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CME

Update/Overview on Pulmonary Embolism

  • Authors: Gregory S Martin, MD, MSc
  • THIS ACTIVITY HAS EXPIRED
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Target Audience and Goal Statement

This activity is intended for physicians, nurses, respiratory therapists, pharmacists, and other healthcare providers caring for patients with acute and chronic pulmonary diseases.

The goal of this activity is to define "state-of-the-art" treatment protocols and clinical strategies for the management of patients with acute and chronic pulmonary diseases, to enhance the care of these patients, and to support quality clinical practice of healthcare professionals involved in their care.

Upon completion of this activity, participants will be able to:

  1. Identify the current treatment strategies and pharmacologic options for pulmonary hypertension.
  2. Discuss recent developments in the diagnosis and management of pulmonary embolism.


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Author(s)

  • Gregory S Martin, MD, MSc

    Assistant Professor of Medicine, Division of Pulmonary and Critical Care, Emory University School of Medicine, Atlanta, Georgia

    Disclosures

    Disclosure: Gregory S. Martin, MD, has no significant financial interests or relationships to disclose.


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CME

Update/Overview on Pulmonary Embolism

Authors: Gregory S Martin, MD, MScFaculty and Disclosures
THIS ACTIVITY HAS EXPIRED

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Deep vein thrombosis (DVT) and pulmonary embolism (PE) are common medical conditions that contribute substantially to individual patient morbidity and mortality as well as global healthcare costs. There are an estimated 600,000 cases of PE each year in the United States, with an inhospital case-fatality rate attributable to PE of approximately 2%.[1,2] These statistics clearly underestimate the extent of the problem, as this does not include patients with DVT, many more PE patients die with PE (even if not from PE), and the mortality with these conditions continues to increase after hospital discharge. In fact, mortality rates from 3 months to 3 years after hospital discharge frequently range from 15% to 30%.[2-4] For patients with hemodynamic compromise, the mortality with PE is substantially higher, in the range of 20% to 30%, while still in the hospital.[1] Mortality rates are higher in men than women and in African-American individuals compared with white individuals, yet mortality rates overall are declining temporally.[5]

One of the first major studies to investigate the optimal way to diagnose PE was the first Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) trial.[6] In this study, 933 patients with suspected PE were studied with ventilation/perfusion (V/Q) lung scanning and/or pulmonary arteriography (PA-gram). Thirty-three percent of patients overall were diagnosed with PE. Almost all patients with PE had abnormal scans of high, intermediate, or low probability, but so did most without PE (test sensitivity = 98%; specificity = 10%).

Table 1. Probability of PE Based on Clinical Suspicion and V/Q Lung Scan[8]

Clinical Suspicion for PE*
V/Q Scan Result High (80% to 100%) Moderate (20% to 79%) Low (0% to 19%)
High 96 (82-99) 88 (78-94) 56 (21-56)
Intermediate 66 (49-80) 28 (22-34) 16 (8-27)
Low 40 (16-68) 16 (11-22) 4 (1-11)
Normal 0 (0-52) 6 (2-16) 2 (0-9)
*Values represent point estimates with 95% confidence intervals in parentheses.

Based on the estimated likelihood of PE in Table 1, the PIOPED investigators concluded that the combination of clinical suspicion and V/Q scanning provided a definitive answer only in a minority of patients -- those with clear and concordant findings, such as with high suspicion and high-probability V/Q scan. The majority of suspected PE patients thus require additional studies or other clinical consideration to reach a definitive diagnosis.

Since that time, there has not been a clear method for diagnosing PE. The traditional studies, including chest x-ray, V/Q scanning, duplex ultrasonography of the legs, PA-gram and general "clinical Gestalt" all suffer from inadequate test characteristics: either poor sensitivity or poor specificity. The ability to diagnose PE is perhaps most important for patients with limited cardiopulmonary reserve, in whom a(nother) PE could be a fatal event. Hull and colleagues[7] studied these patients by following them after nondiagnostic V/Q testing and found that 8% of patients with limited cardiopulmonary reserve died of autopsy-confirmed PE within days of the first suspected PE. Fortunately, there have been a variety of advances in the field since the PIOPED I study.

A significant shift in paradigms involves the consideration of DVT and PE as separate diseases. Because DVT and PE share a common pathophysiology and frequently occur together, they should be considered as a single medical diagnosis termed venous thromboembolism (VTE). In one study, nearly 40% of patients who had DVT without symptoms of PE had evidence of PE on subsequent lung scanning.[8] Conversely, in a study of patients with documented PE, 29% had abnormalities on ultrasonographic studies of the legs.[9]

Diagnostic advances have been made in both confirming and refuting the diagnosis of VTE. The oldest of these traditional criteria, clinical suspicion, has been quantified by Wells and colleagues[10] by using a numeric scoring system to assign points that correlate with increasing risk of PE. The scoring system inTable 2 can be used to create a pretest probability of PE:

< 2 points = low probability
2-6 points = moderate probability
> 6 points = high probability

Table 2. Point-Based Clinical Criteria for Suspected PE[10]

Variable* Points
Signs and symptoms of DVT 3.0
Heart rate > 100 1.5
Immobilization or surgery in prior 4 weeks 1.5
Prior DVT or PE 1.5
Hemoptysis 1.0
Malignancy 1.0
PE most likely diagnosis 3.0
Total  
*For the subjective final variable, assessment should be based upon all available clinical information to the scoring physician, including history, physical examination, chest radiography, blood tests, and electrocardiography.

The advent of more accurate D-dimer testing has allowed this blood test to advance the field of VTE diagnosis. D-dimer testing can be employed in combination with objective clinical criteria, such as those described above, to adequately exclude patients from having had VTE events.[11-15] In fact, for those patients with low clinical suspicion of DVT alone, a negative D-dimer test adequately excludes VTE events such that compression ultrasonography of the lower extremities can be safely omitted.[16] Similar results are known for evaluation of suspected PE.[17]

Another major advance in the diagnosis of VTE came from an advance in technology. Multidetector computed tomography (CT) scanners with timed intravenous contrast injections have emerged as the "PE-protocol CT" that is now commonly used for diagnosing PE. The myriad studies conducted to evaluate the ability of CT to diagnose VTE have resulted in systematic reviews and meta-analyses. Some dispute the accuracy of CT scanning to make the diagnosis (sensitivity varying from 53% to 100% and specificity from 81% to 100%),[18,19] while others report acceptable performance characteristics (average sensitivity 75%, specificity 90%).[20] However, the confidence intervals are wide due to substantial differences in CT performance depending on site and patient population.

The inability to make a clear diagnosis of VTE in a technologically advancing world, particularly with conflicting information on current testing modalities, led to the design and conduct of PIOPED II. This study was designed to prospectively enroll 1068 patients with suspected PE to undergo evaluation including PE-protocol CT (with or without imaging of the pelvic and thigh veins), chest radiograph, digital subtraction angiogram (DSA), lower extremity compression ultrasound (U/S), and V/Q scan. Eligible patients included all patients with suspected PE requiring hospitalization. The primary exclusions for eligibility were increased creatinine, prior anticoagulation, or presenting in a critically ill state (hemodynamically unstable, need for mechanical ventilation, etc). It was felt that requiring a PA-gram, to be used as the gold standard for diagnosis, was unethical because of safety concerns.

The diagnosis of PE was thus considered positive if one of the following were true:

  1. High probability V/Q scan without a prior history of PE,
  2. Positive DSA, or
  3. Positive compression U/S with a nondiagnostic V/Q scan.

PE was considered not present under the following conditions:

  1. Normal V/Q scan,
  2. Negative DSA, or
  3. Low-probability V/Q scan with low clinical suspicion (Wells score < 2) and a negative compression U/S.

Patients were followed throughout hospitalization and until 6 months following discharge to determine clinical outcomes. PE-protocol CTs were conducted in a similar manner using a single breath-hold technique at all institutions. Interpretation was performed locally and studies were transmitted to a central coordinating center for dual consensus interpretation to be used for statistical analysis.

The study ended with 773 patients enrolled. The average age was 52 years, 62% of subjects were female, and 75% were hospitalized from the community. Two percent of all PE-protocol CTs were uninterpretable (5% in patients with a body mass index > 35), 5% of all PE-protocol CTs suffered from significant motion artifact, and 7% of PE-protocol CTs could not be considered because a consensus could not be achieved between 2 interpreting radiologists.

The prevalence of diagnosed PE was 23%. Sixty percent of PEs were diagnosed by high probability V/Q scan, 17% by positive DSA, and 24% by positive U/S. PE was excluded in 46% of cases on clinical grounds, 31% by negative DSA, and 24% by normal V/Q scan. Overall, the sensitivity of PE-protocol CT was 83% and specificity 96%, yielding a positive predictive value of 86% and a negative predictive value of 95%. Using these numbers, the posttest probabilities for diagnosing PE were calculated, as presented in Table 3. During the 6-month period of follow-up, 1 patient died of PE, 1 patient developed a DVT, and 4 patients developed PE.

Table 3. Prevalence of PE According to Clinical Suspicion and PE-Protocol CT Result*

Clinical Suspicion for PE
PE-Protocol-CT Result High (> 6 points) Moderate (2-6) Low (< 2)
Positive 99 89 37
Negative 39 7 0.5
*From the PIOPED II trial, presented at the American College of Chest Physicians 2004 Conference.

Based on these results, the use of PE-protocol CT cannot be advocated as a stand-alone procedure for diagnosing PE. For instance, in patients with moderate clinical suspicion, there would be an 11% false positive rate (100 - 89 = 11). For patients with high clinical suspicion and a positive PE-protocol CT, the diagnosis can be considered confirmed. For patients with low clinical suspicion and a negative PE-protocol CT, the diagnosis can be considered ruled out. For all other patient groups in Table 3, additional testing probably needs to be performed. (The possible exception would be patients with moderate clinical suspicion and a negative PE-protocol CT, yielding a 7% false negative rate -- still too high for most clinicians). While PE-protocol CT has gained tremendous acceptance in hospitals and among radiologists as the test of choice for diagnosing possible PE, the performance characteristics of PE-protocol CT are similar to that of familiar V/Q scanning. This may be particularly true in community-based hospitals where radiologists are less familiar with interpretation of PE-protocol CT, in light of the fact that even in these well-trained research centers, the sensitivity of PE-protocol CT varied widely from 58% to 95%. One additional finding from this study is that the addition of CT contrast venography (scanning the femoral regions for DVT) is a useful addition to PE-protocol CT, thus supporting the importance of considering DVT and PE as a single condition.

In conclusion, PE-protocol CT represents a significant technological advance for the diagnosis of VTE and is increasingly used in hospitals around the world. Unfortunately, the performance characteristics, even in the best hands, are not tremendously better than traditional V/Q scanning. The full report from the PIOPED II study will help to put this into context, with additional data on posttest probabilities, likelihood ratios, and interpretation of PE-protocol CT in the context of other information such as in combination with compression ultrasound.

References

  1. Fedullo PF, Tapson VF. Clinical practice. The evaluation of suspected pulmonary embolism. N Engl J Med. 2003;349:1247-1256. Abstract
  2. Carson JL, Kelley MA, Duff A, et al. The clinical course of pulmonary embolism. N Engl J Med. 1992;326:1240-1245. Abstract
  3. Goldhaber SZ. Pulmonary embolism. N Engl J Med. 1998;339:93-104. Abstract
  4. Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT Study. Arch Intern Med. 1991;151:933-938. Abstract
  5. 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;163:1711-1717. Abstract
  6. PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA. 1990;263:2753-2759. Abstract
  7. Hull RD, Raskob GE, Pineo GF, Brant RF. The low-probability lung scan. A need for change in nomenclature. Arch Intern Med. 1995;155:1845-1851. Abstract
  8. Moser KM, Fedullo PF, LitteJohn JK, Crawford R. Frequent asymptomatic pulmonary embolism in patients with deep venous thrombosis. JAMA. 1994;271:223-225. Abstract
  9. Turkstra F, Kuijer PMM, van Beek EJR, Brandjes DPM, ten Cate JW, B?ller HR. Diagnostic utility of ultrasonography of leg veins in patients suspected of having pulmonary embolism. Ann Intern Med. 1997;12:775-781.
  10. 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;83:416-420. Abstract
  11. Kearon C, Ginsberg JS, Douketis J, et al. Management of suspected deep venous thrombosis in outpatients by using clinical assessment and D-dimer testing. Ann Intern Med. 2001;135:108-111. Abstract
  12. Wells PS, Anderson DR, Rodger M, et al. Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer. Ann Intern Med. 2001;135:98-107. Abstract
  13. Ginsberg JS, Wells PS, Kearon C, et al. Sensitivity and specificity of a rapid whole-blood assay for D-dimer in the diagnosis of pulmonary embolism. Ann Intern Med. 1998;129:1006-1011. Abstract
  14. Kline JA, Israel EG, Michelson EA, et al. Diagnostic accuracy of a bedside D-dimer assay and alveolar dead-space measurement for rapid exclusion of pulmonary embolism: a multicenter study. JAMA. 2001;285:761-768. Abstract
  15. Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med. 2004;140:589-602. Abstract
  16. Wells PS, Anderson DR, Rodger M, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349:1227-1235. Abstract
  17. Dalen JE. When can treatment be withheld in patients with suspected pulmonary embolism? Arch Intern Med. 1993;153:1415-1418.
  18. Mullins MD, Becker DM, Hagspiel KD, Philbrick JT. The role of spiral volumetric computed tomography in the diagnosis of pulmonary embolism. Arch Intern Med. 2000;160:293-298. Abstract
  19. Rathbun SW, Raskob GE, Whitsett TL. Sensitivity and specificity of helical computed tomography in the diagnosis of pulmonary embolism: a systematic review. Ann Intern Med. 2000;132:227-232. Abstract
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