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Guidelines for the use of imaging techniques for the investigation of venous thromboembolic disease
The Journal of Emergency Medicine, Vol. 16, No. 4, pp. 663– 668, 1998 Copyright © 1998 Elsevier Science Inc. Printed in the USA. All rights reserved 0736-4679/98 $19.00 1 .00
PII S0736-4679(98)00050-X
Canadian Perspectives
GUIDELINES FOR THE USE OF IMAGING TECHNIQUES FOR THE INVESTIGATION OF VENOUS THROMBOEMBOLIC DISEASE Anthony Taylor, Marc Beique, Andrew McCallum,
MD FRCPC,*
Robert Beveridge, MD FRCPC,* Michael Barry, MD FRCPC,† David Dowhan, MD FRCPC,§ Brian Holroyd, MD FRCPC,¶ FRCPC,# Bruce McLeod, MD FRCPC,** Barrie Steed, MD FRCPC,†† and Robert Street, MD FRCPC‡‡
MD FRCPC,‡ MD
*The Canadian Association of Emergency Physicians, Ottawa, Ontario, Canada; †Diagnostic Imaging Department, St. John Regional Hospital, St. John, New Brunswick, Canada; ‡Emergency Medicine, Royal Victoria Hospital, Montreal, Quebec, Canada; §Emergency Medicine, Smith Falls, Ontario, Canada; ¶Emergency Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada; #Emergency Services, Medical Department, Sunnybrook Health Science Centre, North York, Ontario, Canada; **Emergency Medicine, Victoria General Hospital, Halifax, Nova Scotia, Canada; ††Department of Diagnostic Imaging, Calgary General Hospital, Calgary, Alberta, Canada; and ‡‡Department of Emergency Medicine, Royal Columbia Hospital, New Westminister, British Columbia, Canada Reprint Address: Dr. Anthony S. Taylor, Department of Emergency Medicine, Foothills Medical Centre, 1403 29th Street N.W., Calgary, Alberta, Canada T2N 2T9
e Abstract—The diagnosis of venous thromboembolic disease remains a difficult challenge. Chest radiography, ventilation/perfusion lung scanning, noninvasive leg testing, and pulmonary angiography were evaluated with regard to sensitivity, specificity, positive and negative predictive values. The need for treatment, observation, or serial testing with respect to risks and benefits of treatment and likelihood of serious outcomes was evaluated. The evidence for conclusions was based on the methodology and values of the Canadian Task Force on the Periodic Health Examination. The Diagnostic Imaging Advisory Group of the Canadian Association of Emergency Physicians developed eight recommendations. © 1998 Elsevier Science Inc.
because there are no reliable clinical features, or laboratory findings with acceptable sensitivity, specificity, positive and negative predictive values. There is considerable controversy in the medical literature about the true incidence or even the importance of pulmonary embolism (PE). One author states that “there is ample evidence in the literature attesting to the problem of under diagnosis” (1) while another claims that PE is over diagnosed and over treated (2). With this great dichotomy, there has been an abundance of literature published on the clinical features, investigation, and diagnosis of PE. Some authors (3) estimate that greater than 500,000 people per year in the United States suffer from PE, with approximately 10% dying within 1 h of the event. Of those who survive greater than 1 h, 66% are thought to go undiagnosed and one-third of this group will die. VTE is the third most common cardiovascular disease after ischemic syndromes and stroke. VTE is thought to be the most common preventable cause of death in hospitals. Despite a better understanding of the epidemiology,
e Keywords—pulmonary embolism; DVT; investigation; diagnosis; doppler ultrasound; V/Q scans; venous thromboembolic disease
INTRODUCTION The diagnosis of venous thromboembolic disease (VTE) remains one of the most difficult diagnostic challenges
Canadian Perspectives is coordinated by James Ducharme, MD, of St. John Regional Hospital, St. John, New Brunswick, Canada
RECEIVED: 26 March 1997; ACCEPTED: 9 October 1997 663
664
A. Taylor et al.
more tests capable of establishing the presence or absence of disease, and better treatment, VTE is still believed to be under diagnosed and therefore under treated. Consequently, the mortality rate does not seem to have changed in 30 years. The benefits of early accurate diagnosis are obvious in terms of decreased lost years of life but there is also a cost associated with the overuse of unnecessary investigations, hospitalization, and treatment. To address the diagnostic challenge and confusion relating to deep vein thrombosis and PE in the emergency setting, evidence based guidelines have been developed. The evidence for conclusions was based on the methodology and values of the Canadian Task Force on the Periodic Health Examination (4).
OBJECTIVES To develop a rational, efficient, and economical approach for the radiological assessment of patients with suspected venous thromboembolic disease (VTE). Prevention of death and significant morbidity associated with the investigations(s), treatment, or observation without treatment were the major determinants of outcome.
MATERIALS AND METHODS A national committee consisting of emergency physicians and radiologists selected by The Canadian Association of Emergency Physicians (CAEP) and The Canadian Association of Radiologists (CAR), respectively, was established. Appropriate sources of evidence published in the medical literature between January 1945 and June 1997 were identified through a MEDLINE search. Articles were assessed for their levels of evidence. The investigative modalities were evaluated in the context of clinical likelihood of VTE. The sensitivity, specificity, positive and negative predictive values of the available investigations, and the need for treatment, observation, or serial testing were assessed with respect to risks and benefits of treatment and likelihood of serious adverse outcomes. The evidence based methodology and values of the Canadian Task Force on the Periodic Health Examination were used (4). The levels of evidence were ascribed according to: Level I Evidence obtained from at least one properly randomized controlled trial.
Figure 1. Flow chart showing strategy for diagnosis of thromboembolic disease (modified from Reference 33).
Level II-1 Evidence obtained from well-designed controlled trials without randomization. Level II-2 Evidence obtained from well-designed cohort or case control analytic studies, preferably from more than one centre or research group. Level II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin in the 1940’s) also could be regarded as this type of evidence. Level III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. Grade A Best evidence at Level I Grade B Best evidence at Level II Grade C Best evidence at Level III RECOMMENDATIONS The recommendations of the Canadian Task Force for the investigation of venous thromboembolic disease are listed below (Figure 1). Recommendation 1: A Chest Radiograph Should Be the Initial Radiological Procedure Used for the Patient Suspected to Have a Pulmonary Embolism. Grade B recommendation; Level of evidence: 4 Level II studies (5– 8).
CAEP VTE Investigation Guidelines
The chest radiograph is an important test in patients with chest pain or other symptoms that may be related to cardiac or pulmonary problems and is felt to be essential for the interpretation of the ventilation/perfusion lung (V/Q) scan (5). The findings on chest radiographs alone cannot be used to reliably diagnose pulmonary embolism (6) but an alternative diagnosis can be made that obviates the need for further investigation for VTE disorders.
Recommendation 2: A V/Q Scan Should Be the First Imaging Modality after the Chest X-ray in Assessment of Patients Thought to Have a PE Grade B recommendation; Level of evidence: 4 Level II studies (9 –12), 1 Level III report (13) . Numerous clinical trials have been done looking at the sensitivity, specificity, positive and negative predictive value of ventilation/perfusion scans. (9 –11) The sensitivity of a high probability scan; high probability and intermediate combined; and high, intermediate, and low probability combined is 41%, 82%, and 98%, respectively. Specificities were 97%, 52%, and 10% for high, intermediate, and low probability scans, respectively. In the samples tested, the positive predictive value of a high probability scan was 88%. The negative predictive value for a low probability scan was 84 – 88%, and for a normal scan was 91–96%.
Recommendation 3: Only Normal or High Probability V/Q Lung Scans Should Be Considered Strong Enough Evidence to Initiate Treatment. Nondiagnostic V/Q Scans Require a Careful Assessment of Clinical Risk and the Need for Further Investigations Grade B recommendation: Level of evidence: 3 Level II studies (9 –15). The results of lung scans can be separated into three major groups: normal, nondiagnostic (low and intermediate probability), and diagnostic (high probability) (14). In the past, radiologists have been reluctant to call V/Q scans normal. Pre-test likelihood is critical when interpreting V/Q scans. With a normal scan, the probability of PE is extremely low (13). With high probability scans (defined as one or more segmental or larger perfusion defects with normal or near normal ventilation), the probability of PE is $85% (14). A nondiagnostic scan includes segmental matched defects, subsegmental defects (matched or unmatched), and scan defects with corresponding abnormalities on the chest x-ray. The probability of PE with a nondiagnostic scan is 10 – 40% (15). Nondiagnostic scans should not be used to guide
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therapy. Interpretations such as intermediate probability, indeterminate, low probability, non-high probability, or near normal have not been used in a standardized fashion. The terms should be avoided because they are not only unhelpful but may be dangerous.
Recommendation 4: Noninvasive Leg Studies Are the Tests of Choice for the Further Investigation of Patients with a Nondiagnostic V/Q Scan. Grade A recommendation; Level of evidence: 1 Level I trial (16), 1 Level II study (17), 4 Level III reports (18 –21). If the ventilation/perfusion lung scan is nondiagnostic, other investigations should be carried out. The next investigation should be a noninvasive leg study. There is a close relationship between proximal deep vein thrombosis (DVT) and pulmonary embolism (PE) in that 80% or more of patients with PE have thrombi that originate in the lower extremities. (22–25) The remaining thrombi arise from the right heart, the upper extremities, the inferior vena cava, and the pelvic veins. Venous ultrasound (18,19) and impedance plethysmography (16,17,26,27) both have been shown to be reliable means of detecting above-the-knee DVT. If noninvasive leg studies are not available, contrast venography is an acceptable alternative, though less desirable due to potential thrombus induction and contrast reactions. (20,21) Contrast venography remains the gold standard.
Recommendation 5: Venous Ultrasonography Is the Preferred Noninvasive Test to Establish the Diagnosis of Proximal DVT Grade B recommendation; Level of evidence: 4 Level II studies (28 –32). Ultrasound has been shown to be more accurate than impedance plethysmography. (28 –31) In the sample tested, the positive predictive value is greater with venous ultrasound (94%) when compared to IPGs (83%). In patients who have a low pre-test probability (pre-test likelihood , 10%), the positive predictive value of doppler is only about 66%, and in high prevalence patients, the negative predictive value is 85–90%; therefore, in this group, the test does not definitively rule out thrombus. The sensitivity for duplex ultrasound is 92–95% and a specificity of 97–100%. The sensitivity of impendance plethyomographys (IPGs) is between 80 –94% for the symptomatic patient (15).
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Recommendation 6: Patients with a nondiagnostic V/Q Lung Scan and Negative Noninvasive Leg Studies Should Have Either a Pulmonary Angiogram, Venogram, or Serial Noninvasive Leg Studies Grade C recommendation; Consensus opinion. There is considerable controversy regarding patients with nondiagnostic V/Q scans and negative noninvasive leg studies. Venography or pulmonary angiography should be done if the clinical suspicion is moderate or high. Serial noninvasive studies should be done if clinical suspicion is low (15,33–35). If the leg studies (venography, venous U/S or IPG) are negative and there is moderate or high clinical suspicion for VTE, the patient should receive heparin and be transferred to a facility with the capability of doing a pulmonary angiogram (Consensus opinion). Pulmonary angiography is considered the gold standard, however, results may be indeterminate in 3–15% of patients (9,12). The test should be performed within 48 h of symptom onset because the resolution of thrombus may lead to an increased risk of a false negative investigation. The mortality and morbidity associated with pulmonary angiography are approximately 0.2% and 4%, respectively (5,9,36,37). An emergent pulmonary angiogram should be performed when the risk of treatment exceeds the risk of the test itself or death is likely without more invasive measures. This is particularly true if extensive thrombus is suspected; comorbid factors such as significant underlying cardiopulmonary disease, bleeding disorders, diabetic retinopathy, vascular abnormalities are present; or aggressive treatments such as fibrinolytic therapy, pulmonary embolectomy, or inferior vena cava interruption are being considered. Notwithstanding the concerns associated with false negative results after 48 h from symptom onset, a negative test is justification for not initiating treatment. If empiric treatment has been started in a patient with a very high pretest likelihood of PE (“high clinical suspicion”) and delayed presentation (.48 h), treatment probably should be continued until further investigations establish an alternate diagnosis or repeat leg studies are negative. One study suggested that patients suspected of having a PE with negative venograms bilaterally do not require anticoagulant therapy regardless of whether they have a PE or not (36). If the venogram is positive for a proximal DVT, then treatment should be instituted. Some authors feel that below-the-knee DVT can be observed with serial noninvasive tests (38) but this probably is not advisable in patients with lower extremity trauma or other major risk factors for VTE where clot extension is most likely to occur (39,40). In patients for whom there is a low clinical suspicion of PE, a repeat duplex ultrasound of the lower extremi-
A. Taylor et al.
ties is warranted. (33,41) A single noninvasive leg test is recommended in patients with nondiagnostic V/Q scans. If the single leg study is negative, the authors recommend serial noninvasive leg studies or pulmonary angiography depending on the cardiorespiratory reserve. If the cardiorespiratory reserve is adequate, then serial leg studies are adequate. Pulmonary angiography remains an option in this group. If the cardiorespiratory reserve is poor, pulmonary angiography should be undertaken. (34) The ACCP Consensus Committee on Pulmonary Embolism believes that serial noninvasive leg tests would be an “appropriate approach to patients with nondiagnostic V/Q scans and a single negative leg test, providing there is good cardiopulmonary reserve” (35). A cost analysis was undertaken looking at three different strategies (42). The strategies were: V/Q scans and pulmonary angiography; V/Q scans, a single noninvasive leg test, and pulmonary angiography; and V/Q scans, serial noninvasive leg tests, and pulmonary angiography. The third strategy resulted in maximum effectiveness without being excessively costly. Occasionally, patients may be anticoagulated without a definitive diagnosis when the risk of anticoagulation is smaller than the risk of a repeat DVT or PE or the investigations are not available. A major unanswered question is how to objectively quantify clinical suspicion. This is a combination of the history, physical examination, risk factor profile, the clinician’s instinct, and possibly the results of preliminary tests. Two landmark studies, the Urokinase Pulmonary Embolism Trial (UPET; Reference 5) and the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED; Reference 9) have been used extensively to help define the clinical factors, risk profiles, and the results of investigations associated with proven PE. While these studies have been helpful in defining the relationship between clinical factors and PE, it should be appreciated that the results may suffer from selection bias. If patients are included in a study because they have positive test results without defining the criteria used to do the test in the first place, it may not be valid to assume that the study findings are applicable to patients being tested for other reasons or those seen in other settings. Whenever a disease is defined from observations made on a population pre-selected by some criteria, it cannot be assumed that these features will be present in the same frequency in a more heterogeneous population that is identified in a different way. Patients seen in a specialty referral clinic are not the same as those seen in primary care, the Emergency Department, or an in patient setting. Furthermore, the use of different gold standards (PE diagnosed only by V/Q or only by pulmonary angiography) can affect the observed clinical profile that is felt to define the disease.
CAEP VTE Investigation Guidelines
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Recommendation 7: An Electrocardiogram Should Be Done When Assessing Patients with Cardiorespiratory Signs and Symptoms but Cannot Be Used to Exclude or Diagnose a Pulmonary Embolism Grade B recommendation; Level of evidence: 1 Level II study (43). The electrocardiogram can help establish an alternative diagnosis, but cannot be used to diagnose or exclude the diagnosis of pulmonary embolism. Recommendation 8: An Arterial Blood Gas Determination Is Helpful in Assessing Patients for Hypoxia, Ventilation, and Metabolic Abnormalities but Cannot Be Used to Exclude or Diagnose Pulmonary Embolism
Grade B recommendation; Level of evidence: 5 Level II studies (6,41,43– 45). There is no role for arterial blood gases in the diagnosis of pulmonary embolism. There are many documented cases with normal PaO2 and A-a gradient (6,44,45). Arterial blood gases are important for the determination of hypoxemia, ventilation, and metabolic abnormalities.
Acknowledgments—The Diagnostic Imaging Advisory Group had financial support from UpJohn Company of Canada, HoechstRoussel Canada Inc., and Burroughs Wellcome Canada.
REFERENCES 1. Sasahara AA. Current problems in pulmonary embolism: Introduction. In: Sasahara AA, Sonnenblick EH, Lesch M, eds. Pulmonary emboli. Philadelphia: Grune and Stratton; 1974:1. 2. Robin ED. Over diagnosis and over treatment of pulmonary embolism: The emperor may have no clothes. Ann Int Med. 1977;87: 775– 81. 3. Dalen JE, Alpert JS. Natural history of pulmonary embolism. Program Cardiovasc Dis. 1975;17:259. 4. Canadian task force on the periodic health examination: The periodic health examination: 2 1987 update. Can Med Assoc J. 1988; 138:618 –26. 5. Urokinase pulmonary embolism trial: Phase I results. JAMA. 1970;214:2163. 6. Stein PD, Terrin ML, Hales CA, et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no pre-existing cardiac or pulmonary disease. Chest. 1991;100:598 – 603. 7. Worsley DF, Alavi A, Aronchick JM, Chen JTT, Greenspan RH, Ravin CE. Chest radiographic findings in patients with acute pulmonary embolism: observation from PIOPED study. Radiology. 1993;189:133–136. 8. Greenspan RH, Ravin CE, Polansky SM, et al. Accuracy of the chest radiograph in diagnosis of pulmonary embolism. Invest Radiol. 1982;17:539 – 43. 9. A collaborative study by the PIOPED investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism—results of the prospective investigation of pulmonary embolism diagnosis. JAMA. 1990;263:2753–9. 10. Gottschalk A, Juni JF, Sostman D, et al. Ventilation-perfusion scintigraphy in the PIOPED study. Part 1. Evaluation of the scintigraphic criteria and interpretations. J Nucl Med. 34:1119 –26. 11. Gottschalk A, Juni JF, Sostman D, et al. Ventilation-perfusion scintigraphy in the PIOPED study. Part 2. Evaluation of the scintigraphic criteria and interpretations. J Nucl Med. 34:1119 –26. 12. Hull RD, Hirsch J, Carter CJ, et al. Diagnostic value of ventilationperfusion lung scanning in patients with suspected pulmonary embolism. Chest. 1985;88:819 –28. 13. Stein PD, Gottschalk A. Critical review of ventilation/perfusion lung scans in acute pulmonary embolism. Prog Cardiovasc Dis. 1994;37:13–24. 14. Stein PD, Hull RD, Saltzman HA, Pineo G. Strategy for diagnosis of patients with suspected acute pulmonary embolism. Chest. 1993;103:1553–9. 15. Hull RD, Raskob GE, Ginsburg JS, et al. A noninvasive strategy for the treatment of patients with suspected pulmonary embolism. Arch Intern Med. 1994;154:289 –97.
16. Hull RD, Hirsh J, Carter CJ, et al. Diagnostic efficacy of impedance plethysmography for clinically suspected deep-vein thrombosis: A randomized trial. Ann Intern Med. 1985;102:21– 8. 17. Heijboer H, Cogo A, Buller H, et al. Detection of deep-vein thrombosis with impedance plethysmography and real-time compression ultrasonography in hospitalized patients. Arch Intern Med. 1992;152:1901–3. 18. Grant BJ. Noninvasive tests for acute venous thromboembolism. Am J Respir Crit Care Med. 1994;19:1044 –7. 19. Cronan JJ. State of the art venous thromboembolic disease. The role of ultrasound. Radiology. 1993;186:619 –30. 20. Weinmann EE, Salzman EW. Medical progress— deep-vein thrombosis. N Engl J Med. 1994;331:1630 – 41. 21. Shepard RFJ. Acute deep venous thrombosis. Cardiovas Clin. 1992;22:47– 66. 22. Cohn R, Walsh J. The incidence and anatomical site of origin of pulmonary emboli. Stranford Med Bull. 1946;4:97–9. 23. Short DS. A survey of pulmonary embolism in a general hospital. Br Med J. 1952;1:79. 24. Byrne JJ, O’Neil EE. Fatal pulmonary emboli: A study of 130 autopsy-proven fatal emboli. Am J Surg. 1952;83:47–54. 25. Goldhaber SZ, Morpurgo M. Diagnosis, treatment, and prevention of pulmonary embolism. JAMA. 1992;268:1727–33. 26. Palevsky HI, Alavi A. A noninvasive strategy for the management of patients suspected of pulmonary embolism. Semin Nuc Med. 1991;21:325–31. 27. Huisman MV, Buller HR, Ten Cate JW, et al. Management of clinically suspected acute venous thrombosis in outpatients with serial impedance plethysmography in a community hospital setting. Arch Intern Med. 1989;149:511. 28. Prandoni P, Lensing AW, Buller HR, et al. Failure of computerized impedance plethysmography in the diagnostic management of patients with clinically suspected deep-vein thrombosis. Thromb Haemostas. 1991;65:233– 6. 29. Anderson DR, Lensing AW, Walls PS, et al. Limitations of impedance plethysmography in the diagnosis of clinically suspected deep-vein thrombosis. Ann Intern Med. 1993;118:25–30. 30. Heijoer H, Buller HR, Lensing AW, et al. A comparison of real-time compression ultrasonography with impedance plethysmography for the diagnosis of deep-vein thrombosis in symptomatic outpatients. N Engl J Med. 1993;329:1365–9. 31. Kristo DA, Perry ME, Koller MH. Comparison of venography, duplex imaging, and bilateral impedance plethysmography for diagnosis of lower extremity deep-vein thrombosis. South Med J. 1994;87:55– 60.
668 32. Kruit WH, DeBoer AC, Sing AK, et al. The significance of venography in the management of patients with clinically suspected pulmonary embolism. J Intern Med. 1991;230:333–9. 33. Fennerty T. The diagnosis of pulmonary embolism. Br Med J. 1997;314:425– 429. 34. Stein PD, Hull RD, Pineo G. Strategy that includes serial noninvasive leg tests for diagnosis of thromboembolic disease in patients with suspected acute pulmonary embolism based on data from PIOPED. Arch Intern Med. 1995;155:2101– 4. 35. ACCP consensus committee on pulmonary embolism. Opinions regarding the diagnosis and management of venous thromboembolic disease. Chest. 1996;109:233–7. 36. Hull RD, Hirsch J, Carter CJ et al. Diagnostic efficacy of impedance plethysmography for clinically suspected deep vein thrombosis: A randomized trial. Ann Int Med. 1985;102:21– 8. 37. Mills SR, Jackson DC, Older RA, et al. The incidence, etiologies, and avoidance of complications of pulmonary angiography in a large series. Radiology. 1980;136:295. 38. Stein PD, Dalen JE, McIntyre KM Sasahara AA, Wenger NK,
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39. 40. 41. 42. 43. 44. 45.
Willis PW III. The electrocardiogram in acute pulmonary embolism. Prog Cardiovasc Dis. 1975;17:247–57. Sveitt S, Gallagher N. Venous thrombosis and pulmonary embolism:. A clinico-pathological study in injured and burned patients. Br J Surg. 1961;48:475– 89. Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest. 1989;95(suppl):S37–5. National cooperative study. The urokinase pulmonary embolism trial. Circulation. 1973;47/48 (suppl II):II-18 –21; II-81– 85. Hull RD, Feldstein W, Stein PD, Pineo G. Cost effectiveness of pulmonary embolism diagnosis. Arch Intern Med 1996;156:68 –72. Overton DT, Brocka JJ. The alveolar-arterial oxygen gradient in patients with documented pulmonary embolism. Arch Intern Med. 1988;148:1617–9. McFarlane MJ, Thomas FI. Use of the alveolar-arterial oxygen gradient in the diagnosis of pulmonary embolism. Am J Med. 1994;96:57– 62. Cvitanic O, Marino PL. Improved use of arterial blood gas analysis in suspected pulmonary embolism. Chest. 1989;95:48 –51.
PII S0736-4679(98)00050-X
Canadian Perspectives
GUIDELINES FOR THE USE OF IMAGING TECHNIQUES FOR THE INVESTIGATION OF VENOUS THROMBOEMBOLIC DISEASE Anthony Taylor, Marc Beique, Andrew McCallum,
MD FRCPC,*
Robert Beveridge, MD FRCPC,* Michael Barry, MD FRCPC,† David Dowhan, MD FRCPC,§ Brian Holroyd, MD FRCPC,¶ FRCPC,# Bruce McLeod, MD FRCPC,** Barrie Steed, MD FRCPC,†† and Robert Street, MD FRCPC‡‡
MD FRCPC,‡ MD
*The Canadian Association of Emergency Physicians, Ottawa, Ontario, Canada; †Diagnostic Imaging Department, St. John Regional Hospital, St. John, New Brunswick, Canada; ‡Emergency Medicine, Royal Victoria Hospital, Montreal, Quebec, Canada; §Emergency Medicine, Smith Falls, Ontario, Canada; ¶Emergency Medicine, University of Alberta Hospital, Edmonton, Alberta, Canada; #Emergency Services, Medical Department, Sunnybrook Health Science Centre, North York, Ontario, Canada; **Emergency Medicine, Victoria General Hospital, Halifax, Nova Scotia, Canada; ††Department of Diagnostic Imaging, Calgary General Hospital, Calgary, Alberta, Canada; and ‡‡Department of Emergency Medicine, Royal Columbia Hospital, New Westminister, British Columbia, Canada Reprint Address: Dr. Anthony S. Taylor, Department of Emergency Medicine, Foothills Medical Centre, 1403 29th Street N.W., Calgary, Alberta, Canada T2N 2T9
e Abstract—The diagnosis of venous thromboembolic disease remains a difficult challenge. Chest radiography, ventilation/perfusion lung scanning, noninvasive leg testing, and pulmonary angiography were evaluated with regard to sensitivity, specificity, positive and negative predictive values. The need for treatment, observation, or serial testing with respect to risks and benefits of treatment and likelihood of serious outcomes was evaluated. The evidence for conclusions was based on the methodology and values of the Canadian Task Force on the Periodic Health Examination. The Diagnostic Imaging Advisory Group of the Canadian Association of Emergency Physicians developed eight recommendations. © 1998 Elsevier Science Inc.
because there are no reliable clinical features, or laboratory findings with acceptable sensitivity, specificity, positive and negative predictive values. There is considerable controversy in the medical literature about the true incidence or even the importance of pulmonary embolism (PE). One author states that “there is ample evidence in the literature attesting to the problem of under diagnosis” (1) while another claims that PE is over diagnosed and over treated (2). With this great dichotomy, there has been an abundance of literature published on the clinical features, investigation, and diagnosis of PE. Some authors (3) estimate that greater than 500,000 people per year in the United States suffer from PE, with approximately 10% dying within 1 h of the event. Of those who survive greater than 1 h, 66% are thought to go undiagnosed and one-third of this group will die. VTE is the third most common cardiovascular disease after ischemic syndromes and stroke. VTE is thought to be the most common preventable cause of death in hospitals. Despite a better understanding of the epidemiology,
e Keywords—pulmonary embolism; DVT; investigation; diagnosis; doppler ultrasound; V/Q scans; venous thromboembolic disease
INTRODUCTION The diagnosis of venous thromboembolic disease (VTE) remains one of the most difficult diagnostic challenges
Canadian Perspectives is coordinated by James Ducharme, MD, of St. John Regional Hospital, St. John, New Brunswick, Canada
RECEIVED: 26 March 1997; ACCEPTED: 9 October 1997 663
664
A. Taylor et al.
more tests capable of establishing the presence or absence of disease, and better treatment, VTE is still believed to be under diagnosed and therefore under treated. Consequently, the mortality rate does not seem to have changed in 30 years. The benefits of early accurate diagnosis are obvious in terms of decreased lost years of life but there is also a cost associated with the overuse of unnecessary investigations, hospitalization, and treatment. To address the diagnostic challenge and confusion relating to deep vein thrombosis and PE in the emergency setting, evidence based guidelines have been developed. The evidence for conclusions was based on the methodology and values of the Canadian Task Force on the Periodic Health Examination (4).
OBJECTIVES To develop a rational, efficient, and economical approach for the radiological assessment of patients with suspected venous thromboembolic disease (VTE). Prevention of death and significant morbidity associated with the investigations(s), treatment, or observation without treatment were the major determinants of outcome.
MATERIALS AND METHODS A national committee consisting of emergency physicians and radiologists selected by The Canadian Association of Emergency Physicians (CAEP) and The Canadian Association of Radiologists (CAR), respectively, was established. Appropriate sources of evidence published in the medical literature between January 1945 and June 1997 were identified through a MEDLINE search. Articles were assessed for their levels of evidence. The investigative modalities were evaluated in the context of clinical likelihood of VTE. The sensitivity, specificity, positive and negative predictive values of the available investigations, and the need for treatment, observation, or serial testing were assessed with respect to risks and benefits of treatment and likelihood of serious adverse outcomes. The evidence based methodology and values of the Canadian Task Force on the Periodic Health Examination were used (4). The levels of evidence were ascribed according to: Level I Evidence obtained from at least one properly randomized controlled trial.
Figure 1. Flow chart showing strategy for diagnosis of thromboembolic disease (modified from Reference 33).
Level II-1 Evidence obtained from well-designed controlled trials without randomization. Level II-2 Evidence obtained from well-designed cohort or case control analytic studies, preferably from more than one centre or research group. Level II-3 Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin in the 1940’s) also could be regarded as this type of evidence. Level III Opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. Grade A Best evidence at Level I Grade B Best evidence at Level II Grade C Best evidence at Level III RECOMMENDATIONS The recommendations of the Canadian Task Force for the investigation of venous thromboembolic disease are listed below (Figure 1). Recommendation 1: A Chest Radiograph Should Be the Initial Radiological Procedure Used for the Patient Suspected to Have a Pulmonary Embolism. Grade B recommendation; Level of evidence: 4 Level II studies (5– 8).
CAEP VTE Investigation Guidelines
The chest radiograph is an important test in patients with chest pain or other symptoms that may be related to cardiac or pulmonary problems and is felt to be essential for the interpretation of the ventilation/perfusion lung (V/Q) scan (5). The findings on chest radiographs alone cannot be used to reliably diagnose pulmonary embolism (6) but an alternative diagnosis can be made that obviates the need for further investigation for VTE disorders.
Recommendation 2: A V/Q Scan Should Be the First Imaging Modality after the Chest X-ray in Assessment of Patients Thought to Have a PE Grade B recommendation; Level of evidence: 4 Level II studies (9 –12), 1 Level III report (13) . Numerous clinical trials have been done looking at the sensitivity, specificity, positive and negative predictive value of ventilation/perfusion scans. (9 –11) The sensitivity of a high probability scan; high probability and intermediate combined; and high, intermediate, and low probability combined is 41%, 82%, and 98%, respectively. Specificities were 97%, 52%, and 10% for high, intermediate, and low probability scans, respectively. In the samples tested, the positive predictive value of a high probability scan was 88%. The negative predictive value for a low probability scan was 84 – 88%, and for a normal scan was 91–96%.
Recommendation 3: Only Normal or High Probability V/Q Lung Scans Should Be Considered Strong Enough Evidence to Initiate Treatment. Nondiagnostic V/Q Scans Require a Careful Assessment of Clinical Risk and the Need for Further Investigations Grade B recommendation: Level of evidence: 3 Level II studies (9 –15). The results of lung scans can be separated into three major groups: normal, nondiagnostic (low and intermediate probability), and diagnostic (high probability) (14). In the past, radiologists have been reluctant to call V/Q scans normal. Pre-test likelihood is critical when interpreting V/Q scans. With a normal scan, the probability of PE is extremely low (13). With high probability scans (defined as one or more segmental or larger perfusion defects with normal or near normal ventilation), the probability of PE is $85% (14). A nondiagnostic scan includes segmental matched defects, subsegmental defects (matched or unmatched), and scan defects with corresponding abnormalities on the chest x-ray. The probability of PE with a nondiagnostic scan is 10 – 40% (15). Nondiagnostic scans should not be used to guide
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therapy. Interpretations such as intermediate probability, indeterminate, low probability, non-high probability, or near normal have not been used in a standardized fashion. The terms should be avoided because they are not only unhelpful but may be dangerous.
Recommendation 4: Noninvasive Leg Studies Are the Tests of Choice for the Further Investigation of Patients with a Nondiagnostic V/Q Scan. Grade A recommendation; Level of evidence: 1 Level I trial (16), 1 Level II study (17), 4 Level III reports (18 –21). If the ventilation/perfusion lung scan is nondiagnostic, other investigations should be carried out. The next investigation should be a noninvasive leg study. There is a close relationship between proximal deep vein thrombosis (DVT) and pulmonary embolism (PE) in that 80% or more of patients with PE have thrombi that originate in the lower extremities. (22–25) The remaining thrombi arise from the right heart, the upper extremities, the inferior vena cava, and the pelvic veins. Venous ultrasound (18,19) and impedance plethysmography (16,17,26,27) both have been shown to be reliable means of detecting above-the-knee DVT. If noninvasive leg studies are not available, contrast venography is an acceptable alternative, though less desirable due to potential thrombus induction and contrast reactions. (20,21) Contrast venography remains the gold standard.
Recommendation 5: Venous Ultrasonography Is the Preferred Noninvasive Test to Establish the Diagnosis of Proximal DVT Grade B recommendation; Level of evidence: 4 Level II studies (28 –32). Ultrasound has been shown to be more accurate than impedance plethysmography. (28 –31) In the sample tested, the positive predictive value is greater with venous ultrasound (94%) when compared to IPGs (83%). In patients who have a low pre-test probability (pre-test likelihood , 10%), the positive predictive value of doppler is only about 66%, and in high prevalence patients, the negative predictive value is 85–90%; therefore, in this group, the test does not definitively rule out thrombus. The sensitivity for duplex ultrasound is 92–95% and a specificity of 97–100%. The sensitivity of impendance plethyomographys (IPGs) is between 80 –94% for the symptomatic patient (15).
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Recommendation 6: Patients with a nondiagnostic V/Q Lung Scan and Negative Noninvasive Leg Studies Should Have Either a Pulmonary Angiogram, Venogram, or Serial Noninvasive Leg Studies Grade C recommendation; Consensus opinion. There is considerable controversy regarding patients with nondiagnostic V/Q scans and negative noninvasive leg studies. Venography or pulmonary angiography should be done if the clinical suspicion is moderate or high. Serial noninvasive studies should be done if clinical suspicion is low (15,33–35). If the leg studies (venography, venous U/S or IPG) are negative and there is moderate or high clinical suspicion for VTE, the patient should receive heparin and be transferred to a facility with the capability of doing a pulmonary angiogram (Consensus opinion). Pulmonary angiography is considered the gold standard, however, results may be indeterminate in 3–15% of patients (9,12). The test should be performed within 48 h of symptom onset because the resolution of thrombus may lead to an increased risk of a false negative investigation. The mortality and morbidity associated with pulmonary angiography are approximately 0.2% and 4%, respectively (5,9,36,37). An emergent pulmonary angiogram should be performed when the risk of treatment exceeds the risk of the test itself or death is likely without more invasive measures. This is particularly true if extensive thrombus is suspected; comorbid factors such as significant underlying cardiopulmonary disease, bleeding disorders, diabetic retinopathy, vascular abnormalities are present; or aggressive treatments such as fibrinolytic therapy, pulmonary embolectomy, or inferior vena cava interruption are being considered. Notwithstanding the concerns associated with false negative results after 48 h from symptom onset, a negative test is justification for not initiating treatment. If empiric treatment has been started in a patient with a very high pretest likelihood of PE (“high clinical suspicion”) and delayed presentation (.48 h), treatment probably should be continued until further investigations establish an alternate diagnosis or repeat leg studies are negative. One study suggested that patients suspected of having a PE with negative venograms bilaterally do not require anticoagulant therapy regardless of whether they have a PE or not (36). If the venogram is positive for a proximal DVT, then treatment should be instituted. Some authors feel that below-the-knee DVT can be observed with serial noninvasive tests (38) but this probably is not advisable in patients with lower extremity trauma or other major risk factors for VTE where clot extension is most likely to occur (39,40). In patients for whom there is a low clinical suspicion of PE, a repeat duplex ultrasound of the lower extremi-
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ties is warranted. (33,41) A single noninvasive leg test is recommended in patients with nondiagnostic V/Q scans. If the single leg study is negative, the authors recommend serial noninvasive leg studies or pulmonary angiography depending on the cardiorespiratory reserve. If the cardiorespiratory reserve is adequate, then serial leg studies are adequate. Pulmonary angiography remains an option in this group. If the cardiorespiratory reserve is poor, pulmonary angiography should be undertaken. (34) The ACCP Consensus Committee on Pulmonary Embolism believes that serial noninvasive leg tests would be an “appropriate approach to patients with nondiagnostic V/Q scans and a single negative leg test, providing there is good cardiopulmonary reserve” (35). A cost analysis was undertaken looking at three different strategies (42). The strategies were: V/Q scans and pulmonary angiography; V/Q scans, a single noninvasive leg test, and pulmonary angiography; and V/Q scans, serial noninvasive leg tests, and pulmonary angiography. The third strategy resulted in maximum effectiveness without being excessively costly. Occasionally, patients may be anticoagulated without a definitive diagnosis when the risk of anticoagulation is smaller than the risk of a repeat DVT or PE or the investigations are not available. A major unanswered question is how to objectively quantify clinical suspicion. This is a combination of the history, physical examination, risk factor profile, the clinician’s instinct, and possibly the results of preliminary tests. Two landmark studies, the Urokinase Pulmonary Embolism Trial (UPET; Reference 5) and the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED; Reference 9) have been used extensively to help define the clinical factors, risk profiles, and the results of investigations associated with proven PE. While these studies have been helpful in defining the relationship between clinical factors and PE, it should be appreciated that the results may suffer from selection bias. If patients are included in a study because they have positive test results without defining the criteria used to do the test in the first place, it may not be valid to assume that the study findings are applicable to patients being tested for other reasons or those seen in other settings. Whenever a disease is defined from observations made on a population pre-selected by some criteria, it cannot be assumed that these features will be present in the same frequency in a more heterogeneous population that is identified in a different way. Patients seen in a specialty referral clinic are not the same as those seen in primary care, the Emergency Department, or an in patient setting. Furthermore, the use of different gold standards (PE diagnosed only by V/Q or only by pulmonary angiography) can affect the observed clinical profile that is felt to define the disease.
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Recommendation 7: An Electrocardiogram Should Be Done When Assessing Patients with Cardiorespiratory Signs and Symptoms but Cannot Be Used to Exclude or Diagnose a Pulmonary Embolism Grade B recommendation; Level of evidence: 1 Level II study (43). The electrocardiogram can help establish an alternative diagnosis, but cannot be used to diagnose or exclude the diagnosis of pulmonary embolism. Recommendation 8: An Arterial Blood Gas Determination Is Helpful in Assessing Patients for Hypoxia, Ventilation, and Metabolic Abnormalities but Cannot Be Used to Exclude or Diagnose Pulmonary Embolism
Grade B recommendation; Level of evidence: 5 Level II studies (6,41,43– 45). There is no role for arterial blood gases in the diagnosis of pulmonary embolism. There are many documented cases with normal PaO2 and A-a gradient (6,44,45). Arterial blood gases are important for the determination of hypoxemia, ventilation, and metabolic abnormalities.
Acknowledgments—The Diagnostic Imaging Advisory Group had financial support from UpJohn Company of Canada, HoechstRoussel Canada Inc., and Burroughs Wellcome Canada.
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