Evaluating Pulmonary Embolism with CT: Time for a New Paradigm?

Author: Grant S. Lipman, MD, Clinical Instructor of Surgery, Division of Emergency Medicine, Stanford University School of Medicine, Palo Alto, California; Bao Duong, MD, Resident, Stanford/ Kaiser Emergency Medicine, Palo Alto, California

Peer Reviewer: Amal Mattu, MD, Associate Professor & Program Director, Emergency Medicine, University of Maryland School of Medicine, Baltimore, Maryland

Introduction

As biomedical technology progresses, the medical practitioner is presented with rapidly changing multiple options to diagnose acute disease states. Advances in technology often outpace the supporting literature, and health care providers may find themselves in the unenviable position asking, "What do I do with the results of a negative test?" Nowhere is this more true in acute care than in diagnosing pulmonary embolism (PE) and deep vein thrombosis (DVT), the two diseases that form the spectrum known as venous thromboembolism (VTE).

VTE remains an elusive diagnosis; presenting signs and symptoms may be vague and indistinguishable by clinical or laboratory tests from a multitude of other diseases. The need for an accurate diagnosis is crucial; it is estimated that more than 400,000 cases of PE are missed annually in the United States, leading to 100,000 deaths in patients undiagnosed and untreated.1

The 1989 PIOPED study, the largest multicenter PE study to date, combined clinical pretest probability with a number of noninvasive as well as invasive diagnostic tests to confirm or exclude the diagnosis of PE. The study used ventilation-perfusion (V/Q) as the imaging modality of choice, and conventional pulmonary angiography as the "gold standard" diagnostic tool. Recent advances with multidetector computerized tomography (CT) angiography have revolutionized our ability to diagnosis VTE. But new technology raises new issues: the inherent risks of radiation, ability to detect subsegmental arterial disease, and the accuracy of a negative test result.

Articles were selected for review based upon their ability to present up-to-date information as well as provide answers to timely questions that are relevant to clinical practice. While the majority of the literature reviewed is from the last two years, less recent studies are included that have clinical applicability. The objective of this article is to provide the reader with the latest information regarding the clinical validity of different options available to diagnose VTE in this rapidly changing technological landscape, and to answer the question: Is it time for a new paradigm?

Evaluation

Source: Fedullo PF, et al. Clinical practice. The evaluation of suspected pulmonary embolism. NEJM 2003; 349; 13:1247-1256.

This comprehensive review article defines the approach to evaluating a patient with suspected VTE. The authors discuss the varied clinical presentations of VTE and the importance of combining standardized risk prediction rules with diagnostic tests, to increase the diagnostic accuracy of detecting PE. Prediction rules classify patients into low (subgroup prevalence of 10% or less), intermediate (subgroup prevalence of 25-40%), and high probability (subgroup prevalence of 70% or higher). (See Table 1.) The degree of clinical suspicion should guide both the choice of the initial test and the subsequent decision process. High and intermediate clinical probability of PE require that a negative CT or low/intermediate probability V/Q scan be followed by lower extremity duplex ultrasonography, and if negative, evaluated further by pulmonary angiography. This differs from low clinical probability PE that can be effectively ruled out by two approaches: either a negative enzyme-linked immunoadsorbent assay (ELISA) d-dimer test or a negative doppler ultrasound following a negative CT scan or low/intermediate probability V/Q scan.

Commentary

The authors updated the recommendations of the original PIOPED study to include the advances in helical CT technology and d-dimer assays. However, the recent advent of multidetector CT with higher resolution, faster scanning times, better peripheral visualization, and less motion artifact have further revolutionized our approach to the evaluation of VTE. This article is important in that it gives us a context on which much of the current and upcoming research is based.

From the calculated clinical probability, a variety of noninvasive and invasive tests may be employed to definitively confirm or exclude the diagnosis of VTE. The authors applied different testing strategies depending upon the patient's pre-test probabilities—and developed a logical stepwise approach to diagnostic testing. They commented about special clinical circumstances that may dictate which tests are most useful. D-dimer tests, such as the ELISAs, are highly sensitive as a screening tool for low-risk patients. However, it is a nonspecific test and may give false-positive results in those patients with advanced age, pregnancy, or any inflammatory state.

While V/Q scans have held a central role in diagnosing PE for almost three decades, the majority of patients who undergo scanning do not have findings that are considered definitive, which leads to further imaging studies. Helical CT has a wide range of sensitivities due to technological variations and emboli location. Isolated subsegmental emboli occur in 6-30% of patients, and the sensitivity of detecting these is 71-84%. The study used risk stratification and reviewed outcome studies to recommend that it is safe to withhold anticoagulation therapy in patients with a negative CT scan and negative ultrasound study of the lower extremities except in those patients with a high or intermediate pre-test probability of embolism.

What to do with a negative CT scan

Source: Quiroz R, et al. Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism. A systematic review JAMA 2005; 293(16): 2012-17.

Quiroz and colleagues authored a review article that examined the ability of CT angiography to detect isolated peripheral pulmonary emboli, long considered the principal limitation of CT, and the safety of withholding treatment after a negative CT scan. The authors acknowledged that a prospective validation study would establish true diagnostic accuracy, but pulmonary angiography's poor ability to detect peripheral emboli (45-66%) makes it an unpractical comparison. The approach used to establish the validity of CT and the clinical significance of the findings was to conduct a systematic review of the outcome in patients who had a negative CT scan, and were not treated with anticoagulation therapy. A meta-analysis of 15 studies with a minimum of 30 patients and at least 3 months follow-up provided 3500 negative CT scans, with only 42 cases of subsequent thromboembolic disease. The calculated negative likelihood ratio (NLR) was 0.07, and the negative predictive value (NPV) was 99.1%. These values are comparable to those reported in the literature for conventional pulmonary angiography.

Commentary

Recent trends and technological refinements have seen the increasing use of CT scans to study patients with suspected PE. Current recommendations suggest that a negative CT scan cannot be used singly to adequately rule out the diagnosis, but must be used in conjunction with additional tests that subsequently increase health care costs, radiation exposure, and risk of invasive complications. Single-detector helical CT scanners were used in the majority of studies reviewed in the meta-analysis, with miss rates of 30% and higher for peripheral emboli. The results in this study concur with another meta-analysis by Moores2 who found similar low rates of recurrent VTE in those with a negative CT scan and not anticoagulated—indicating that isolated peripheral emboli have little impact on patient outcome.

Many studies in the analysis often used CT in combination with V/Q scans or lower extremity ultrasonography. The authors appropriately noted that adding additional imaging to the CT will lower the NLR and raise the NPV for a recurrent VTE more than CT alone. The authors also recommended additional imaging tests in the high-risk patient with a negative CT scan. More studies are needed to prospectively determine the relevance of peripheral emboli and treatment.

CT or V/Q?

Source: Katsouda E, et al. Evaluation of spiral computed tomography versus ventilation/perfusion scanning in patients clinically suspected of pulmonary embolism. In vivo 2005;19: 873-8.

For the last three decades, ventilation-perfusion (V/Q) scanning has been the test of choice in most practitioners for evaluating patients with suspected PE. This study sought to prospectively evaluate the diagnostic accuracy of CT versus V/Q scanning.

Patients who were considered to have a high clinical probability for PE were evaluated, undergoing both CT and V/Q scanning within a 12-hour period. Only high probability V/Q scans were considered positive. PE was diagnosed in 42 of the 63 patients. The sensitivity of spiral CT and V/Q scanning was 92.9% and 57.1%, respectively, and specificity was 85.7% and 42.9%, respectively. A total of 28 V/Q scans had interpretable findings of high probability or normal, while the remaining exams were indeterminate. The sensitivity and specificity of V/Q scans were significantly worse in those older than 50 years. In addition, a survey of participants revealed greater satisfaction and comfort with CT over V/Q scanning (85.7 % vs 14.3%).

The authors concluded that helical CT was superior to V/Q scanning in detection and exclusion of disease, and should be used as the first-line imaging modality for patients suspected of PE.

Commentary

The subject of choosing the optimal imaging modality to diagnose PE remains a contentious issue among clinicians. This study shows the startling difference between helical CT and V/Q scanning by comparing the two on the same patient population. Sensitivity and specificity for helical CT were comparable to previous studies.3,4

Katsouda and colleagues chose to report intermediate and low probability V/Q scans as negative, which contributed to the poor sensitivity of this test. However, studies have shown that the sensitivity of V/Q scanning can approach 98% if only normal scans are considered negative and grouping the remaining outcomes as positive,5 which causes specificity to fall dramatically. In clinical practice, the only useful findings from a V/Q scan are high probability or normal.

Low and intermediate probability scans require further testing to prove or disprove the diagnosis. In the PIOPED study, a majority of all scans were nondiagnostic and required additional studies to be performed.

Potential weaknesses from this study are the small number of participants and the selected patient population. High pre-test probability patients were enrolled in this study, therefore the selection bias makes the study both difficult to reproduce, as well as artifactually increasing the NPV.

Regardless, the abysmal performance of V/Q scans in a head-to-head comparison reflects the growing disenchantment with this test among many practitioners.

The new technology

Source: Patel S, et al. Helical CT for the evaluation of acute pulmonary embolism. AJR July 2005;185:135-49.

In this review article, the authors summarized the role and emerging trends of helical CT in the evaluation of PE. Technological advances have allowed better visualization of the distal pulmonary vasculature, while being more cost-effective than either V/Q scanning or pulmonary angiography and improving interobserver agreement. The authors reviewed the clinical outcomes in 18 studies (a total of 4,233 patients with a negative CT angiogram and a negative CT venograph), resulting in a weighted incidence of 1.3% for recurrent VTE and 0.4% for fatal PE.

Commentary

This article furthers the support for multidetector computed tomography (MDCT) in the evaluation of the subsegmental branches in the pulmonary vasculature, and supports the clinician's decision to withhold anticoagulation after a negative study. The pivotal argument that helical CT lacks the ability to detect peripheral emboli needs to be clinically weighed and rethought.

The multicenter prospective PIOPED II study, yet to be published, examined 773 patients to evaluate the accuracy and precision of MDCT. The researchers found that patients with low or intermediate pre-test probability with negative CT scans had low post-test probabilities of having VTE, 0.5% and 7%, respectively. In contrast, patients with a high probability undergoing a negative CT scan and a concordant negative venography, still were associated with a significant risk of 28% (although this scenario only occurred in 2% of evaluated patients). This study and resulting guidelines will help quantify the capabilities and limits of MDCT.

In this review, the benefits of MDCT were extensively discussed with minimal mention of the risks. Nickoloff states that the impact of thin cuts increases radiation exposure up to 36%.6 Most notably, the potential long-term sequelae of this technology are still unclear.

MDCT: One-stop shopping?

Source: Revel MP, et al. Diagnosing pulmonary embolism with four-detector row helical CT: prospective evaluation of 216 outpatients and inpatients. Radiology 2005; 234:265-73.

The advent of the MDCT offers impressive advantages over single-detector row helical CT, including the ability to reduce image acquisition time and section thickness, thereby, limiting motion artifact and increasing diagnostic yield. Until this paper, there has been no large-scale prospective clinical study looking at the quality of these new images and how they facilitate the diagnosis of PE. Prevalence of PE was 24.5 % (54 of 220), with 8 (15%) isolated subsegmental emboli. Adjunctive CT venography was performed on all the patients older than 40 years, demonstrating DVT in 15% (26 of 178). In the 3-month follow-up obtained of 111 patients with a negative CT angiography and CT venography, there were only 2 cases of (1.8%) recurrent VTE. Concordance between radiologists reading these studies at different sessions was good (kappa 0.88). Nondiagnostic scans occurred at a rate of 9%, mostly due to respiratory motion artifact. The authors concluded that multi-row detector CT scanners are more accurate than previously thought in evaluating peripheral emboli, and that CT venography may be an effective adjunctive test to verify thromboembolic disease.

Commentary

This is the first, with probably more to come, of articles prospectively evaluating the benefits of MDCT in the diagnosis of PE. Revel and colleagues detected a greater proportion of isolated subsegmental emboli than prior single-detector CT studies.4,7,8 However, the true incidence of peripheral emboli is hard to determine and, even with pulmonary angiography, varies widely from 6% in PIOPED to 30% by Oser and colleagues.9 The authors stated that with the documented poor interobserver agreement of subsegmental arterial findings in angiography as well as the accuracy of MDCT, pulmonary angiography should no longer be considered the standard in diagnosing distal PE.

Some disappointing results from this study are the minimal improvements in sensitivity, specificity, and the percentage of nondiagnostic studies. In spite of shorter acquisition times with MDCT, 18 of the 20 nondiagnostic studies were due to respiratory motion artifacts.

In addition to helical CT of the chest, delay-timed venography of the lower extremities also was performed. Current guidelines recommend CT imaging of the chest along with Doppler ultrasonography of the lower extremity to comprehensively evaluate a patient for VTE. CT venography has comparable sensitivity and specificity to ultrasound.10,11 Combination of chest CT with venography shows promise as a complete package to offer the patient "one-stop shopping" for the evaluation of thromboembolic disease.

Right ventricular dysfunction

Source: Gibson N, et al. Prognostic value of echocardiography and spiral computed tomography in patients with pulmonary embolism. Curr Opin Pulm Med 2005;11:380-4.

Pulmonary embolism is a potentially fatal disease that can rapidly progress to circulatory collapse. While aggressive therapies are available, such as thrombolysis and embolectomy, it remains difficult to predict which stable patients are at greater risk of developing hemodynamic compromise. The authors performed a literature review, comparing the prevalence and prognostic value of right ventricular dysfunction (RVD) on echocardiography (ECHO) and CT as an indicator of adverse outcomes. Seven studies were reviewed using ECHO in a total of 3468 patients; RVD was associated with a mortality of 4-33% compared with 2-14% mortality in those with normal ventricular function.

Meanwhile, 6 studies with 786 patients were reviewed, showing that RVD determined with CT has a less clear association with mortality. The CT studies were plagued with differences in definition of what constituted RVD, and indices could not be computed. Two studies allowed direct comparison of RVD in 83 patients, finding similar prevalence between CT and ECHO (22% vs 30%, and 81% vs 71%, respectively). The authors concluded that it is still too early to draw conclusions on the usefulness of CT in evaluation of RVD in those with known PE.

Commentary

Identifying patients with PE who are at risk for severe morbidity or mortality early in the disease process is important if they are to benefit from more aggressive monitoring and early treatment. The reviewed data supports ECHO-diagnosed RVD as an early indicator of increased mortality, especially during the in-hospital period (PPV of 12-18% for short-term mortality). However, in hemodynamically stable patients, the PPV for short-term mortality was only 4-5%. This contrasts with findings in a study comparing 256 patients with "submassive PE" who had stable hemodynamic parameters and RVD on ECHO: The group without early thrombolysis was associated with almost three times the risk of death or clinical deterioration.12

Details of what compromises RVD on CT remain debatable, and the reviewed journals had differing quantitative and qualitative descriptions, affecting the prevalence of RVD in each study. Among the various articles, RVD was defined as anything from the ratio between the right and left ventricular diameter with various cutoff values, to the diameter of the central pulmonary artery and superior vena cava. Consensus on a uniform set of criteria for the diagnosis of RVD in CT is imperative before significant progress can be made in this area of study. The prospect of utilizing CT not only to diagnose disease, but also to predict prognosis is a powerful draw. However, large randomized studies are needed before any management decisions can be made based on the CT findings.

Imaging and pregnancy

Source: Winer-Muram, et al. Pulmonary embolism in pregnancy patients: Fetal radiation dose with helical CT. Radiology 2002;224(2):487-92.

Pregnancy is a known risk factor for thromboembolic disease, increasing the risk by a factor of five over nonpregnant women. Winer-Muram and colleagues attempted to calculate the mean fetal radiation dose from helical chest CT. The authors studied the geometric relationship of 23 pregnant women and applied varying calculation models to determine the absorbed scattered radiation at differing gestational ages. They found the estimated doses in the first trimester to be 0.003-0.02 mGy, 0.008-0.07 mGy in the second trimester, and 0.05-0.13 mGy in the third trimester, values all less than those of V/Q scans, estimated at 0.1-0.37 mGy.

Commentary

PE is a major cause of maternal mortality, occurring in 0.5-3.0 of 1,000 pregnancies. The risks are highest in the third trimester and immediately post-partum, but some estimate that VTE happens with equal frequency in all trimesters. Pregnancy induces an inflammatory state that makes the d-dimer assay, with its high false-positive rate, a useless test. Considering the high frequency of nondiagnostic V/Q scanning, there is a high likelihood of requiring further imaging, compounding radiation exposure.

The authors of this paper attempted to define the most appropriate diagnostic test that would limit the risk of radiation exposure to the fetus. Other reports estimated radiation exposure of helical CT to be 0.01-0.12 mGy and V/Q to be 0.9-1.8 mGy, consistent with the estimates in this article.13,14

A weakness of this study is that direct measurements were not obtained, only mathematical models, which may not fully represent the actual in utero exposure. However, until a safe method is found to directly measure radiation, mathematical models may be our only source of data. This article supports the author's conclusion that helical CT appears to be the diagnostic test of choice for a pregnant patient.

Current trends

Source: Stein PD, et al. Trends in the use of diagnostic imaging in patients hospitalized with acute pulmonary embolism. Am J Cardiol 2004;93: 1316-17.

It has been suggested that spiral CT should replace V/Q scans as the primary diagnostic method to evaluate patients suspected of an acute VTE. This study examined trends in the proportion of diagnostic tests ordered between 1979 and 2001, using the National Hospital Discharge Survey. In 1979, V/Q scans represented 83% of diagnostic imaging tests obtained in patients discharged from the hospital with PE, this decreased to 32% by 2001. Alternately, CT imaging increased in the late 1990s to 36%, 2.56 times the use of pulmonary angiography and 1.12 times the use of V/Q scans.

Commentary

Collecting hospital discharge data from only 8% of U.S. hospitals may incompletely identify diagnostic studies, therefore using proportions and not absolute numbers of tests obtained is the appropriate focus of this paper. However, there is an unavoidable selection bias in this form of retrospective data analysis: Only patients who have been diagnosed with a PE are included. The reported prevalence of PE is 25% in those studied, therefore, one can imagine that the majority of imaging tests ordered would be negative, which were not included in this study. Also, patients who received multiple studies due to nondiagnostic results were not identified, an important point in this era of health care fiscal reform.

In 2001, CT scanners were available in a larger percentage of hospitals in the United States than radioisotope facilities (87% vs 62%, respectively). This trend is mirrored in Australia and the Netherlands, while the majority of hospitals in the United Kingdom in 1999 had only V/Q scanners. The pattern is emerging that V/Q scans may become obsolete, but the author's opinion is that they are still a necessary adjunct in the work-up of a patient suspected with PE.

The risks

Source: Lee CI, et al. Diagnostic CT scans: assessment of patient, physician, and radiologist awareness of radiation dose and possible risk. Radiology 2004; 231(4):393-8.

This study is the first to prospectively examine awareness levels among patients, ED physicians, and radiologists regarding radiation dose and possible risks associated with diagnostic CT. In the United States, CT accounts for 70% of the collective radiation dose administered to patients, and with MDCT refinement, this rate can be expected to rise. The authors reported that only 7% of patients stated that they were told about risks and benefits of undergoing CT imaging, while 22% of ED physicians reported that they had provided the information. Forty-seven percent of radiologists believed that there was an increased cancer risk, while this was true in 9% of ED physicians and 3% of patients. All patients and physicians were unable to accurately estimate the radiation dose received from a CT scan compared with that of a chest radiograph.

Commentary

We have set high expectations for CT as a diagnostic tool, but must not be ignorant of the fact that this beneficial instrument also comes with inherent risks and dangers. There is continued controversy over the actual cancer risk from diagnostic CT scans, with some estimates as high as 700 annual deaths attributable to head scans performed during childhood.15 While these findings and their implications are heavily debated, the authors demonstrated that nearly all of the sampled patients were not provided with enough information to make an informed decision. Furthermore, the physician needs to be educated regarding the magnitude of radiation to which the patient is exposed: approximately 100-250 times that of a chest radiograph.

Limitations of this study include the small sample size and the fact that patients with mild to moderate discomfort undergoing abdominal/ flank CT were enrolled—requiring us to extrapolate the results to the clinical setting of CT chest in a dyspneic population. The authors appropriately noted the difficulty in engaging in lengthy communications in the subset of patients who present in extremis or are unable to give informed consent. They also stated that educational policies should be instituted for both ordering physicians and their patients— but in a manner that will not cause public panic.

Conclusion/Recommendations

There is a changing paradigm in how we evaluate a patient with suspected PE. Given a patient without renal insufficiency or contrast allergy, there is rarely a time to choose a modality other than helical CT angiography to confirm or exclude the diagnosis. While guidelines to date have recommended secondary studies after a negative CT scan to confidently rule out VTE, Fedullo and colleagues presented a logical approach to evaluating the low-risk patients without an additional work-up.

Perhaps the most important point of this article is the elaboration on clinical validity of a negative helical CT scan for excluding VTE. Several of the papers either directly or indirectly demonstrated the safety of withholding treatment after a negative CT scan. Current evidence suggests that MDCT can reliably detect the presence of emboli in the peripheral pulmonary vasculature as well, if not better, than the traditional diagnostic standard of pulmonary angiography. And if these locations are truly responsible for 30% of PE, a larger question is raised: What is the clinical significance of the isolated subsegmental arterial obstruction? In a meta-analysis review, Quiroz and associates demonstrated the low morbidity and mortality among those with "missed" single peripheral emboli. Ultimately, prospective studies with extended follow-up will settle the debate whether withholding treatment is a safe alternative.

For the clinician working in the middle of the night there may be only one diagnostic option available for use. However, the physician should be able to articulate the risks, benefits, and rationale for choosing one imaging modality over another. The findings of Katsouda and Winer-Muram showed the superiority of helical CT over V/Q scanning in most clinical settings, even with the pregnant patient. Its greater availability in the United States is only one advantage.

Helical CT allows the clinician to differentiate alternative causes for the patient's symptoms, such as pneumonia or aortic dissection. In conjunction with EKG-gated technology, researchers are using the 64-row detector CT scanners to study the flow of coronary arteries. A consensus rule defining RVD to make Gibson's study stronger cannot be far in the future. MDCT is clearly the way of the future, and when combined with a lower extremity scan as in the Revel article, will soon replace V/Q scans and duplex sonography as the primary noninvasive imaging modality.

References

1. Marx JA, et al. Rosen's Emergency Medicine, 5th ed. CV Mosby;2002. Ch.83:1211.

2. Moores LK, et al. Meta-analysis: Outcomes in patients with suspected pulmonary embolism managed with computed tomographic pulmonary angiography. Ann Inter Med 2004; 141:11.

3. Qanadli SD, et al. Pulmonary embolism detection: prospective evaluation of dual-section helical CT versus selective pulmonary arteriography in 157 patients. Radiology 2000; 217:447-455.

4. Remy-Jardin M, et al. Diagnosis of pulmonary embolism with spiral CT: comparison with pulmonary angiography and scintigraphy. Radiology 1996;200:699-706.

5. Value of the ventilation/perfusion scan in acute pulmonary embolism. JAMA 1990; 263:2753-2759.

6. Nickoloff E. Current adult and pediatric CT doses. Pediatr Radiol 2002; 32:250-260.

7. Goodman LR, et al. Detection of pulmonary embolism in patients with unresolved clinical and scintigraphic diagnosis: helical CT versus angiography. AJR 1995;164:1369-1374.

8. van Rossum AB, et al. Pulmonary embolism: validation of spiral CT angiography in 149 patients. Radiology 1996;201:467-470.

9. Oser RF, et al. Anatomic distribution of pulmonary emboli at pulmonary angiography: implications for cross-sectional imaging. Radiology 1996; 199:31-35.

10. Cham MD, et al. Deep venous thrombosis: detection by using indirect CT venography. Radiology 2000;216:744-751.

11. Loud PA, et al. Deep venous thrombosis with suspected pulmonary embolism: detection with combined CT venography and pulmonary angiography. Radiology 2001;219: 498-502.

12. Konstandinides S. Heparin plus alteplas compared with heparin along in patient with submassive pulmonary embolism. NEJM 2002; 347(15):1143-1150.

13. Huda W. When a pregnant patient has a suspected pulmonary embolism, what are the typical embryo doses from a chest CT and a ventilation/perfusion study? Pediatr Radiol 2005;35:452-453.

14. Cook JV et al. Radiation from CT and perfusion scanning in pregnancy. BMJ 2005;331:350.

15. Brenner et al. Estimated risks of radiation-induced fatal cancer from pediatric CT. AJR 2001;176: 289-296.

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