Pulmonary embolism: A diagnostic approach.(Disease/Disorder overview)

Annals of Thoracic Medicine January 1, 2006 | Abdelaziz, Muntasir; Wali, Siraj; Hamad, Mahir; Krayem, Ayman; Samman, Yaseen Byline: Muntasir. Abdelaziz, Siraj. Wali, Mahir. Hamad, Ayman. Krayem, Yaseen. Samman Despite the availability of many diagnostic modalities and the advent of new tests, the diagnosis of pulmonary embolism (PE) remains a challenge. Clinical manifestations can be notoriously deceptive and there is not a single test, that can be relied on solely, to exclude PE. Although it has been regarded as the gold standard test, pulmonary angiography has not been tested against a reference standard and thromboembolic events have been reported after a normal study. Therefore the diagnosis of PE depends on judicious utilization of the available tests in the right clinical setting, as the accuracy of the results of the investigations, depends largely on the pretest clinical probability. Simple investigations such as chest radiograph, electrocardiogram and arterial blood gas, are used to enhance the clinical probabilities, rather than confirming or refuting the diagnosis of PE. On the other hand, Perfusion ventilation (VQ) scan and computerized tomographic pulmonary angiography (CTPA), are the main screening tests used for patients with suspected PE. Recently CTPA has largely replaced VQ scan, in many centres. As both VQ scan and CTPA have their limitations, other diagnostic modalities, such as D-dimer and Compression ultrasound of the legs (CUS), are used as adjunctive diagnostic investigations. High probability and normal VQ scan, especially when combined with the concordant clinical probability, has a high positive and negative predicative value, respectively. On the other hand, CTPA is more sensitive and specific than VQ scan, though it has to be combined with CUS and clinical probability, to reduce the chance of missing PE. Although many diagnostic algorithms have been advocated, the discretion of the clinician and clinical experience, still has a major role to play in the diagnosis of PE. In this article, we try to come with a plausible approach to the diagnosis of PE, based on the current literature.

Pulmonary embolism is a frequent and potentially fatal clinical problem. A study by Dalen and Alpert in 1975, estimated that the mortality rate of untreated PE could approach 30%.[1] The condition can also be recurrent and complicated in some patients, by pulmonary hypertension and cor pulmonale.[2],[3] The incidence of PE in the United States has been estimated to be 1.22 in 1000, among the adult population.[4],[5] However, the diagnosis of PE can be a real challenge and the condition seems to be under-diagnosed. It has been estimated, that only one in three cases of venous thromboembolism (VTE) is detected.[6],[7] Indeed, post-mortem studies have demonstrated, that 4 to 5% of patients had pulmonary embolism as the cause of death, rather than merely in association with death.[6],[7] Although the literature is rich in the subject, the diagnosis of PE remains elusive and can be very difficult. Also, there are some guidelines such as the American Thoracic Society (ATS; 1999) and British Thoracic Society (BTS; 2003) available, but they have deferent diagnostic pathways. Furthermore, several very recent publications and work in the subject have become available and needs to be addressed. In this review, we have tried to come with a plausible diagnostic approach, based on the current literature.

There is no test that can 100% rule out the diagnosis of PE. Although pulmonary angiography is regarded as the gold standard test with a very high sensitivity approaching 100%, it has not been tested against another reference standard test and its current position has not been established by default. Indeed, thromboembolic events have been observed, following normal pulmonary angiographic studies.[8] Consequently, the diagnosis of PE depends on interpreting the results of investigations, in the context of the pre-test clinical probability[9],[10],[11],[12],[13] [Table 1]. Therefore, making the diagnosis of PE has two components:

1.Determining the pretest clinical probability 2.Performing special screening and diagnostic tests to substantiate the clinical suspicion.

Clinical Probability of Pulmonary Embolism Symptoms and clinical signs of PE are non-specific and deceptive, which necessitate the need for diagnostic imaging.[2],[4],[9],[10],[11],[12],[13],[14] The most common presentation of PE is dyspnoea and tachypnoea, with or without pleuritic chest pain and hemoptysis. However, in massive PE, the patient may present with syncope and hemodynamic instability. Rarely does PE present as indolent pneumonia, heart failure, or exacerbation of obstructive pulmonary disease, especially in the elderly.[2],[4] In spite of the non-specific features of PE, clinicians are fairly good in estimating the clinical probability of the condition. Studies have shown that a low clinical probability of PE has a high negative predictive value, reaching 89-96%.[12],[15],[16],[17],[18],[19] Similarly, a high clinical probability of PE has a fairly good positive predictive value of 67.7%, though far less than the negative predictive value of low clinical probability.[12] However, in most cases (about two third), it is difficult to categorize patients into high or low clinical probability of PE. In addition, the clinical probability of suspected acute PE, is determined most of the time by junior staff, who are less experienced than their seniors in estimating the likelihood of the condition.[20] This emphasizes the need of a structured system to determine the clinical probability of PE.

Determining the clinical probability of PE should always be encouraged, as it may improve the clinical assessment and the overall diagnosis of the condition.[12],[19] Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, demonstrated that the likelihood of PE can be either increased or decreased, by combining pretest clinical probability assessment with the isotope scan probability (see below).[12] Similarly, Musset and colleagues demonstrated that, the likelihood of missing the diagnosis of VTE with negative testing on both computerized tomography pulmonary angiography (CTPA) and venous ultrasonography, depends on the clinical probability.[19] Evaluating clinical probability of PE depends on three criteria put together:

1. Presence or absence of risk factors.

2. Clinical features suggestive of PE. These include clinical presentations and simple but not diagnostic tests, such as arterial blood gas, electrocardiogram and chest radiograph.

3. Presence or absence of other alternative diagnosis that can explain the clinical presentation.

Different validated schemes to determine the clinical probability, have been advocated.[10],[16],[17],[21],[22],[23],[24] Clinical probability is classified according to the above-mentioned criteria, into high (presence of risk factors with no alternative diagnosis), intermediate (either presence of a risk factor plus an alternative diagnosis or absence of a risk factor but no alternative diagnosis), or low (no risk factors plus the presence of an alternative diagnosis). This simple and practical system has been advocated by the British Thoracic Society (BTS) [Figure 1] and validated against other scoring detailed and complex systems.[10],[24] Wells et al , based on more or less the same criteria, has introduced one more detailed scoring system.[21],[22],[23] Other ways of determining the clinical probability using scoring systems, have been introduced by Miniati et al [16] and Wicki et al .[17] Simple but non-diagnostic Tests These are tests, which are normally performed to improve the clinical probability. They should not be used solely as screening tests to rule in or rule out the diagnosis of PE. They include arterial blood gas (ABG), electrocardiogram (ECG) and chest radiograph (CXR).

Arterial blood gas Typical changes encountered in patients with PE are hypoxemia, hypocapnia and respiratory alkalosis.[9],[10],[25] Acidosis may be seen in massive PE.[10] However, the diagnosis of PE should not be excluded merely on the basis of normal ABG, especially in young persons with good respiratory reserve.[8],[10],[25] Normal ABG can be found in 29% and 3% of young and old subjects with PE, respectively.[26] In the PIOPED study, the diagnosis of PE in the absence of cardiorespiratory disease, was difficult, when based on PaO[sub] 2 and alveolar-arterial gradient only.[12] Stein et al , demonstrated that when relying on ABG alone, that PE could not be excluded in more than 30 and 14% of patients, with and without cardiopulmonary disease, respectively.[27] Recently, Rodger et al found that ABG alone, or with other variables, failed to give good prediction for the presence or absence of PE.[28] Chest radiograph Abnormalities in the chest radiograph are usually encountered in patients with PE, but they are not specific. Characteristic changes include Hampton hump (pleural-based shadow due lung infarction), plate-like atelectasis, small pleural effusion, raised hemi-diaphragm, Flichner sign (amputated prominent pulmonary artery) and Westermak sign (oligaemia peripheral to a prominent pulmonary artery).[2],[9],[10],[25],[29] Conversely, CXR may show no abnormalities in patient with PE. Indeed in the setting of severe dyspnoea and hypoxemia without evidence of bronchospasm a normal CXR should prompt the physician to consider the diagnosis of PE.[9] Furthermore, chest radiograph is an important factor in determining the screening test to be used (CTPA versus VQ) in the diagnosis of PE and a valuable tool for the interpretation of VQ scan.

Electrocardiogram ECG changes of PE are not specific.[9],[10],[12] Changes, which would be encountered in PE, include non-specific ST segment/T wave changes and sinus tachycardia.[2],[10] Acute right bundle branch block, right ventricular strain pattern and S[sub] 1 Q[sub] 3 T[sub] 3 are observed in massive PE.[25],[29] Diagnostic Tests Diagnostic tests are used after determining the clinical probability, to make the final diagnosis of PE. They include D-dimer, Compression ultrasound of the lower limbs (CUS), CTPA and pulmonary angiography.

D-dimer D-dimer is the proteolytic derivative of degraded fibrin.[30],[31],[32],[33] High level of D-dimer can be detected in VTE, as well as many other conditions, including inflammatory disorders, trauma, infections and neoplasia and therefore does not necessarily indicate that PE is present.[31],[32] On the other hand, a negative test has a high negative predictive value in excluding the diagnosis of VTE. The sensitivity of the test is significantly improved, when combined with the clinical probability. However, commercially available D-dimer assays vary in their sensitivity and specificity and therefore the diagnostic value of one test cannot be extrapolated to another.[11],[32],[34],[35] It can be measured by several methods such as latex agglutination, red blood cell (RBC) agglutination and enzyme-linked immunosorbent assay (ELISA).[29],[30],[31] Latex agglutination is the least sensitive and most specific, while ELISA is the most sensitive and least specific.[32],[36],[37][38] Red blood cell agglutination has an intermediate sensitivity and specificity.[22],[32],[39],[40] Assays that are studied extensively, are VIDAS (ELISA) and SimpliRED (RBC agglutination).

SimpliRED Studies have demonstrated variable sensitivities of RBC agglutination assays in the diagnosis of PE, ranging from 68%[39] to 85%.[40] However, Ginsberg’s group in a large study (1177 patients), demonstrated that the sensitivity of SimpliRED test in the diagnosis of PE would improve from 85 to 97%, in patients with low clinical probability and negative D-dimer.[40] Similarly, Wells et al showed that the sensitivity of SimpliRED could be enhanced, when combined with low clinical probability.[22] This group studied 930 patients with suspected PE and determined the clinical probability according to a validated scoring system. Patients with low clinical probability and a negative D-dimer (n=437), did not go for further imaging, nor received anticoagulant therapy. Only one patient of this group developed PE, on follow up. Taking these findings in consideration, it has been recommended that the combination of a negative SimpliRED with a low clinical probability, can be used to exclude PE without the need of further imaging.[11],[22],[40] ELISA ELISA test has been shown to have a high sensitivity (91-93%) and a low specificity of 25-42%, in the diagnosis of PE.[41],[42] Although the ELISA test in the diagnosis of PE has been reported to have a higher sensitivity value than other methods, the assay is time consuming. In addition, the very low specificity of the test indicates, that most of the patients with suspected PE will have positive results and therefore imaging will be avoided in only few patients. These two points make the ELISA test less appealing for clinical use. Consequently, a rapid ELISA test has been developed (VIDAS), without compromising its high sensitivity. Perrier et al . studied 918 patients with suspected PE or DVT, using this assay.[43] In this study, only those with a positive test were investigated further. Those with a negative test were not treated and followed for 3 months, during which, only two developed VTE.[43] Accordingly, it has been recommended, that PE could be excluded without further imaging, in patients with a negative VIDAS test, combined with a low/intermediate pretest clinical probability.[10],[43] Recently, Stein et al . analyzed the prospective ELISA studies, that either compared the assay with a reference standard, or have a high methodological quality, tested against preset criteria.[44] This analysis suggested that a negative ELISA is as good as a normal or near normal VQ scan, or a negative duplex ultrasonography, in excluding PE or DVT, respectively. More recently, Perrier et al . identified 674 patients with low/intermediate clinical probability out of 756 consecutive patients with suspected PE, 232 of which had negative VIDAS and none of them were investigated further or received anticoagulant for VTE (10 patients received anticoagulant for reasons other than VTE). A three-month follow up showed no VTE events among this group.[45] Latex agglutination As D-dimer test is used to exclude rather than confirm the diagnosis of PE, techniques with low sensitivity, such as latex agglutination, is not recommended. However, MDA is a new latex agglutination test with a very high sensitivity. Indeed, studies have shown that a negative MDA can exclude PE in patients with low/intermediate pretest clinical probability, without the need of further imaging.[46] Summary of the role of D-dimer Although it has been recommended that combining negative results of some of the D-dimer assays with clinical probability (SimpliRED plus low clinical probability; Vidas/MDA plus low/intermediate pre-test clinical probability) may be relied on to exclude PE without imaging, we feel that this approach should be adopted with caution. Specific scoring system and relatively experienced and senior medical staff, usually determine clinical probability in studies, which is not always the case in normal practice. Therefore, it is reasonable for the time being, to limit the use of D-dimer, to patients with low pre-test clinical probability. However, in patients of intermediate clinical probability, the above recommendation may be used with caution. It must be emphasized here, that in case of high clinical probability, the use of D-dimer is not recommended, as it is most likely to be positive and if negative, would not influence the decision of undertaking further tests and imaging.

Compression ultrasound of the lower limbs Compression ultrasound of the lower limbs, is the standard screening test for suspected DVT and has almost completely replaced contrast venography. Studies have demonstrated that, in clinical DVT, serial CUS has the same diagnostic accuracy as venography and saves the patient, the risk of an invasive procedure and contrast allergy and nephropathy.[9],[10],[11],[47],[48],[49] As well, it has been shown that it is safe to withhold anticoagulant medications in a patient with suspected DVT and a negative single CUS, provided that the patient will have a second ultrasound study within 5-7 days.[9],[10],[11],[50] However, this cannot be extrapolated to those with suspected PE, where the situation is different and CUS is not as reliable as in DVT. Although most cases of PE arise from the proximal vein of the leg, CUS is positive in only one third of patients with proven PE.[51] Possible explanations for negative CUS in patients with PE, include other source of emboli (e.g., upper limb), intra-vascular non-occluding thrombus, an already dislodged leg thrombus and false negative studies.[52] Nevertheless, CUS still has a place in the diagnostic work up of PE and can be used as an adjunctive test in a patient with suspected PE, with non-conclusive isotope lung imaging, or negative CTPA. in our site pulmonary embolism symptoms

The chance of missing PE, following a non-diagnostic isotope scan and a negative CUS, depends on the clinical probability, VQ scan probability and whether single or serial ultrasound studies were used. Daniel and co-workers performed a prospective study in 2 large teaching hospitals and examined the sensitivity of CUS in patients with suspected PE and non-diagnostic VQ scan (Low, intermediate and indeterminate).[53] These authors found the sensitivity of CUS in these patients (n=156) to be 54%, suggesting that a nondiagnostic VQ scan plus a single negative CUS, does not exclude PE confidently.[53] Also, Meyerovitz et al , in a retrospective study, examined the sensitivity of CUS in 62 patients who underwent angiography, because of a high clinical suspicion of PE, despite a low probability VQ scan and negative CUS.[53] Five patients (8%) of this group had PE on angiography, indicating that the combination of low VQ probability and negative CUS, is not sufficient in excluding PE, when there is a high clinical probability.[54] In contrast, in case of low clinical probability, Perrier et al found that the chance of missing PE, can be as low as 1.7% (5/180) in patients, with a non-diagnostic isotope lung scan and a negative one time leg ultrasound imaging.[55] On the other hand, it has been suggested that when using serial leg ultrasound studies in patients with non-diagnostic isotope lung scanning, the diagnosis of PE may be overlooked in very few patients. Hull et al in a prospective study, examined the chance of missing PE in patients with non-diagnostic scan and negative serial non-invasive tests, for proximal-vein thrombosis.[56] These Authors used Impedance plethysmography (IPT), which is less sensitive than CUS, in detecting proximal DVT. They found that on long term follow up of 627 patients with non-diagnostic lung scans and negative serial IPT, only 12 patients (1.9%) had VTE.[56] However, the approach of serial CUS or IPT, after a negative initial non-invasive test, may have some financial and resource implications and subsequent studies have not supported this approach. Bendick et al performed serial CUS in 94 patients with non-diagnostic VQ scan and a negative initial CUS.[57] In this prospective study, results of serial examinations of 92 patients remained normal bilaterally, while the remaining 2 patients had below knee DVT, which cast some doubt on the value of serial CUS in this clinical setting.[57] Similarly, CUS has been used as an adjunctive test to CTPA (see below) and again, the diagnostic value of this approach depends on the clinical probability. The chance of missing the diagnosis of PE with negative CTPA and CUS, was found to be 1.8%, with intermediate/low clinical probability and 5%, with high clinical probability.[19] Ventilation/perfusion Isotopes Scan Until recently, ventilation/perfusion isotopes (VQ) scan has been used as the standard screening test for the diagnosis of PE. It still holds this position in many institutions, especially in patients with normal chest radiograph. A landmark study in the diagnosis of PE (PIOPED), showed that a high VQ probability has a high positive predictive value, with the likelihood of having PE to be as high as 87%, though few patients will have false positive results.[12] Conversely, a normal or near normal VQ scan, virtually excludes PE. Furthermore, the predictive value of VQ scan is increased or decreased further, if combined with the clinical probability. The likelihood of PE could be increased from 87 to 96%, if the high VQ probability is combined with a high clinical probability. [12] On the other hand, the likelihood of PE could be decreased from 14% to 4%, if the low VQ probability is combined with a low clinical probability.[12] Unfortunately, most patients (57%) will have non-diagnostic (intermediate/low/indeterminate probability) results in VQ scan testing, which pause a diagnostic dilemma for most clinicians. This is particularly true for patients with abnormal CXR, or cardiopulmonary disease. Therefore VQ scan should be supplemented with other diagnostic tests, in these patients.

Computerized Tomographic Pulmonary Angiography Unlike VQ scan, there is no large multi-center study with a reference test, that could provide the final verdict on the accuracy of CTPA, in the diagnosis or exclusion of PE. However, the literature is very rich with heterogeneous studies investigating the role of CTPA in the diagnosis of PE, many of them of with variable methodology, size and outcome. We have no level A studies (Large randomized trials with gold standard Reference test) evaluating the diagnostic value of CTPA in PE and we have to rely on level B studies (Large randomized trials with no Gold standard Reference test). Nevertheless, many of these level B studies, especially the most recent ones, have a robust methodology with large number of patients. Here, we would like to mention that there were few studies, which have used pulmonary angiography as a reference test, but the number of patients enrolled was very small, for the study to be graded as level A.

Computerized tomographic scan has virtually replaced VQ scan as a screening diagnostic test for PE, in many institutions. When compared with VQ scan, CTPA is quicker to perform, easier to read, even in the presence of cardio-pulmonary disease or abnormal CXR, can give an alternative diagnosis in many cases and provide quantitative assessment of PE, which correlate well with the severity of the clinical picture.[58],[59] In addition, CT venography of the iliac veins and the inferior vena cava, can be performed simultaneously with high sensitivity (97%) and specificity (100%). Although this can be performed with no additional contrast, it entails significant additional radiation dose to the reproductive organs, which should be taken into account, while investigating young people.[60] Earlier, diagnostic studies examined the role of CTPA in the diagnosis of PE and were reviewed by several authors. Kline et al reviewed 14 studies (total number of 935 patients) and found the pooled specificity and sensitivity of CTPA to be 93 and 86%, respectively.[61] These studies were before 2000 and most of them were criticized on the basis of the size of the study, patient selection, or their methodology. Rathbun et al examined the validity of 15 studies against predefined criteria and none of these studies m et al l these criteria.[62] These studies showed varying sensitivity ranging from 53-100% and specificity from 81-100%.[62] More recent studies also demonstrated variable sensitivities and specificities of CTPA. Qanadli et al , using pulmonary angiography as a reference standard test, studied 157 patients with suspected PE and found that the specificity and sensitivity of CTPA would approach 94 and 90%, respectively.[63] On the other hand, Perrier and co-workers studied the diagnostic value of CTPA in 287 patients, presented to emergency room with suspected PE and a positive D-dimer.[64] Although these authors did not use pulmonary angiography in all patients, they applied fairly vigorous and tough methodological criteria and used other tests (VQ and CUS) when angiography was not used, as reference investigations. All patients were followed for 3 months. While the reported CTPA specificity was 91.2%, its sensitivity was worryingly low (70%).[64] Pulmonary embolism in this study, was diagnosed in 118 patients on the basis of a high probability VQ scan (61/118), a positive CUS plus a clinical suspicion of PE (44/118), or positive pulmonary angiographic findings (12/118). One patient, who was regarded as having no PE initially on the basis of a near normal VQ, developed DVT clinically on CUS, 10 weeks after the study. Of these, 118 patients with proven PE, CTPA was done in 116 patients and found to be negative in 35 patients (30%). The diagnosis of PE in these 35 patients, with negative or inconclusive CTPA, was established by other tests, which is a very alarming finding, suggesting that CTPA should not be used alone, to rule out PE.[64] Subsequent new studies focused on the outcome of patients with suspected PE and examined the safety of withholding anticoagulant therapy, following negative findings on CTPA plus CUS. Although these studies did not use pulmonary angiography as a gold standard test, the methodology was robust and the number of patients enrolled was quite large. Three studies are worth mentioning here, where two of them used single detector CT-PA,[18],[64] while the third used multi-detector-row CTPA.[45] All suggested that it is safe to withhold anticoagulant therapy with negative CTPA and CUS results, especially if the clinical probability was low or intermediate. Musset et al investigated 1041 patients with suspected PE, in a large prospective multi-centre study involving 14 French hospitals and assessed the safety of withholding anticoagulation therapy after a negative CTPA and lower limb ultrasonography.[8] There was no gold standard test, but patients were followed for three months. The study demonstrated that PE is likely to be missed with negative testing, on both CTPA and venous ultrasonography in 1.8% of patients with low/intermediate clinical probability, compared to 5.3% (4 out of 76) of patients with high clinical probability. Similarly, van Strijen in the Netherlands, using the same approach, studied 510 patients (from 3 hospitals) with suspected PE.[65] Patients with negative single detector CTPA findings for PE, were divided into two groups. Those with negative CTPA for PE, but no alternative diagnosis (246 patients), underwent ultrasound study of the legs, which was repeated twice on day 4 and day 7, if the initial ultrasound was negative. All these patients had the initial CUS on day one, but only 77% of patients came for the repeat ultrasounds on day 4 and day 7. The second group included patients with no PE, but with alternative diagnosis on CTPA (130 patients). This group received specific treatment according to the diagnosis, with no anticoagulation or further test (No CUS). Clinical probability was not included in the study and there was no gold standard test. A three-month follow up revealed that VTE occurred in 0.4% (1 out of 246), in the first group (patients with negative CTPA and no alternative diagnosis). However, 1.5% (2 out of 130) of patients in the second group (those with no PE but alternative diagnosis on CTPA), were found to have VTE on follow up. None of the patients in the second group had CUS initially, which may explain the slightly higher percentage VTE (1.5%) on follow up, compared to first group who underwent both CTPA and CUS (0.4%). Interestingly, initial ultrasound detected DVT in only 2 out of the 246 patients with negative CTPA, but no ultrasonographic abnormalities were found in the repeat ultrasound studies on day 4 and day 7.[65] These findings cast some doubt on the benefit and cost effectiveness of serial ultrasound studies in patients with negative CTPA and a negative initial CUS. Very recently, Perrier et al in a prospective trial with 3-month follow-up, studied 756 consecutive patients with suspected PE, using multi-detector CTPA. This study revealed that the risk of VTE among patients with positive D-dimer (VIDAS) and low/intermediate clinical probability is 1.7%, after negative findings in both CTPA and CUS.[45] Therefore, the results of these three well-designed multi-centre studies would suggest, that it is safe to withhold anticoagulant in patients with low/intermediate clinical probability and negative CTPA and CUS.

Recently, PIOPED II investigated the role of multi-detector CTPA on the diagnosis of PE in 773 patients.[66] Unlike the original PIOPED, in this study, angiograpgy was not used as a gold standard reference test, but performed only when required. PE was considered to be positive when there was a high-probability V/Q scan, a positive digital subtraction angiogram, or a positive CUS with a non-diagnostic VQ scan. Patients were followed for 6 months. Although the results of this trial was not officially published, initial reports suggested that CTPA is fairly accurate in the diagnosis or exclusion of PE, in case of a positive scan with a high clinical suspicion, or a negative scan with a low clinical probability, respectively. However, in the presence of intermediate clinical probability and negative CTPA and CUS, the chance of missing PE could be as high as 7%, which is unacceptably high. Therefore, further tests are probably needed to evaluate patients with intermediate clinical probability and negative CTPA and CUS, in order to rule out PE confidently.

The CTPA has some limitations and drawbacks, such as its high cost, allergy, contrast nephropathy and radiation exposure. However, the major limitation of CTPA is the relatively poor sensitivity in detecting sub-segmental PE.[59],[60] Although their clinical significance is not well known, sub-segmental emboli may be of clinical significance in patients with limited cardiopulmonary reserve and could represent fragmentation from more central emboli. Fortunately, sub-segmental PE accounted for only 6% of PE in the PIOPED study.[12] Furthermore, sensitivity of CTPA in detecting sub-segmental emboli is enhanced, when multi-slice version is used, which has replaced the single detector CT machine in many hospitals.[67],[68] Multi-slice detector CT also allows completion of the examination in a shorter time, but involves more radiation.[68] However, a recent study by Prologo et al found that although using multi-detector CTPA increased the visualization of small and peripheral arteries, it did not affect the clinical outcome, when compared with single detector CTPA.[69] Interestingly, Perrier et al in his latest study, multi-detector CTPA, detected PE in 188 patients and only one of these was an isolated sub-segmental clot.[45] Although this study did not compare the multi-detector scan against single-detector, it shows that isolated sub-segmental PE may be a rarity and cast some doubt over the superiority of this new multi-slice modality over the conventional CTPA, in the diagnosis of PE.

Pulmonary Angiography Pulmonary angiography is regarded as the gold standard diagnostic technique for PE. Although it has not been tested against a reference test, its validity has been confirmed in the PIOPED study,[12] where one year-follow up of patients revealed clinical courses entirely consistent with the angiographic diagnosis. Recently van Beek et al reviewed the literature between 1965 and 1999 and selected 8 prospective studies involving patients (n=1050) with suspected PE and normal pulmonary angiographic findings, who remained untreated and were followed up for a minimum of 3 months. Recurrent thromboembolic events were described in 18 patients (1.7%), out of which, three (0.3%) had fatal events.[8] With the advent of CTPA, the use of pulmonary angiography has become very limited. It is usually indicated, when there is a high clinical suspicion of PE with non-diagnostic scan and the diagnosis can not be established by less invasive tests.[9] Complications related to pulmonary angiography, include death (0.2-0.5%), severe cardiopulmonary compromise requiring intubation or cardiopulmonary resuscitation (0.4%), renal failure requiring dialysis (0.3%), groin hematomas requiring transfusion (0.2%) and an elevation in the serum creatinine without the need for dialysis (0.9%).[12],[70],[71] The inter-observer agreement in interpreting pulmonary angiography was found in the PIOPED to be 92% for the presence of PE and 82% for the absence of PE. It was 98 percent for lobar PE, 90 percent for segmental PE and only 66 percent for sub-segmental emboli.[12] Angiography was not diagnostic in 3%.[12] Recently, digital subtraction angiography has been introduced with several advantages over conventional angiography, including shorter procedure time and less contrast with equivalent accuracy.[59] Echocardiography Although it can be frequently abnormal in patients with PE, echocardiography has low specificity for PE and is not normally used as an initial screening test in this condition. Echocardiographic abnormalities encountered in PE, include change in right ventricular size or function and Doppler abnormalities of tricuspid regurgitatant flow velocity.[72],[73],[74],[75] Regional wall motion abnormalities that spare the right ventricular apex (McConnell’s sign), were found to be very suggestive of pulmonary embolism, with 77% sensitivity and 95% specificity.[76] In addition, trans-esophageal echocardiography has been utilized successfully, to detect PE in the right heart and main pulmonary artery.[77] However, the role of echocardiography in the diagnosis of PE, is still not well determined. Nevertheless, echocardiography can be useful in case of massive PE, especially when decision about thrombolytic therapy may be needed.[78],[79] Diagnostic Approach and Conclusion The diagnosis of PE can be very difficult and elusive. It depends on the clinical probability, combined with sensible use of available screening tests. The following approaches are suggested, based on the current literature and depend on the available resources [Figure 2][Figure 3][Figure 4].

Patients with possible PE should be evaluated for clinical probability. D-dimer should be always considered with the clinical probability. Patients with low clinical probability plus negative D-dimer, are unlikely to have PE and probably do not need further tests. Those with positive D-dimer or intermediate/high clinical probability should have VQ scan or CTPA as screening test, depending on the availability of the test and resources.

VQ as the main screening test Normal V/Q scan virtually excludes PE, without the need for further tests. In contrast, a high V/Q probability scan is consistent with the diagnosis of PE, especially when combined with high clinical probability. Non-diagnostic VQ scan should be supplemented by further testing, such as lower limb study, CTPA, or angiography, depending on the clinical probability [Figure 2]. However, patients with low clinical probability plus low VQ scan probability, are less likely to have PE (4% in the PIOPED study) and possibly do not need further testing.

CTPA as the main screening test A negative CTPA, combined with a negative CUS, virtually exclude PE, if the clinical probability is low. Although it has been suggested, that it is also safe to withhold treatment with a negative CTPA and CUS, in case of intermediate clinical suspicion of PE, PIOPED II throws some doubt on the accuracy of this approach. A negative CTPA combined with a negative CUS, does not confidently exclude PE, in patients with high clinical probability and further testing may be needed [Figure 3].

Which test to use as the main screening test? This depends on the availability of the different tests and cost. It is generally recommended in order to reduce cost, for patients with normal CXR to have VQ scan, while CTPA is reserved for patients with abnormal CXR, or non-diagnostic VQ scan.[11],[80] Adopting this approach will decrease the use of CTPA in 30% of patients, while only 13% will have both VQ and CTPA [Figure 4].[80] As mentioned above, this diagnostic strategy is based on the current international guidelines and recent literature. However, it has to be emphasized here, that these algorithms, as others advocated elsewhere, are not to be followed rigidly and should be modified to accommodate the local resources and according to the individual clinical settings and circumstances. Clinicians will often find themselves facing individual cases, where these suggested algorisms and guidelines are not applicable and there will be no substitution to a good clinical acumen and experience.

References 1. Dalen JE, Alpert JS. Natural history of pulmonary embolism. Prog Cardiovasc Dis 1975;17:259-70.

2. Hyers TH. Venous thromboembolism. Am J Respir Crit Care Med 1999;159:1-14.

3. Pengo V, Lensing AW, Prins MH, Marchiori A Davidson BL, Tiozzo F, et al . Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Eng J Med. 2004;350:2257-64.

4. Goldhaber SZ. Pulmonary embolism. Lancet 2004;363:1295-305.

5. Silverstein MD, Herit JA, Mohr DN, Petterson TM, O’ Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population based study. Arch Intern Med 1998;158:585-93. go to website pulmonary embolism symptoms

6. Rubinstein I, Murray D, Hoffstein V. Fatal pulmonary emboli in hospitalized patients. An autopsy study. Arch Intern Med 1988;148:1425-6.

7. Stein PD, Henry JW. Prevalence of acute pulmonary embolism among patients in a general hospital and autopsy. Chest 1995;108:978-81.

8. van Beek EJ, Brouwerst EM, Song B, Stein PD, Oudkerk M. Clinical validity of a normal pulmonary angiogram in patients with suspected pulmonary embolism-a critical review. Clin Radiol 2001;56:838-42.

9. ATS Board of Directors, February 1999: Published by The American Thoracic Society. Am J Respir Crit Care Med 1999;160:1043-66.

10. British Thoracic Society: Suspected acute pulmonary embolism: a practical approach. Thorax 1997;52:S1-24.

11. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism: A practical approach. Thorax 2003;58:470-84.

12. A collaborative Study by the PIOPED investigators. Value of ventilation/perfusion scan in acute pulmonary embolism – results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990;263:2753-9.

13. Hyers TM. Diagnosis of pulmonary embolism. Thorax 1995;50:930-2.

14. Fennerty AG, Shetty HG, Paton D, Robert G, Routledge PA, Campbell IA. Clinical Presentation and investigation of patients proceeding to Isotope lung scanning for suspected PE. Postgrad Med J 1999;66:285-9.

15. Wells PS, Ginsberg JS, Anderson DR, Kearon C, Gent M, Turpie AG, et al . Use of clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med 1998;129:997-1005.

16. Miniati M, Prediletto R, Formichi B, Marini C, Di Ricco G, Tonelli L, et al . Accuracy of clinical assessment in the diagnosis of pulmonary embolism. Am J Respir Crit Care Med 1999;159:864-71.

17. Wicki J, Perneger TV, Junod AF, Bounameaux H, Perrier A. Assessing the clinical probability of pulmonary embolism in the emergency ward: A simple score. Arch Intern Med 2001;161:92-7.

18. Chagnon I, Bounameaux H, Aujesky D, Roy PM, Gourdier AL, Cornuz J, et al . Comparison of two clinical prediction rules and implicit assessment among patients with suspected pulmonary embolism. Am J Med 2002;113:269-75.

19. Musset D, Parent F, Meyer G, Maitre S, Girard P, Leroyer C, et al . Diagnostic strategy for patients with suspected pulmonary embolism: A prospective multi centre outcome study. Lancet 2002;360:1914-20.

20. Rosen M, Sands D, Morris J, Drake W, Davis RB. Does a physician’s ability to accurately assess the likelihood of pulmonary embolism increase with training? Acad Med 2000;75:1199-205.

21. Wells PS, Ginsberg JS, Anderson DR, Kearon C, Gent M, Turpie AG, et al . Use of a clinical model for safe management of patients with suspected pulmonary embolism. Ann Intern Med 1998;129:997-1005.

22. Wells PS, Anderson DR, Rodger M, Stiell I, Dreyer JF, Barnes D, 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 23. Wells PS, Anderson DR, Rodger M, Ginsberg JS, Kearon C, Gent M, et al . Derivation of a simple clinical model to categorize patient probability of pulmonary embolism: Increasing the models utility with the SimpliRED D-dimer. Thromb Haemost 2000;83:416-420.

24. Davies CW, Bell D, Wimperis J, Green S, Pendry K. Validation of pretest probability (PTP) scored to predict pulmonary embolism in routine practice. Thorax 2003;58:S82-3.

25. Dalen JE, Master MP. Pulmonary embolism: What have we learned since Virchow? Chest 2002;122:1440-56.

26. Green RM, Meyer TJ, Dunn M, Glassroth J. Pulmonary embolism in younger adults. Chest 1992;101:1507-11.

27. Stein PD, Goldhaber SZ, Henry JW, Miller AC. Arterial blood gas analysis in the assessment of suspected acute pulmonary embolism. Chest 1996;109:78-81.

28. Rodger MA, Carrier M, Jones GN, Rasuli P, Raymond F, Djunaedi H, et al . Diagnostic value of arterial blood gas measurement in suspected pulmonary embolism. Am J Respir Crit Care Med 2000;162:2105-8.

29. Stein PD, Terrin ML, Hales CA, Palevsky HI, Saltzman HA, Thompson BT, 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.

30. Szucs MM Jr, Brooks HL, Grossman W, Banas JS Jr, Meister G, Dexter L, et al . Diagnostic sensitivity of laboratory findings in acute pulmonary embolism. Ann Intern Med 1971;74:161-6.

31. Whitaker AN, Elms MJ, Massci PP, Bundesen PG, Rylatt DB, Webber AJ, et al . Measurement of cross-linked fibrin derivatives in plasma: An immunoassay using monoclonal antibodies. J Clin Pathol 1984;37:882-7.

32. Hirsh J, Lee AY. How we diagnose and treat deep venous thrombosis. Blood 2002;99:3102-10.

33. Sadosty AT, Goyal DG, Boie ET, Chiu CK. Emergency department D-dimer testing. J Emerg Med 2001;21:423-9.

34. Bounameaux H, Cirafici P, de Moerloose P, Schneider PA, Slosman D, Reber G, et al . Measurement of D-dimer in plasma as diagnostic aid in suspected pulmonary embolism. Lancet 1991;337:196-200.

35. Becker DM, Philbrick JT, Bachhuber TL, Humphries JE. D-dimer testing and acute venous thromboembolism: A shortcut to accurate diagnosis? Arch Intern Med 1996;156:939-49.

36. Moser KM. Diagnosing pulmonary embolism. Br Med J 1994;309:1525-6.

37. Ginsberg JS, Brill-Edwards PA, Demers C, Donovan D, Panju A. D-dimer in patients with clinically suspected pulmonary embolism. Chest 1993;104:1679-84.

38. de Moerloose P, Minazio P, Reber G, Perrier A, Bounameaux H. D-dimer determination to exclude pulmonary embolism: A two step approach using latex assay as a screening tool. Thromb Haemost 1994;72:89-91.

39. Farrell S, Hayes T, Shaw M. A negative SimpliRED D-dimer assay result does not exclude the diagnosis of deep vein thrombosis or pulmonary embolus in emergency department patients. Ann Emerg Med 2000;35:121-5.

40. Ginsberg JS, Wells PS, Kearon C, Anderson D, Crowther M, Weitz JI, et al . Sensitivity and specificity of a rapid whole-blood assay for D-dimer in the diagnosis of pulmonary embolism. Ann Intern Med 1998;129:1006-11.

41. Heit JA, Minor TA, Andrews JC, Larson DR, Li H, Nichols WL. Determination of plasma fibrin D-dimer sensitivity for acute pulmonary embolism as defined by pulmonary angiography. Arch Pathol Lab Med 1999;123:235-40.

42. Goldhaber SZ, Simons GR, Elliot CG, Haire WD, Toltzis R, Blacklow SC, et al . Quantitative D-dimer levels among patients undergoing pulmonary angiography for suspected pulmonary embolism. JAMA 1993;270:2819-22.

43. Perrier A, Desmarais S, Miron MJ, de Moerloose P, Lepage R, Slosman D, et al . Non-invasive investigation of VTE in outpatients. Lancet 1999;353:190-5.

44. Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, et al . D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism. Ann Intern Med 2004;140:589-602.

45. Perrier A, Roy PM, Sanchez O, Le Gal G, Meyer G, Gourdier AL, et al . Multidetector-row computed tomography in suspected pulmonary embolism. N Eng J Med 2005;352:1812-4.

46. Bates SM, Grand Maison A, Johnston M, Naguit I, Kovacs MJ, Ginsberg JS, et al . A latex D-dimer reliably excludes venous thromboembolism. Arch Intern Med 2001;161:447-53.

47. Heijboer H, Buller HR, Lensing AW, Turpie AG, Colly LP, ten Cate JW. 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.

48. Birdwell BG, Raskob TL, Whitsett TL, Durica SS, Comp PC, George JN, et al . The clinical validity of normal compression ultrasonography in outpatients suspected of deep venous thrombosis. Ann Intern Med 1998;128:1-7.

49. Cogo A, Lensing AW, Koopman MM, Piovella F, Siragusa S, Wells PS, et al . Compression ultrasonography for diagnostic management of patients with clinically suspected deep vein thrombosis: prospective cohort study. BMJ 1998;316:17-20.

50. Elias A, Mallard L, Elias M, Alquier C, Guidolin F, Gauthier B, et al . A single complete ultrasound investigation of the venous network for the diagnostic management of patients with a clinically suspected first episode of deep venous thrombosis of the lower limbs. Thromb Haemost 2003;289;221-7.

51. Turkstra F, Kuijer PM, van Beck EJ, Brandijes DP, ten Cate JW, Buller HR. Diagnostic utility of ultrasonography of leg veins in patients suspected of having pulmonary embolism. Ann Intern Med 1997;126:775-81.

52. Davidson BL. Controversies in pulmonary embolism and deep venous thrombosis. Am Fam Physic 1999;60:1969-80.

53. Daniel KR, Jackson RE, Kline JA. Utility of lower extremity venous ultrasound scanning in the diagnosis and exclusion of pulmonary embolism in outpatients. Ann Emerg Med 2000;35:547-54.

54. Meyerovitz MF, Manning F, Polak JF, Goldhaber SZ. Frequency of pulmonary embolism in patients with low probability lung scan and negative lower extremity venous ultrasound. Chest 1999;115:980-2.

55. Perrier A, Miron MJ, Desmarais S, de Moerloose P, Slosman D, Didier D, et al . Using clinical evaluation and lung scan to rule out suspected pulmonary embolism: Is it a valid option in patients with normal results of lower-limb venous compression ultrasonography? Arch Intern Med 2000;160:512-6.

56. Hull RD, Raskob GE, Ginsberg JS, Panju AA, Brill-Edwards P, Coates G, et al . A non invasive strategy for the treatment of patients with suspected pulmonary embolism. Arch Intern Med 1994;154:289-97.

57. Bendick PJ, Glover JL, Brown OW, Ranaval TJ. Serial duplex ultrasound examinations for deep vein thrombosis in patients with suspected pulmonary embolism. J Vasc Surg 1996;24:732-7.

58. Cuteo SM, Cavanaugh SH, Benenson RS, Redclift MS. Computed tomography scan versus ventilation-perfusion lung scan in the detection of pulmonary embolism. J Emerg Med 2001;21:155-64.

59. Bankier AA, Janata K, Fleischmann D, Kreuzer S, Mallek R, Frossard M, et al . Severity assessment of acute pulmonary with spiral CT: evaluation of two modified angiographic scores and comparison with clinical data. J Thorac Imaging 1997;12:150-8.

60. Srivastava SD, Eagleton MJ, Greenfield LJ. Diagnosis of pulmonary embolism with various imaging modalities. Semin Vasc Surg 2004;17:173-80.

61. Kline JA, John KL, Colucciello SA, Israel EG. New diagnostic tests for pulmonary embolism. Ann Emerg Med 2000;35:168-80.

62. 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;132:227-32.

63. Qanadli SD, Hajjam ME, Mesurolle B et al . Pulmonary embolism detection: Prospective evaluation of dual-section helical CT versus selective pulmonary arteriography in 157 patients. Radiology 2000;217:447-55.

64. Perrier A, Howarth N, Didier D, Loubeyre P, Unger PF, de Moerloose P, et al . Performance of helical computed tomography in unselected outpatients with suspected pulmonary embolism. Ann Int Mede 2001 ; 135 : 88-97.

65. van Strijen MJ, de Monye W, Schiereck J, Kieft GJ, Prins MH, Huisman MV, et al . Single-detector helical computed tomography as the primary diagnostic test in suspected pulmonary embolism: A multicenter clinical management study of 510 patients. Ann Intern Med 2003;138:307-14.

66. Gottschalk A, Stein PD, Goodman LR, Sostman HD. Overview of prospective investigation of pulmonary embolism diagnosis II. Semi Nucl Med 2002;32:173-82.

67. Raptopoulos V, Boiselle PM. Multi-detector row spiral CT pulmonary angiography: Comparison with single-detector row spiral CT. Radiology 2001;221:606-13.

68. Patel S, Kazerooni EA, Casade PN. Pulmonary embolism: optimization of small pulmonary artery visualization at multi-detector row CT scan. Radiology 2003;227:455-60.

69. Prologo JD, Gilkeson RC, Diaz M, Cummings M. The effect of single-detector CT versus MDCT on clinical outcomes in patients with suspected acute pulmonary embolism and negative results on CT pulmonary angiography. AJR Am J Roentgenol 2005;184:1231-5.

70. Dalen JE, Brooks HL, Johnnson LW, Meister SG, Szucs MM Jr, Dexter L. Pulmonary angiography in acute pulmonary embolism: Indications, techniques and results in 367 patients. Am Heart J 1971;81:175-85.

71. Mills SR, Jackson DC, Older RA, Heaston DK, Moore AV. The incidence, etiologies and avoidance of complications of pulmonary angiography in a large series. Radiology 1980;136:295-9.

72. Gibson NS, Sohne M, Buller HR. Prognostic value of echocardiography and spiral computed tomography in patients with pulmonary embolism. Curr Opin Pulm Med 2005;11:380.

73. Kucher N, Rossi E, De Rosa M, Goldhaber SZ. Prognostic role of echocardiography among patients with acute pulmonary embolism and a systolic arterial pressure of 90 mm Hg or higher. Arch Intern Med 2005;165:1777.

74. Come PC. Echocardiographic evaluation of pulmonary embolism and its response to therapeutic interventions. Chest 1992;101:151S.

75. Grifoni S, Olivotto I, Cecchini P, Pieralli F, Camaiti A, Santoro G, et al . Short-term clinical outcome of patients with acute pulmonary embolism, normal blood pressure and echocardiographic right ventricular dysfunction. Circulation 2000;101:2817.

76. McConnell MV, Solomon SD, Rayan ME, Come PC, Goldhaber SZ, Lee RT. Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embolism. Am J Cardiol 1996;78:469-73.

77. Pruszczyk P, Torbicki A, Pacho R, Chlebus M, Kuch-Wocial A, Pruszynski B, et al . Noninvasive diagnosis of suspected severe pulmonary embolism: transesophageal echocardiography versus spiral CT. Chest 1997;112:722-8.

78. Goldhaber SZ, Haire WD, Feldstein ML, Miller M, Toltzis R, Smith JL, et al . Alteplase versus heparin in acute pulmonary embolism: randomized trial assessing right ventricular function and pulmonary perfusion. Lancet 1993;341:507-11.

79. Kasper W, Meinertz T, Henkel B, Eissner D, Hahn K, Hofmann T, et al . Echocardiographic findings in patients with proved pulmonary embolism. Am Heart J 1986;112:1284-90.

80. Wilson HT, Meagher TM, Williams SJ. Combined Helical Computed Tomographic pulmonary angiography and lung perfusion scintigraphy for investigating acute pulmonary embolism. Clin Radiol 2002;57:33-6.

Abdelaziz, Muntasir; Wali, Siraj; Hamad, Mahir; Krayem, Ayman; Samman, Yaseen