Houston, Tex
    • ,
  • Thomas A. Sos, MD

      Affiliations

    • Department of Radiology, Weill Cornell Medical College, New York, NY
    • ,
  • Deborah A. Quinn, MD

      Affiliations

    • Department of Medicine, Massachusetts General Hospital, Boston
    • Harvard Medical School, Boston, Mass
    • ,
  • Kenneth V. Leeper Jr, MD

      Affiliations

    • Department of Medicine, Emory University, Atlanta, Ga
    • ,
  • Russell D. Hull, MBBS, MSc

      Affiliations

    • Department of Medicine, University of Calgary, Calgary, Alberta, Canada
    • ,
  • Charles A. Hales, MD

      Affiliations

    • Department of Medicine, Massachusetts General Hospital, Boston
    • Harvard Medical School, Boston, Mass
    • ,
  • Alexander Gottschalk, MD

      Affiliations

    • Department of Radiology, Michigan State University, East Lansing
    • ,
  • Lawrence R. Goodman, MD

      Affiliations

    • Department of Radiology, Medical College of Wisconsin, Milwaukee
    • ,
  • Sarah E. Fowler, PhD

      Affiliations

    • The Biostatistics Center, Department of Epidemiology and Biostatistics, George Washington University, Rockville, Md
    • ,
  • John D. Buckley, MD, MPH

      Affiliations

    • Department of Medicine, Henry Ford Hospital, Detroit, Mich.

Article Outline

Abstract 

Purpose

To formulate comprehensive recommendations for the diagnostic approach to patients with suspected pulmonary embolism, based on randomized trials.

Methods

Diagnostic management recommendations were formulated based on results of the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) and outcome studies.

Results

The PIOPED II investigators recommend stratification of all patients with suspected pulmonary embolism according to an objective clinical probability assessment. D-dimer should be measured by the quantitative rapid enzyme-linked immunosorbent assay (ELISA), and the combination of a negative D-dimer with a low or moderate clinical probability can safely exclude pulmonary embolism in many patients. If pulmonary embolism is not excluded, contrast-enhanced computed tomographic pulmonary angiography (CT angiography) in combination with venous phase imaging (CT venography), is recommended by most PIOPED II investigators, although CT angiography plus clinical assessment is an option. In pregnant women, ventilation/perfusion scans are recommended by many as the first imaging test following D-dimer and perhaps venous ultrasound. In patients with discordant findings of clinical assessment and CT angiograms or CT angiogram/CT venogram, further evaluation may be necessary.

Conclusion

The sequence for diagnostic test in patients with suspected pulmonary embolism depends on the clinical circumstances.

Keywords: Pulmonary embolism, Venous thromboembolism, Computed tomographic angiography, D-dimer, Pulmonary scintigraphy, Clinical assessment

 

The choice of diagnostic tests depends on the clinical probability of pulmonary embolism, condition of the patient, availability of diagnostic tests, risks of iodinated contrast material, radiation exposure, and cost. Recommendations can now be formulated based on the results of the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II)1 and other studies,2, 3, 4 albeit with continued reliance on the physician’s judgment. The following recommendations include both evidence-based recommendations and opinions based on information available at this time. Both are subject to revision as further data become available. Information related to radiation exposure,5, 6, 7, 8, 9, 10, 11, 12 charges for tests, and positive predictive values of clinical probability assessments2, 13, 14, 15, 16, 17, 18, 19 are shown in Table 1, Table 2, Table 3.

Clinical significance

 


•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.

Table 1. Charges (Including Physicians’ Fees) at a Community Hospital
ProcedureCharges (Dollars)
Pulmonary angiography6106
Contrast-enhanced spiral CT1739
Ventilation/perfusion lung scan917
Ultrasound, both legs631
D-dimer (Rapid ELISA)24

CT = computed tomography; ELISA = enzyme-linked immunosorbent assay.

Table 2. Radiation Exposure
ExaminationEffective Whole Body Dose (mSv)Refs
Chest PA and lat0.0711
Perfusion scan0.87
Ventilation/perfusion scan1.2-2.07, 10
CT angiography1.6-8.3
CT venography5.710
Pulmonary digital subtraction angiogram3.2-30.16, 7, 8, 9, 10
Background radiation/year2.55
Max allowable/year radiation workers5012
Avg allowable/year radiation workers2012

PA = posterior-anterior; Lat = lateral; CT = contrast-enhanced multidetector computed tomographic angiography; Max = maximum; Avg = average.

Table 3. Probability of Pulmonary Embolism According to Clinical Assessment⁎
Clinical Low Pulmonary Embolism (%)Clinical Moderate Pulmonary Embolism (%)Clinical High Pulmonary Embolism (%)Refs
Empirical10316114, 17, 18
Wells (extended)430682, 13, 14
Wells (simplified)15295914, 15, 16
Geneva score11387916, 17
Geneva revised8297419

⁎Pooled data.

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Clinical assessment 

Physicians with experience in pulmonary embolism showed similar results with empirical assessment14, 17, 18 and by objective assessment (Table 3).2, 13, 14, 15, 16, 17, 19 Objective assessment may be more robust when applied by nonexperts.

Recommendations for clinical assessment:

•Clinical assessment should be made before imaging.

•Clinical assessment should be made by an objective method.

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Patients with low probability clinical assessment 

The quantitative rapid enzyme-linked immunosorbent assay (ELISA), with a sensitivity of 95%, showed the most clinically useful values among the various D-dimer assays.20 When used in combination with a low probability objective clinical assessment, which ranges from 4% to 15%2, 14, 15, 16, 17, 19 (Table 3, Figure 1), the post-test probability of pulmonary embolism ranges from 0.7% to 2% with a normal D-dimer rapid ELISA.20, 21 No further testing is required if D-dimer is normal in a patient with a low probability clinical assessment. Additional testing with venous ultrasound or gadolinium enhanced magnetic resonance venography22 is optional.

  • View full-size image.
  • Figure 1. 

    Pathway for D-dimer by quantitative rapid ELISA in combination with clinical assessment. If clinical assessment is low or moderate probability, and D-dimer rapid ELISA is negative, pulmonary embolism would be excluded. If clinical assessment is high probability, further testing is necessary irrespective of the results of D-dimer testing. ELISA=enzyme-linked immunosorbent assay.

An abnormal D-dimer indicates the need for further testing if pulmonary embolism is suspected. The majority of PIOPED II investigators preferred the combination of contrast-enhanced multidetector computed tomographic pulmonary angiography (CT angiography) and venous phase imaging of the proximal leg veins (CT venography). A CT angiogram had a sensitivity of only 83% in PIOPED II and would be inadequate in the absence of clinical assessment or CT venography.1

Radiation exposure can be reduced by omitting the iliac veins and inferior vena cava in the CT venogram. Among patients who showed thrombi on CT venography, the iliac veins or the inferior vena cava showed thrombi in the absence of femoral or popliteal vein thrombi in only 3 of 105 (3%).1

In PIOPED II among patients with a low probability clinical assessment, if CT angiography was negative, pulmonary embolism was present in 4%. If CT angiography/CT venography was negative, pulmonary embolism was present in 3% (Figure 2).1 In outcome studies of untreated patients with normal CT angiography and clinical assessment that ranged from low probability to “likely,” 1.3% had venous thromboembolism and 1.5% would have had pulmonary embolism or deep venous thrombosis on 3-month follow-up.3, 4

  • View full-size image.
  • Figure 2. 

    Pathway for diagnosis with CT angiography or CT angiography/CT venography following testing with D-dimer in combination with low probability clinical assessment. CT angiography = contrast-enhanced multidetector computed tomographic pulmonary angiography; CT venography = contrast-enhanced multidetector computed tomographic venous phase imaging of the veins of the lower extremities; NPV = negative predictive value; PPV = positive predictive value.

If CT angiography was positive in a patient with a low probability clinical assessment, pulmonary embolism was present in 58%. With a positive CT angiogram/CT venogram, pulmonary embolism was present in 57%.1 However, if the CT angiography showed pulmonary embolism in a main or lobar pulmonary artery, pulmonary embolism was present in 97%.1 If the largest vessel showing pulmonary embolism was in a segmental branch, pulmonary embolism was present in 68%. If in a subsegmental branch, pulmonary embolism was present in 25% of patients, but data are sparse in the subsegmental group.1

Recommendations for patients with low probability clinical assessment (Figure 2):

•Perform a D-dimer rapid ELISA.

•No further testing is required if D-dimer is normal.

•If D-dimer is positive, CT angiography/CT venography is recommended by most PIOPED II investigators.

•CT venography of only the femoral and popliteal veins is recommended to reduce radiation.

•If CT angiography or CT angiography/CT venography is negative, treatment is unnecessary.

•With main or lobar pulmonary emboli on CT angiography, treatment is indicated.

•With segmental or subsegmental pulmonary emboli the certainty of the CT diagnosis should be re-assessed.

•CT angiography or CT angiography/CT venography should be repeated if image quality is poor.

•In patients with segmental or subsegmental pulmonary emboli, pulmonary scintigraphy, a single venous ultrasound in those evaluated by CT angiography only, serial venous ultrasound examinations,13, 23 or pulmonary digital subtraction angiography are optional.

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Patients with a Moderate Probability Clinical Assessment 

Patients with objectively measured moderate clinical probabilities of pulmonary embolism were shown to have pulmonary embolism in 29% to 38%.2, 14, 15, 16, 17, 18, 21 The posttest probability of pulmonary embolism with a 30% clinical probability of pulmonary embolism is 5% with a normal rapid ELISA.20, 21

With a moderate clinical probability assessment, if the CT angiogram was negative, pulmonary embolism was present in 11%. If CT angiogram/CT venogram was negative, pulmonary embolism was present in 8%.1 Outcome studies showed pulmonary embolism 3 months after a negative CT angiogram in ≤1.5% of patients.3, 4

If CT angiography was positive in a patient with a moderate probability clinical assessment, pulmonary embolism was present in 92%, and with a positive CT angiogram/CT venogram combination, pulmonary embolism was present in 90%.1 The predictive values with lobar, segmental, and subsegmental pulmonary emboli and recommendations for further imaging are as described in the section on low probability clinical assessment.

Recommendations for patients with a moderate probability clinical assessment (Figure 3):

•We recommend a D-dimer rapid ELISA.

•If D-dimer rapid ELISA is negative, no further testing is necessary, but a venous ultrasound or magnetic resonance venography is optional.

•If D-dimer is positive, CT angiography/CT venography is recommended by most PIOPED II investigators.

•Treatment with anticoagulants while awaiting the outcome of diagnostic tests may be appropriate, particularly if the tests cannot be obtained immediately.24

•If CT angiography or CT angiography/CT venography are negative, no treatment is necessary, but a venous ultrasound is recommended for those with a negative CT angiogram alone.

•If CT angiography or CT angiography/CT venography are positive, treatment is recommended.

•With segmental or subsegmental pulmonary emboli, the certainty of the CT diagnosis should be re-assessed and options followed according to recommendations for patients with a low probability clinical assessment.

  • View full-size image.
  • Figure 3. 

    Pathway for diagnosis with CT angiography or CT angiography/CT venography following testing with D-dimer in combination with moderate probability clinical assessment. CT angiography = contrast-enhanced multidetector computed tomographic pulmonary angiography; CT venography = contrast-enhanced multidetector computed tomographic venous phase imaging of the veins of the lower extremities; NPV = negative predictive value; PPV = positive predictive value.

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Patients with a high probability clinical assessment 

A D-dimer is not helpful because a negative D-dimer does not exclude pulmonary embolism in >15% of patients with a high probability clinical assessment.20, 21

If either CT angiography alone or CT angiography/CT venography combination were positive in a patient with a high probability clinical assessment, pulmonary embolism was present in 96% in PIOPED II.1 If CT angiography was negative in a patient with a high probability assessment, pulmonary embolism was present in 40%, and if CT angiography/CT venography was negative, pulmonary embolism was present in 18%.1 If considering ventilation/perfusion lung scans for further testing, or a perfusion lung scan alone if the chest radiograph is normal or nearly normal,25 the proportion of patients with a nondiagnostic pulmonary scintiscan is lower with a normal chest radiograph than with an abnormal chest radiograph26, 27 and has been reported to be only 9%.27

Recommendations for patients with a high probability clinical assessment (Figure 4):

•D-dimer testing need not be done because a negative D-dimer in a patient with a high probability clinical assessment may not exclude pulmonary embolism.

•Treat with anticoagulants while awaiting the outcome of diagnostic tests.24

•Most PIOPED II investigators recommend CT angiography/CT venography.

•If CT angiography is negative and CT angiography/CT venography was not done or was technically inadequate, a venous ultrasound or magnetic resonance venography is recommended.

•If CT angiography or CT angiography/CT venography are negative, other options include serial venous ultrasound examinations, pulmonary digital subtraction angiography, and pulmonary scintigraphy.

•If CT angiography or CT angiography/CT venography are positive, treatment is recommended.

  • View full-size image.
  • Figure 4. 

    Pathway for diagnosis with CT angiography or CT angiography/CT venography in patients with a high probability clinical assessment. CT angiography = contrast-enhanced multidetector computed tomographic pulmonary angiography; CT venography = contrast-enhanced multidetector computed tomographic venous phase imaging of the veins of the lower extremities; NPV = negative predictive value; PPV = positive predictive value.

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Optional pathways, all patients 

Venous ultrasound detects deep venous thrombosis in 13% to 15% of patients with suspected pulmonary embolism28, 29 and in 29% with proven pulmonary embolism,29 thereby allowing treatment with no further obligatory testing.

Recommendation for optional pathways:

•A venous ultrasound before imaging with CT angiography or CT angiography/CT venography is optional and may guide treatment if positive.

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Patients with allergy to iodinated contrast material 

If clinical assessment and D-dimer fail to exclude pulmonary embolism, a venous ultrasound may be positive and guide therapy. Patients with mild to moderate iodine allergies may be pretreated with steroids and then imaged with CT. With severe iodine allergy, pulmonary scintigraphy may be a useful alternative. A low probability ventilation/perfusion scan combined with a low probability clinical assessment showed pulmonary embolism in only 4%.18 A high probability ventilation/perfusion scan in a patient with a high probability clinical assessment showed pulmonary embolism in 96%.18 With other combinations, pulmonary embolism was present in 16% to 88%, and further evaluation is needed. Further evaluation may include serial venous ultrasound13, 23 or gadolinium-enhanced CT angiography (0.3-0.4 mmol/kg).30 Preliminary investigations suggest that gadolinium-enhanced magnetic resonance imaging may be useful.31, 32, 33, 34

Recommendations for patients with allergy to iodinated contrast material:

•D-dimer with clinical assessment is recommended to exclude pulmonary embolism.

•Patients with mild iodine allergies may be treated with steroids before the CT imaging.

•Venous ultrasound and pulmonary scintigraphy are recommended as alternative diagnostic tests in patients with severe iodine allergy.

•Serial venous ultrasound and gadolinium-enhanced CT angiography are options.

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Patients with impaired renal function 

In PIOPED II, only 1 of 824 patients who had CT angiography (0.1%) developed renal failure.1 Nonionic contrast material was used.1 Patients with abnormal serum creatinine levels were excluded. If the creatinine clearance is only somewhat elevated, whether to proceed with CT imaging depends on clinical judgment. Nonionic contrast material appears to be less nephrotoxic35 and generally better tolerated36 than ionic contrast material, although some reported no difference in nephrotoxicity.37 Prophylactic hydration with sodium bicarbonate before contrast exposure reduces the risks of renal dysfunction in patients with renal insufficiency and has been reported to be more effective than hydration with sodium chloride.38 An isotonic solution of sodium bicarbonate 3 mL/kg per hour for 1 hour before and 1 mL/kg per hour for 6 hours after the administration of contrast material has been recommended.38, 39

Nonsteroidal anti-inflammatory drugs and dipyridamole were discontinued in PIOPED II. They should be discontinued as early as possible before the administration of contrast material.40 Metformin (Glucophage) also should be discontinued before the injection of contrast material, because if contrast-induced renal failure occurs, metformin accumulation in body tissues could cause lactic acidosis.41 Metformin, however, does not cause renal failure.41 In emergency or urgent situations, if renal function is normal, the study may proceed with little risk.41 If renal function is abnormal or unknown, metformin should be discontinued, and hydration, as well as other precautions listed above should be taken.41 Therapy with metformin can be resumed when renal function has been shown to be normal.40, 41 Results with angiotensin-converting enzyme inhibitors have been equivocal.40

Recommendations for patients with impaired renal function:

•D-dimer with clinical assessment is recommended to exclude pulmonary embolism.

•Venous ultrasound is recommended and, if positive, treatment is indicated.

•Pulmonary scintigraphy is recommended if venous ultrasound is negative.

•Serial venous ultrasound is an option.

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Women of reproductive age 

Female breast radiation is a concern, but the risk of death from undiagnosed pulmonary embolism far exceeds the risk of radiation-induced malignancy. The absorbed dose to the breast with CT angiography has been calculated as 10-50 mGy.42, 43, 44 The absorbed dose to the breast with a perfusion lung scan has been estimated to be 0.28 mGy.42 The absorbed dose to the breast with standard 2-view mammography is 3 mGy.43

Pulmonary scintigraphy would minimize breast radiation. In PIOPED, a ventilation/perfusion scan in patients with a normal chest radiograph was diagnostic (high probability or normal/nearly normal) in 52% of patients with suspected pulmonary embolism.26 More recently, a ventilation/perfusion scan was shown to be diagnostic in 91% of patients with suspected pulmonary embolism and a normal chest radiograph.27

Recommendations for women of reproductive age:

•If D-dimer rapid ELISA is positive, venous ultrasound as the next diagnostic test is optional.

•Pulmonary scintigraphy is recommended by some PIOPED investigators as the next imaging test.

•A CT angiogram with venous ultrasound is an acceptable alternative.

•If a CT venogram is deemed necessary, it is advisable to start at the acetabulum to reduce gonadal irradiation.

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Pregnant patients 

In pregnant women, D-dimer testing may be useful even though it may be positive due to the pregnancy.45 Venous ultrasound detects deep venous thrombosis in 13% to 15% of patients with suspected pulmonary embolism28, 29 and in 29% with proven pulmonary embolism,29 eliminating the need for radiographic imaging. If radiographic imaging is necessary, some have recommended46 or used47 CT angiography rather than ventilation/perfusion lung scans. Magnetic resonance imaging requires further validation.31, 32, 33, 34 However, adequate and well-controlled studies of gadopentetate dimeglumine have not been conducted in pregnant women.48 It is not known to what extent it is excreted in human milk.48

Some indicate that the radiation dose to the fetus from 16-slice CT angiography, 0.24-0.47 mGy at 0 months and 0.61-0.66 mGy at 3 months, is of the same magnitude as a ventilation/perfusion scan, 0.25-0.36 mGy at 0 months and 0.31-0.32 mGy at 3 months, or a perfusion scan alone, 0.21 mGy at 0 months and 0.30 mGy at 3 months.49 Others indicate that the absorbed dose to the fetus is less with CT angiography than a perfusion scan (0.01 mGy vs. 0.12 mGy).42

Recommendations for pregnant patients:

•D-dimer with clinical assessment should be obtained.

•If D-dimer is positive, venous ultrasound is recommended before imaging tests with ionizing radiation.

•Some PIOPED II investigators recommend pulmonary scintigraphy, and some recommend a CT angiogram.

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Patients in extremis 

The sensitivity of transthoracic echocardiography for right ventricular enlargement or dysfunction in patients with massive pulmonary embolism or unstable patients, combining data from 3 case series, was 33 of 33 (100%).50, 51, 52 If any 2 of the following 3 assessments were positive (clinical probability high, echocardiogram and ultrasound), the sensitivity for massive pulmonary embolism was 33 of 34 (97%) and the negative predictive value was 98%.53

Recommendations for patients in extremis:

•Bedside echocardiography and bedside leg ultrasonography in combination are recommended as rapidly obtainable bedside tests.

•Right ventricular enlargement or poor right ventricular function, in a proper clinical setting, can be interpreted as resulting from pulmonary embolism.

•A positive venous ultrasound in the appropriate clinical setting also indicates pulmonary embolism.

•A portable perfusion scan is recommended by some.

•Immediate transfer to an interventional catheterization laboratory is recommended by some.

•A combination of a negative bedside echocardiogram and venous ultrasound indicate the need for CT angiography if it is feasible.

•When the patient stabilizes, appropriate imaging studies should be performed.

In conclusion, the PIOPED II investigators recommend stratification of all patients with suspected pulmonary embolism according to an objective probability assessment. A negative D-dimer rapid ELISA with a low or moderate probability clinical assessment can safely exclude pulmonary embolism. If pulmonary embolism is not excluded, CT angiography/CT venography is recommended by most PIOPED II investigators, although CT angiography alone is an option. In patients with discordant findings on clinical assessment and CT imaging, further evaluation depends on clinical judgment. In pregnant women, ventilation/perfusion scans are recommended by many PIOPED II investigators as the first imaging test.

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 Supported by Grants HL63899, HL63928, HL63931, HL063932, HL63940, HL63941, HL63942, HL63981, HL63982, and HL67453 from the U.S. Department of Health and Human Services, Public Health Services, National Heart, Lung, and Blood Institute, Bethesda, MD.Diagnostic Pathways in Acute Pulmonary Embolism: Recommendations of the PIOPED II Investigators by Stein et al is being jointly published by The American Journal of Medicine and Radiology. A similar article will appear as an editorial in the January 2007 issue of Radiology.

PII: S0002-9343(06)00779-0

doi:10.1016/j.amjmed.2006.05.060

The American Journal of Medicine
Volume 119, Issue 12 , Pages 1048-1055, December 2006

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