Diagnosing acute pulmonary embolism with computed tomography: imaging update.

SYMPOSIUM REVIEW ARTICLE

Diagnosing Acute Pulmonary Embolism With Computed Tomography Imaging Update Anand Devaraj, MD, MRCP, FRCR,* Charlie Sayer, MBBS, FRCR,w Sarah Sheard, MBBS FRCR,w Sisa Grubnic, MBBS, FRCR,w Arjun Nair, MD, MRCP, FRCR,z and Ioannis Vlahos, MBBS, MRCP, FRCRw

Abstract: Acute pulmonary embolism is recognized as a difficult diagnosis to make. It is potentially fatal if undiagnosed, yet increasing referral rates for imaging and falling diagnostic yields are topics which have attracted much attention. For patients in the emergency department with suspected pulmonary embolism, computed tomography pulmonary angiography (CTPA) is the test of choice for most physicians, and hence radiology has a key role to play in the patient pathway. This review will outline key aspects of the recent literature regarding the following issues: patient selection for imaging, the optimization of CTPA image quality and dose, preferred pathways for pregnant patients and other subgroups, and the role of CTPA beyond diagnosis. The role of newer techniques such as dual-energy CT and single-photon emission–CT will also be discussed. Key Words: computed tomography pulmonary angiogram, pulmonary embolism, D-dimer, dual-energy computed tomography, dose

(J Thorac Imaging 2015;30:176–192)

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he clinical symptoms of acute pulmonary embolism (PE), although nonspecific, are most commonly dyspnea and chest pain.1 Therefore, it is not surprising that patients with acute PE present in acute or emergency settings. When faced with these patients, emergency and acute medical physicians are well aware of widely publicized figures in the literature that illustrate the importance of a rapid diagnosis. For example, it has been estimated that undiagnosed PE is responsible for >200,000 deaths annually in Europe.2 At the heart of ensuring a rapid diagnosis of acute PE is the computed tomography pulmonary angiogram (CTPA), which will form the principal focus of the review article. In particular, practical aspects such as recent literature on improving CTPA quality and the prognostic role of CTPA will be examined. Issues relating to treatment of PE (including overdiagnosis and catheter-directed thrombolysis),

From the *Department of Radiology, Royal Brompton Hospital; wDepartment of Radiology, St George’s Hospital; and zDepartment of Radiology, Guy’s and St Thomas’ Hospitals, London, UK. Dr Ioannis Vlahos receives research support from GE Healthcare and Siemens Medical Systems. The remaining authors declare no conflicts of interest. Correspondence to: Anand Devaraj, MD, MRCP, FRCR, Department of Radiology, Royal Brompton Hospital, Sidney Street, London SW3 6NP, United Kingdom (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

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although of relevance to radiologists, are beyond the scope of this article. Although acute PE can be rapidly fatal, it is at the same time a diagnosis that can be difficult to make. Thus, the first part of this review will be devoted to examining recently published data on improving patient pathways from the emergency room to the imaging department. Finally, newer imaging techniques for diagnosing PE will be discussed.

CTPA IN ACUTE PE—APPROPRIATENESS, PATIENT SELECTION, AND DIAGNOSTIC YIELD CTPA is a test that is readily available in many emergency departments, can be performed in seconds, has the ability to reliably diagnose a life-threatening condition, and can simultaneously rule out or identify a number of alternative differential diagnoses. It is not surprising therefore that referrals for CTPA from emergency departments worldwide have increased substantially over the last decade.3 Although this could be said to be true of many imaging tests, CTPA appears to stand out as a test for which referral practices have gained particular scrutiny. The twin issues of falling diagnostic yield and referral inappropriateness have attracted much attention.3 This is understandable when one considers the downside of CTPA overuse, namely, radiation exposure, potential nephrotoxicity, and health care costs. A number of studies have reported on the prevalence rate of PE in CTPAs. In the PIOPED II study,4 pulmonary emboli were identified in 22.6% of cases. In more recent analyses, there has been a trend toward lower diagnostic yield rates in the order of 10% to 15%.5–7 Within hospitals, wide variations in yield have also been reported among clinicians.5 Such studies raise 2 important questions: (1) does an optimum diagnostic yield exist? And (2) if so what should that figure be? There is no widely accepted figure for appropriate CTPA PE diagnostic yield, although it has been suggested that a figure of 95–100 beats/min Recent surgery Hemoptysis Current malignancy Signs of DVT PE most likely diagnosis clinically Heart rate 75–94 beats/min Unilateral lower limb pain Age >65 y

Wells Score

Revised Geneva Score

Simplified Geneva Score

1.5 1.5

3 5

1 2

1.5 1 1 3 3

2 2 2 4 NA

1 1 1 1 NA

NA

3

1

NA

3

1

NA

1

1

The Wells score, but not the Geneva score, incorporates a subjective assessment of PE probability. DVT indicates deep venous thrombosis; VTE, venous thromboembolism.

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group.16 This contrasted with a 42% PE prevalence (153/ 368 patients) in the “PE likely” group.

PE Rule-out Criteria (PERC) The PERC scoring system differs from the Wells and Geneva scores in 2 aspects. First, it relies on identifying the absence of 8 criteria to exclude PE. As its name suggests, this 1-way score aims to rule out PE, but is not intended to determine who should receive further testing. Second, it is not used in conjunction with D-dimer testing. Indeed, its rationale is to safely prevent not only unnecessary imaging but also D-dimer testing. In the original publication, emergency department patients who were clinically regarded as being low likelihood, and who satisfied all PERC criteria, had a PE incidence of approximately 1% (although the figure was only 7% for the whole group).17 Although the utility and high negative predictive value of the PERC rule was confirmed in a later meta-analysis,18 questions have been raised as to the validity of the PERC in groups other than those at very low risk for PE.19

Comparison of Pretest Probability Scorings Systems and Clinical Gestalt Meta-analyses have found no differences in performance between Wells and Geneva scores,20 and prospective cohort studies have shown no difference between simplified and standard scores.21 Clinical gestalt is the subjective estimate of the probability of a disease based on a clinician’s impression. In 2011, Lucassen and colleagues performed a meta-analysis evaluating a total of 23 studies investigating clinical decision rules or clinical gestalt along with D-dimer testing, for the diagnosis of PE. This study not only showed that clinical gestalt was equally safe at diagnosing PE (false-negative rate 0.7%) compared with clinical decision rules, but also confirmed that individual scoring systems were comparable to each other.22 However, an important additional finding was that clinical gestalt was less specific, in keeping with the observation that clinicians may tend to subjectively overestimate PE likelihood compared with when using clinical decision rules. Since that meta-analysis, a more recent retrospective study, across 116 emergency departments on 1038 patients, found contradictory results. Penaloza et al23 actually demonstrated that clinical gestalt performed better than the Wells or Geneva scores in discriminating patients with and without PE. It was postulated that the reason for the superiority of clinical gestalt was the ability of the clinician to consider, as part of the assessment, variables not typically included within pretest probability scores (such as sudden onset of symptoms for example). How should this substantial amount of accumulated data on PE prediction be interpreted as far as implementing policy at a local level is concerned? This is a question that is perhaps best answered by individual emergency departments, on the basis of local practice and expertise. Indeed, the American College of Emergency Physicians in 201124 concluded that either objective criteria or clinical gestalt could be used to risk stratify patients with suspected PE.

The D-Dimer Test—Pitfalls and New Directions D-dimers are fibrin degradation products and a marker of thrombus formation. However, D-dimers can be elevated in various conditions other than venous thromboembolism including renal failure, malignancy, ischemic heart disease, inflammatory processes, and pregnancy.

2015 Wolters Kluwer Health, Inc. All rights reserved.

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Consequently, the specificity and positive predictive value for venous thromboembolism detection is low. With sensitive enzyme-linked immunosorbent assay techniques, a commonly used threshold to signify D-dimer positivity is 500 mg/L, which correlates with a specificity of approximately only 40%25 (although the recommended cutoff may vary according to the assay used). Recent work has examined whether varying the D-dimer cutoff can improve its specificity without compromising its high sensitivity. In particular, some investigators have looked at whether pretest probability algorithms could be made more sophisticated by using different cutoff values for different levels of PE likelihood. In 1 study, it was calculated that doubling the D-dimer threshold to 1000 mg/L for patients who were categorized as PE unlikely on the basis of the Wells score would have increased the false-negative rate for PE from 3.8% to 5.4%. Although the authors stated that most of the additional missed PEs would have been subsegmental emboli, false-negative rates of 3.8% and 5.4% are higher than previous studies using conventional thresholds.26 Although there may be some doubt as to whether conventional D-dimer thresholds can be safely raised across the board, there is promising recent evidence to suggest that this may be appropriate to do in elderly patients, on the basis that D-dimer levels are known to increase with age. The Adjust-PE study27 recently reported the findings of a prospective investigation in >3000 emergency department patients, with a 19% PE prevalence rate. In this study, an age-adjusted D-dimer cutoff (calculated using the formula: age 10 mg/L) was used for patients over the age of 50 instead of a fixed figure of 500 mg/L. It was found that the additional diagnostic failure rate of this intervention was only 0.3%, yet at the same time it produced a 23% reduction in the need for further imaging. It should be stressed that in published algorithms and studies to date, D-dimers have been designed to be used after an adequate pretest probability assessment. The indiscriminate use of D-dimers in very low–risk groups with very low PE prevalences (akin to a screening test) has the potential to dramatically increase the false-positive rate of this test and consequently drive up imaging volumes.28 In addition, it is known that in low PE prevalence groups, clinicians may sometimes wish to perform imaging tests irrespective of a negative D-dimer result.5 The reasons for this combination of actions are likely to be complex, but the ability of CTPA to provide immediate diagnostic information to clinicians and advance the patient pathway in individuals with nonspecific symptoms such as dyspnea are probably important factors. The use of electronic clinical decision support systems that mandate certain information before tests can be ordered may have a role to play in reducing this phenomenon,29 although further work needs to be done to evaluate its impact on outcomes.

Volume 30, Number 3, May 2015

reduce these artifacts and improve the overall quality of CTPA studies are discussed below.

Optimizing the Timing of CTPA Acquisition The magnitude of contrast enhancement in the pulmonary arteries is directly proportional to the volume and concentration of iodine administered, as well as the injection flow rate. However, high-quality CTPAs are achieved not only by maximizing peak attenuation values within the main pulmonary artery (PA) but also by ensuring that image acquisition coincides with peak attenuation. The latter is made possible by 1 of 2 well-known techniques, namely, bolus-tracking and the test-bolus method. The test-bolus method uses an initial injection of a small volume of contrast medium (typically 10 to 20 mL), which is then monitored as it passes through the pulmonary trunk, where attenuation is measured against time. Typically, a variable delay of 4 to 6 seconds is added to the time to peak value, which takes into account the time required for the additional volume of contrast medium injection.31 This maximizes the chance of acquisition taking place during the plateau of peak enhancement: longer duration scans should commence earlier with shorter delays, and vice versa for rapid acquisition CTs. Bolus tracking, however, simply monitors attenuation in the region of interest during injection of the main contrast bolus, triggering the scan a short time (4 to 8 s typically) after a predefined threshold (commonly 100 to 150 HU) is reached. A main advantage of bolus tracking is that it is quicker to conduct, which may be of importance when imaging patients referred from the emergency department. A disadvantage, however, is that this method assumes that opacification continues to increase at the same rate for every patient once the threshold has been reached. In theory, this can be offset by faster scanners, which allow for higher thresholds (closer to peak attenuation) and shorter delays to be used. In a study comparing the reliability of the 2 methods, Rodrigues et al32 found that the test-bolus method gave improved mean vessel attenuation in the main pulmonary arteries when compared with bolus tracking (mean 361 vs. 256 HU, respectively). Saade et al33 also reported superiority of the test-bolus method, but other investigators have not.34 Many practitioners have found that the test-bolus method particularly yields superior opacification for highpitch (>3.0) protocols, although, interestingly, in the study by Kerl et al,34 no difference in CTPA quality was found between the 2 methods despite using a high-pitch 128detector CT protocol. Such contrasting results between studies can partially be explained by the large number of factors that influence PA contrast enhancement (both technical and patient factors), which are difficult to correct for entirely in studies of this nature.

Optimizing Contrast Agent Concentration and Injection Flow Rate in CTPA OPTIMIZING CTPA QUALITY—PRINCIPLES Despite advances in scanning technology, nondiagnostic CTPAs remain a problem (with an approximate incidence of 5% to 10%).30 Patient factors such as respiratory and cardiac motion artifact have to some extent been reduced by the rapid acquisition afforded by multidetector CT, but inadequate contrast opacification has conversely become a more relevant problem because of the narrower window for optimal vessel opacification. Techniques to


For a given injection rate and volume of contrast, both peak attenuation and the duration of acceptable contrast enhancement increase with contrast medium concentration. Furthermore, for a given iodine mass, smaller volumes of higher concentrations of contrast will achieve greater peak attenuation values at equivalent flow rates (because the same amount of iodine is delivered over a shorter duration).35 The use of high-concentration agents (eg, 350 to 400 mg/mL iodine) mandates the use of a saline flush,

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Imaging Pulmonary Embolism—Update

although the problem of beam hardening artifacts caused by residual contrast medium in the superior vena cava (SVC) can occur regardless of the use of contrast medium concentration. A saline flush of at least 30 mL is normally sufficient to remove injected contrast from the injection route. So-called split bolus contrast administration has also been advocated as a beneficial technique to reduce streak artifacts from the SVC. In 1 study, a CTPA protocol of 50 mL of contrast (400 mg/mL Iodine), followed by 30 mL of dilute contrast (70% saline:30% contrast mix), followed by 50 mL of saline at 4 mL/s achieved a near 50% reduction in mean Hounsfield unit values in the SVC compared with a standard protocol using a 30 mL saline chaser, while preserving diagnostic adequacy.36 More recently, the variation of the rate of contrast administration (as opposed to concentration) during the course of injection has been investigated, referred to as “bolus-shaping.” This describes the sophisticated method by which contrast flow rates are gradually reduced using software, to broaden the plateau of peak contrast enhancement. Goble and Abdulkarim37 demonstrated how it was possible to take advantage of this technique to reduce the total quantity of iodine administered without impacting on the diagnostic quality, in a study of 139 CTPAs.

Optimizing Dose and Peak Kilovoltage (kVp) in CTPA A number of strategies are available to reduce patient dose in thoracic CT.38 Many of these strategies are not unique to CTPA and include, for example, angular 4D dose mAs modulation to adapt exposure factors to patient size. However, modulation of kVp has been the subject of particular interest in PE imaging. Over the last few years, it has become increasingly clear that standard kVp parameters can be reduced without affecting CTPA diagnostic quality in many instances.39,40 The effect of lowering kVp in CTPA is 2-fold: first, attenuation in pulmonary arteries that contain iodinated contrast increases as the beam energy reaches the k-edge of iodine (33 keV) (Fig. 1); second, as a consequence of reduced photon transmission and quantum mottle, noise within vessels increases. However, because contrast to noise ratio is maintained, image quality is preserved. This has been confirmed in studies that have demonstrated that using 100 kVp instead of 120 kVp39 and using 80 kVp instead of 100 kVp40 both achieved an approximately 40% reduction in radiation dose, while preserving image quality. Even with compensation for higher required mAs, overall radiation dose exposure is reduced. Low-kVp settings should be used with caution in patients unable to elevate their arms or when there are focal high-density materials or equipment in the imaging volume, as beam hardening errors from these structures are inordinately greater at lower kVp. A further potential impediment to low-kVp imaging occurs with larger-sized patients. At low-kVp CTPA, the mAs required to deliver a diagnostic scan may exceed the tube mA capacity and in turn increase scan duration.41 Newer-generation scanners show promise in imaging large patients at low tube potential, by being able to deliver higher maximum tube currents. A unique advantage of dual-source systems is the ability to minimize the tube mA burden by splitting the dose between 2 tubes operating at the same kVp. These “obese” mode Copyright

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FIGURE 1. A and B, CTPA at 140 kVp (A) and 100 kVp (B) (acquired simultaneously as part of a dual-source dual-energy CT). At 100 kVp, attenuation and noise are increased, but overall contrast to noise ratio is enhanced, thus improving diagnostic quality.

protocols are generally reserved for very large patients (Fig. 2). Another benefit of using low kVp is that the rate of administration or volume of contrast needed to achieve the same attenuation level can be reduced. Viteri-Ramirez and colleagues randomized patients into 2 groups to receive either 80 kVp with 60 mL of iohexol or 100 kVp with 80 mL iohexol. The low-kV group had a >100 HU increase in attenuation of the central vessels compared with the second group, with no significant difference in the signal to noise ratio.42 Iterative reconstruction (IR) is a dose reduction technique achieved by reducing image noise compared with standard filtered back projection. It is now provided by all major CT vendors but is nevertheless still undergoing major evolution. The extent of dose saving depends largely on the IR algorithm and the user’s tolerance of image appearance. In general, the higher the “generation” of IR the greater the potential dose savings, although there may be some artificial quality to the images often described as “plastic” (Fig. 3). To date, most evaluations of IR have focused on evaluation of normal anatomy or overall image quality rather than diagnostic accuracy. Reported experience of using IR in CTPA has been somewhat limited. By taking advantage of noise reduction, some investigators have used



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recent studies are reviewed below. It should be noted, however, that not every variable is consistently described in some of the studies. In addition, it should not necessarily be assumed that reported protocols can automatically be extrapolated to different institutions and patient groups. Indeed, it is impractical (and impossible) to provide an imaging protocol to take into account every variable. For example, although certain parameter modifications can be advocated for patients with increased body weight, how does one tackle the overweight patient with poor venous access, low cardiac output, and mild renal impairment? Table 2 summarizes the principles behind parameter modification in certain commonly encountered scenarios.

Scenario 1: Pregnant Patients With Suspected PE

FIGURE 2. In dual-source CT, so-called “obese” protocol CTPA can be performed in very large patients. Scout image (A) shows not only very large body habitus but also the right arm placed down, potentially increasing image noise further. B, Dual-source CTPA “obese” protocol using both tubes at 120 kvP produced excellent PA enhancement. This protocol allows for greater tube current during acquisition and achieves noise reduction. Increasing contrast volume and flow rate are also important considerations in CTPA of large patients.

IR to maintain image quality in obese patients at standard kVp,43 whereas other have used it to improve diagnostic quality when using low-kVp imaging.44 A potential concern that has been raised is that small emboli may be erroneously “smoothed” to an average density by this technique.45 Overall, the combined approach of several dose-saving strategies with advances in IR are likely to be additive and one of the major areas of exciting imaging evolution in CTPA imaging in the coming years. In testing the boundaries of such an approach with CTPA, a recent study demonstrated feasibility of sub 1 mSv IR CTPA using a high-pitch 80 kVp acquisition with only 20 mL of iodinated contrast.46

OPTIMIZING CTPA QUALITY—PREGNANT PATIENTS AND OTHER SCENARIOS ENCOUNTERED IN THE EMERGENCY DEPARTMENT In some scenarios, it may be necessary to modify CT acquisition and contrast injection protocols on a caseby-case basis. Many centers have reported their own experience of how parameter modifications can improve CTPA quality in specific patient groups, and some of these


Acute PE is an important and potentially fatal disease in pregnant women, estimated to be responsible for 18% of maternal deaths in the United States,47 with the postpartum period representing an even greater risk.48 However, establishing the diagnosis of PE in pregnancy is challenging for a number of reasons: (i) Clinically, there is an overlap between the physiological changes in pregnancy and the signs and symptoms of PE or deep venous thrombosis. (ii) There are currently no validated clinical prediction guidelines for determining the pretest probability of PE in pregnancy such as the Wells or Geneva criteria. (iii) From a radiologic perspective, dose and image quality become paramount considerations in comparison with imaging availability, when choosing the optimal imaging test. CTPAs are known to be particularly susceptible to poor image quality during pregnancy because of hyperdynamic circulation and increased blood volume. These physiological changes serve to reduce the peak attenuation values and minimize the duration of peak attenuation. In addition, contrast arrival time is reduced. The effects have previously been found to cause a 3-fold increase in the number of nondiagnostic CTPAs in pregnancy.49 However, more recently, it has been shown that by carefully selecting appropriate scanning parameters, these effects can be mitigated in pregnancy.50,51 Suggested modifications include increasing flow rates (5 to 6 mL/s), increasing contrast volume, increasing the trigger for bolus tracking to as much as 200 HU with short scan delays, and using saline chasers. Deep inspiration should be avoided to reduce the contribution of unopacified inferior vena cava (IVC) blood to the right heart. The decision to perform CTPA or ventilation/perfusion (V/Q) scanning in pregnancy is heavily influenced by dose considerations. For both V/Q scan and CTPA, the delivered fetal radiation dose is low and equivalent to the dose absorbed by the fetus (0.5 to 1 mGy) from naturally occurring background radiation during the 9-month gestational period.52 The estimated maternal risk from radiation is much higher than that to the fetus, with breast and lung cancers most likely to account for any increase in radiation-induced cancer mortality.53 There are significant differences in the calculated doses to breast and lung tissue from CTPA and V/ Q scans, estimated to be in the range of 10 to 60 mGy (breast) and 39.5 mGy (lung) with CTPA, as opposed to 1 mGy (breast) and 5.7 to 13.5 mGy (lung) with V/Q scanning.54,55 It is therefore imperative that, wherever possible, dose reduction techniques be used. For V/Q scanning, ventilation scans can often be avoided, and a perfusion-only scan using one half the usually administered activity of Technetium-99m (Tc-99m) macroaggregated albumin is performed instead. For CTPA, reduced z-axis coverage

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FIGURE 3. A, 1 mm filtered back projection CTPA. Central arterial noise present in a patient with extensive parenchymal consolidation. B, 1 mm IR (SAFIRE 3). Improved homogeneity and contrast to noise ratio of main PA. C, 1 mm SAFIRE 5 (stronger IR reconstruction). Greater homogeneity but more “plastic” appearance.

(from the aortic arch to the dome of the diaphragm) has been proposed by some groups as a means of significant dose reductions without compromising diagnostic yields.56 Other dose-minimizing techniques include using tube-current dose modulation and low (100) kVp. The latter also is to be recommended, as it will also counteract the effects of pregnancy on reducing peak attenuation values (see above). Bismuth breast shields have been available for some time but are a subject of controversy.57 If used appropriately they can reduce CTPA breast exposure by a reported 40%.58 Although initial reports suggested that these did not affect image quality, particularly in very thin patients, the shield may yield some artifact in the anterior lung (Fig. 4). The effect can be significantly ameliorated by the introduction of a thin layer of padding between the shield and the breast without loss of the breast radiation dose savings, even when the patient is out of the imaging isocenter.59 A Copyright

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key practical point is that they are applied after the scout examination has been performed and the dosimetry for the patient’s dose modulation calculated. However, breast shields must not be used if CT scanners use real-time dose modulation, as dose will paradoxically increase. An alternative consideration for breast dose reduction is organbased dose modulation. Typically, this technique utilizes a reduction of dose in an anterior 120-degree arc sector of the image acquisition compensated by an increased dose in the remainder of the helical acquisition. In theory, breast organ dose reductions of up to 30% to 40% are achievable. In practice, however, this technique requires idealized positioning of the breast tissue in the anterior reduced dose sector. Breast tissue that lies lateral to the sector may inadvertently result in higher dose exposure.60 A more theoretical consideration is the risk to the fetus of possible induction of neonatal hypothyroidism from



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TABLE 2. Common Causes for Nondiagnostic CTPA in Emergency Department Patients, and Techniques to Enhance CTPA Diagnostic Quality

Scenario

Issues

Modifications

Pregnant patients

Increased cardiac output Increased blood volume (dilution) Reduced peak attenuation Reduced duration of peak Earlier peak attenuation

Increase flow rate Reduce delay Use test bolus or raise bolus-tracking threshold Increase contrast volume Avoid deep inspiration Use saline chaser Lower kVp

Patients with increased body mass index

Increased noise Reduced iodine concentration

Increase contrast volume Avoid low kVp in older scanners and for very large patients Review 2 mm reconstructions Use “obese” protocols in dual-source CT for very large patients (2 tubes at same kVp)

Patients with poor venous access

Reduced flow rates Reduced peak attenuation (but increased duration of peak) Increased time to peak attenuation

Increase delay Increase contrast volume Use low kVp

Patients prone to deep inspiration/Valsalva or unable to comply with breathing instructions

Dilution of contrast in pulmonary arteries from IVC blood Increased attenuation in SVC

Acquire during shallow inspiration or free breathing Increase pitch Acquire caudocranially

Patients at risk of contrast nephropathy

Reduced iodine load required

Reduce contrast volume Reduce concentration Increase flow rate Reduce kVp

Risks and benefits of performing CTPA should always be assessed, and some scenarios may require alternative imaging strategies to be considered entirely.

iodinated intravenous contrast administration. This has not translated, however, into a real effect in practice.61,62 The investigation of pregnant patients with suspected PE should therefore take into account all of the above considerations, but guidelines are available from a number of professional groups. This article will not explore these in detail, but the readers are directed to the document of the American Thoracic Society and Society of Thoracic Radiology63 (Fig. 5). Particular points worthy of note from these guidelines are: (i) There is some merit in performing compression ultrasound of the lower limbs as first-line investigation but only in those women who have clinical signs or symptoms of deep venous thrombosis. (ii) In patients with normal chest x-rays, V/Q scanning is preferred to CTPA, with the acknowledgement that in some patients with indeterminate V/Q scans, further CTPA will be necessary. (iii) D-dimers are not recommended in pregnant women because of poor specificity (although Ddimers are recognized to be normal in up to half of pregnant women in the first trimester64). Magnetic resonance imaging offers the ability to image the pulmonary arteries in pregnancy without ionizing radiation; however, contrast-enhanced magnetic resonance pulmonary angiography is relatively contraindicated because of the uncertain long-term effect of gadolinium on the fetus. Magnetic resonance protocols using motion-resistant bright blood techniques, such as steady-state free precession (SSFP), without the need for gadolinium, have shown some promise in accurately depicting the central, lobar, and segmental arteries in the pregnant patient population.65

patients with poor venous access. In this setting, the radiologist could legitimately insist that the appropriate venous access is obtained before imaging, to maximize diagnostic quality, although this may result in delays in establishing a diagnosis. There is some limited evidence that CTPAs can still reliably be performed with the help of small caliber (22 G) peripheral cannulae at low flow rates (2 to 3 mL/s).66 In such a situation, particular attention needs to be paid to increasing the delay to image acquisition, because the time to peak attenuation is inversely related to flow rate.31

Scenario 2: Patients With Poor Venous Access Although rapid injection rates (5 to 6 mL/s) are preferable to achieve greater enhancement of the pulmonary arteries, radiologists are not uncommonly faced with


FIGURE 4. Bismuth shield in unenhanced thoracic CT shows artifact limited to just below the shield.

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Signs and Symptoms of DVT

No

Yes

Leg Ultrasound

Positive

Negative

CXR normal

CXR abnormal

V/Q

CTPA

Treat as DVT Indeterminate Indeterminate

Repeat Study or Ultrasound

FIGURE 5. Adapted from ATS/STR guidelines for the management of suspected PE in pregnancy (note that if V/Q or CTPA is positive or negative, treat or stop as appropriate).

Additional consideration should be given to increasing the volume of intravenous contrast in these cases, with the aim of achieving sustained higher peak attenuation values (again necessitating a longer delay time). Lower kVp protocols may also help in increasing iodine conspicuity. The impact of increasing the concentration of iodine, however, is not so clear-cut in patients with poor venous access. Although in theory such a protocol would enhance the overall iodine delivery rate and maintain image quality, lower concentration contrast agents might be more suited to patients with poor venous access, because of their lower viscosity.67

Scenario 3: Patients Unable to Comply With Breathing Instructions Breathing is an important factor in contrast bolus dynamics. Studies have shown that forced deep inspiration (especially in fit young patients) can disproportionately increase the inflow of unopacified blood from the IVC68 (Fig. 6). Deep inspiration can also result in an inadvertent Valsalva maneuver, which acts to reduce thoracic venous inflow by causing positive intrathoracic pressure.68 The result is CTPAs characterized by a combination of high density in the SVC, poor opacification of the pulmonary arteries yet with significant aortic enhancement. Consequently, unless scan durations are prolonged, deep inspiration should be avoided. In patients who are unable to carry out shallow inspiratory breath-hold or who are dyspneic, either expiratory breath-hold69 or shallow free breathing is preferred.70 Although these maneuvers may result in poorer evaluation of the lung parenchyma,69 Bauer et al70 showed that using a dual-source system enabling ultra–high pitch (> 3.0) acquisition, CTPA performed during free breathing (Fig. 7) could achieve improved vessel attenuation without significant motion artifact compared with a single-source, inspiratory control group.

THE ROLE OF CTPA IN RISK STRATIFICATION FOR ACUTE PE

FIGURE 6. Coronal 5 mm maximum intensity projection CTPA shows high attenuation in the right subclavian vein. There is also simultaneous opacification of the left heart, but underopacification of the PA. This combination of appearances is the consequence of the patient taking a deep inspiratory breath and performing a Valsalva maneuver. This results in dilution of contrast by unopacified blood from the IVC (referred to as interruption of contrast), as well as reduced inflow from the subclavian vein, due to raised intrathoracic pressure.

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Central to the management of confirmed acute PE is the stratification of patients into high-risk and non–highrisk groups. This stratification is based primarily on clinical evaluation with evidence of shock or hypotension characterizing patients at the highest risk of mortality. However, the reported mortality in those without these critical signs is still substantial (E5%),71 and, therefore, there is a clear imperative to substratify these patients into more prognostically homogenous groups. Earlier stratification into “massive,” “submassive,” and “nonmassive” PE categories was not entirely satisfactory, as these terms were not stringently defined, but more recent guidelines have proposed either clearer definitions of these



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FIGURE 7. A, CTPA performed in dyspneic patient with an acquisition time of 5 seconds shows motion degradation of the vessels. Repeat study (B) with dual-source high-pitch 3.2 (0.8 s) acquisition shows improved image quality. High-pitch protocols may also be useful in ventilated patients.

terms72 or an alternative nomenclature altogether73 (Table 3). Conventionally, peripherally delivered systemic thrombolysis has been reserved for patients with massive PE. Thrombolysis in submassive PE is a more controversial area but may be appropriate in selected patients.72 Here we consider the contribution of CT parameters to the stratification process.

High-risk Groups in PE—Pathophysiology In high-risk groups, acute PE leads to a chain of events, in which right ventricular (RV) dysfunction plays a crucially important role. Briefly, obstruction of the vascular bed (estimated in excess of 25% to 30%) causes increased pulmonary vascular resistance (PVR) and consequently

acute pulmonary arterial hypertension.74 This increased PVR is not solely a function of the mechanical obstruction caused by the embolus but also due to reflex pulmonary arterial vasoconstriction triggered by vasoactive agents. The increased PVR leads to an increased RV afterload, eventually resulting in RV dysfunction and dilatation with a reduction in RV stroke volume. RV dilatation can also cause bowing of the interventricular septum into the left ventricle (LV), decreasing the LV cavity size and thus LV preload. This in turn leads to decreased overall cardiac output, resulting in decreased coronary perfusion and increased RV dysfunction. Simultaneously, systemic arterial hypoxemia resulting from the increased PVR and

TABLE 3. Definition of Categories of Severity of Acute PE According to American Heart Association (AHA) and European Society of Cardiology (ESC) Guidelines

Guidelines AHA 2011

ESC 2008

Massive Submassive Low risk

High risk Non–high risk (intermediate) Non–high risk (low)

Markers of Adverse Outcome Hemodynamic Status: Shock or Hypotension

RV Dysfunction*

Yes No No

NRw No

Myocardial Injury or Necrosis

NRw One or other present No

*AHA guidelines indicate that evidence of RV dysfunction may be identified by echocardiography, CT, electrocardiography, or brain natriuretic peptide. wIn the presence of shock or hypotension, the presence of RV dysfunction or myocardial injury are not required for categorizing an acute PE as high-risk or massive. NR indicates not required.


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decreased LV preload also contribute to myocardial ischemia, leading to a downward spiral of falling systemic pressure, biventricular hypoxemia, and progressive biventricular dysfunction.75

Identifying High-risk Groups—The RV/LV Ratio on CT The observation of RV enlargement with comparative attenuation of LV size on CT offers the opportunity to identify the morphologic correlate of the pathophysiological processes described above. In particular, the RV/LV ratio simultaneously captures the hemodynamically pertinent observations of both RV dilatation and decreased LV cavity size in a single metric. The RV/LV ratio sign was first described by Reid and Murchison in 1998,76 and this sign has become widely used in CTPA reporting practice as an indicator of right heart strain in acute PE. However, a vast amount of apparently conflicting data has subsequently emerged on the value of the CT-derived RV/LV ratio as a prognostic determinant. For example, in a large retrospective review of >1100 patients with PE, investigators found that RV/LV diameter ratio was not able to predict short-term or long-term mortality.77,78 A recent prospective study designed to specifically assess the significance of this sign in normotensive patients with PE found that all-cause mortality at 30 days was not predicted by an RV/LV ratio of >0.9 when adjusted for confounding variables.71 In contrast, other studies have demonstrated the ability of the RV/LV ratio to predict 30-day mortality.79 Such apparent contradictions necessarily reflect variations in study design, mortality rates, end-points, and treatment strategies. It is telling that despite such heterogeneity, a recent robust meta-analysis of 36 studies by Becattini et al80 found significant odds ratios of death at 30 days and at 3 months for increased RV/LV ratios, even when confined to studies specifically reporting on hemodynamically stable patients. It is also worth remembering that the original paper by Reid and Murchison76 described an RV/LV ratio >1.5 as indicative of right heart strain. Lower cutoff values, although relevant to echocardiography,81 may not be suitable discriminators on transaxial CT.82 The method by which the RV/LV ratio is measured on CT may significantly influence the prognostic ability of this sign. Although it has previously been demonstrated that RV/LV diameter ratio measurement on a multiplanar 4chamber view may offer greater sensitivity and improved prediction of mortality and adverse events than on transverse images,83 such analysis, although elegant and reproducible, may be time-consuming and not applicable in patients with poor contrast opacification (thus limiting volumetric segmentation). Furthermore, recent evidence has emerged supporting the notion that a simple visual (subjective) assessment of RV:LV enlargement can perform equally well84 (Fig. 8). Such data reinforce the prognostic power of a simple statement regarding the presence or absence of RV dilatation on a CTPA report, without compromising speed and convenience. In fact, in the latter study by Kumamaru et al,84 it was shown that determining the presence or absence of RV:LV enlargement by visual means had superior interobserver agreement (k = 0.83) compared with manual measurements. This is perhaps not surprising given the complex shape of the RV and motion artifact sometimes caused by the interventricular septum (Fig. 8). Indeed, there is a lack of agreement as to how RV:LV ratios on axial images should be measured. Copyright

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FIGURE 8. CTPA demonstrating right heart strain (and left lower lobe peripheral infarct). Subjective visual evaluation of the comparative size of the RV and LV performs as well as calliper measurements in this case. Using subjective assessment alone, it is clear that the RV is as least 1.5 times larger than the LV maximal diameter. Note also the motion of the interventricular septum. This may contribute to inaccuracies in calliper measurements in tachycardic patients, despite high-pitch protocols.

In most studies, the largest RV and LV diameters (even if on different craniocaudal slices) have been measured perpendicular to the interventricular septum (Fig. 9), whereas others have specified that diameters should be measured in the valvular plane or at the same level for both chambers.

Identifying High-risk Groups—Other CT Signs Several other signs of RV dysfunction may offer information on outcome. Deviation of the interventricular septum has shown inconsistent results as a prognostic marker across several studies on non–electrocardiography-gated CT studies. Such deviation can be classified as normal (convex toward the RV), flattened, and septal bowing (convex toward the LV).85 A number of studies have shown no prognostic benefit of reporting this sign.82,86 In any case, the usefulness of this sign is somewhat limited by its moderate degree of reproducibility between observers (k = 0.44).87 Reflux of intravenous contrast due to tricuspid insufficiency into the IVC, especially if there is reflux into the hepatic veins, is another surrogate CT sign of RV dysfunction in PE that may be associated with an adverse outcome. Using a 6-point visual scale for grading IVC reflux, Aviram et al88 found that more severe reflux (defined as reflux into the IVC and opacifying the proximal, mid, or distal hepatic veins) (Fig. 10) was associated with reduced survival in patients with a positive PE. However, if the hepatic veins are not opacified, this sign must be interpreted with a degree of caution, as its specificity for right heart dysfunction at high contrast injection rates is diminished. Several other quantitative measurements that may indicate RV dysfunction have also been evaluated, such as diameters of the SVC, azygos vein, and PA and the ratio of the PA to the ascending aorta. These metrics probably do not add additional information in the setting of acute PE, compared with more direct measures of RV size. Finally, a novel parenchymal CT sign that has also been investigated as a prognostic marker is pulmonary infarction. This is typified by peripheral consolidation, which may demonstrate central lucencies or the reverse halo



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FIGURE 10. Coronal reformat CTPA in patient with extensive pulmonary emboli and right heart strain (same patient as Fig. 8) shows reflux of intravenous contrast into the hepatic veins. This degree of hepatic venous contrast reflux is not likely to be due to high intravenous contrast injection rates, which can sometimes be the cause of sole IVC opacification in patients without right heart failure.

FIGURE 9. A, Maximal RV and LV diameters on axial CTPA are often situated on different craniocaudal slices. In this example, at the level of maximal LV diameter (A), the RV and LV are comparable in size. However, maximal RV diameter (more appropriately measured on image [B]) is underestimated if measured on (A). RV diameter is often greatest when measured in close proximity to the tricuspid valve, although there is a lack of standardization for RV measurements on CTPA.

sign89 (Fig. 11). One study found pulmonary infarction to be positively associated with the need for intensive care unit stay90 but not mortality.

Identifying High-risk Groups—CT-derived Measures of Pulmonary Vascular Obstruction Several scoring systems have been developed for semiquantitative evaluation of the extent and severity of pulmonary arterial thrombus (referred to as the clot burden or pulmonary or vascular obstruction index). The initial scoring systems were based on conventional pulmonary angiographic scores, which were adapted to CTPA, whereas


the scores proposed by Qanadli et al91 and Mastora et al92 were developed specifically for use on CTPA. Early work suggested that clear prognostic separation could be achieved using the Qanadli score.79 At a cutoff of 40% obstruction, van der Meer and colleagues reported a 11.2fold increase in PE-specific 3-month mortality despite anticoagulation, whereas Wu et al93 demonstrated remarkable prognostic separation using a higher obstruction cutoff of 60% (1.9% vs. 83% mortality). However, more recent studies have not demonstrated a clear association between pulmonary obstruction scores and mortality.78,94 The notion of a threshold of obstruction, that acts as a “tipping point” beyond which RV decompensation occurs, has also been put forward by Wong et al.95 In this study, stronger correlations between obstruction scores and RV/LV diameter ratios were found only after obstruction scores reached a defined threshold. The lack of consistent associations between obstruction scores and mortality may in part reflect the fact that these scoring systems do not take into account preexisting cardiovascular reserve or factors such as pulmonary vasoconstriction at the microcirculation level. In this regard, dual-energy CT (DECT) provides a unique opportunity to quantitatively assess both clot burden and pulmonary perfusion defects. This is described in greater detail below. As risk assessment in patients with PE involves the evaluation of cardiovascular status, signs of RV dysfunction, and biomarkers of myocardial injury, it is reasonable to expect that the combination of CT and clinical parameters could offer more prognostic information than any single CT metric in isolation.96 Although studies evaluating this concept are limited, models incorporating different parameters may have a future role in defining which patients can, for example, be treated on an outpatient basis and which require more intensive monitoring.

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of patients with suspected PE. DECT can at present be acquired by 2 widely available but different approaches. Dual-source CT systems can separate the low-kVp and high-kVp spectra between 2 different tubes. Single detector systems, in contrast, with highly responsive gemstone detector materials, can also generate dual-energy images by rapidly alternating the kVp during a single projection ray of the acquisition spiral. In both instances, the overall radiation dose is divided between the low-kVp and high-kVp spectra, and, therefore, there is no incremental radiation exposure compared with single energy acquisition CT.97 The simultaneous acquisition of thoracic imaging at 2 distinct kVp energies permits calculation of the amount of iodine within the imaged volume on a voxel by voxel basis. Within the lung parenchyma, this enables the generation of pulmonary blood volume (PBV) maps, which are a reflection of lung enhancement at a single time point. These images are typically color-coded and fused with images combining the low-kVp and high-kVp spectra to permit a simultaneous conventional grayscale evaluation of the vasculature and a calculated color scale image of the lung parenchymal enhancement. The emerging interest in this

FIGURE 11. CTPA on lung (A) and mediastinal (B) windows showing PE (B) and pulmonary infarction (A and B). Characteristics of pulmonary infarction include peripheral triangulated consolidation, with reverse halo sign and central lucencies. There is an absence of air bronchograms. Recognition of this appearance may be of importance on unenhanced thoracic CT wherein PE may not be clinically suspected. It should prompt repeat CTPA if appropriate clinically.

At the same time, however, robust prognostic separation in a model incorporating a plethora of parameters and weighting factors will be meaningless if the model is too unwieldy to be used at the point of care to make therapeutic decisions.

IMAGING IN ACUTE PE—NEWER TECHNIQUES DECT The advent and evolution of DECT-capable acquisition systems has added a new dimension to the evaluation Copyright

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FIGURE 12. A and B, Dual-energy CT. Central grayscale images are superimposed on color-coded PBV images. A, Saddle embolus with extensive lobar and segmental PBV defects. B, The associated grayscale images of the heart demonstrate the associated RV dilatation with LV chamber compression indicating right heart strain. This is not an uncommon manifestation in patients with this extent of PBV defects.



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FIGURE 13. A and B, SPECT CT in a patient with acute PE, demonstrating perfusion defect (arrow [A]) in the right upper lobe. Corresponding CT reformats (C) confirm that lung parenchyma is clear. Note: the CT component is typically performed during quiet breathing (V = ventilation scan, Q = perfusion scan).

field relates to using PBV maps of lung enhancement as a simplified surrogate of parenchymal perfusion.98 There is as yet limited evidence that the use of PBV images alone improves the sensitivity of CTPA imaging for the detection of PE. However, in combination with simultaneous availability of low-kVp imaging that improves the conspicuity of iodinated contrast media (see above), the diagnostic confidence for the determination of exclusion of embolic disease in both central and peripheral vessels may be improved.99 A more valuable benefit of DECT PBV imaging appears to relate to the insights gained into the physiological


effects of PE. Several studies have confirmed that PBV imaging may assist in the stratification of PE severity. In clinical practice, the majority of pulmonary emboli do not typically result in visible defects in PBV maps. In a study of 117 suspected PE patients, incorporating 17 positive patients, only 19 of 75 (25%) emboli were associated with a PBV defect.100 However, when distinguishing emboli that were totally occluding the vessel lumen from emboli that were only partially occlusive, PBV defects were far more common (82% vs. 9%). Therefore, the presence of PE-associated PBV defects may be an indicator of the cardiovascular impact of PE.

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Extensive PBV defects have been associated not only with CT evidence of right cardiac strain (Fig. 12) but also with clinical parameters of cardiovascular strain such as troponin I.101 Another study demonstrated reduced survival in acute PE patients with PBV defects >5% of their total lung volume.102 It is important to note that PBV images are commonly associated with artifacts, and users must be aware of these and attempt to mitigate them by technique adaptation. Most of these are easily recognizable as being caused by streak artifacts from high-density contrast material in the central venous system. Lesser artifacts may be generated by respiratory diaphragmatic and cardiac pulsatility motion. Although DECT demonstrates promise for the better characterization of acute PE, further evaluation is needed to determine the role of this modality in PE management. In particular, areas of future interest include the evaluation of the additive prognostic value of PBV to other imaging and clinical parameters, the value of PBV evaluation as an independent negative predictor for PE, and the study of its ability to predict the risk of unresolving PE or evolution to chronic thromboembolic disease.103

V/Q SPECT CT Traditional planar V/Q imaging can be limited by summation of overlapping segments, contributing to indeterminate studies. SPECT imaging, using multidetector g cameras, can overcome this problem and has long been used in cardiac imaging. SPECT V/Q can produce images in multiple planes and has been shown to reduce indeterminate studies to

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Computed tomography of acute pulmonary embolism: state-of-the-art.

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