European Journal of Radiology 84 (2015) 1202–1211

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European Journal of Radiology

journal homepage: www.elsevier.com/locate/ejrad

Review

Triage for suspected acute Pulmonary Embolism:

Think before opening Pandora’s Box
David Levin a , Joon Beom Seo b , David G. Kiely c , Hiroto Hatabu d , Warren Gefter e ,
Edwin J.R. van Beek f , Mark L. Schiebler g,∗ , on behalf of the 2013 International
Workshop for Pulmonary Functional Imaging (IWPFI)
a
Department of Radiology, Mayo Clinic, Rochester, MN, USA
b
Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
c
Sheffield Pulmonary Vascular Disease Unit, M-15, M-Floor, Royal Hallamshire Hospital, Sheffield, UK
d
Department of Radiology, Brigham and Women’s Hospital and Harvard Medical School Boston, MA, USA
e
Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA
f
Clinical Research Imaging Centre, University of Edinburgh, Scotland, UK
g
Department of Radiology, UW-Madison School of Medicine and Public Health, 600 Highland Avenue, Madison, WI 53792-3252, USA

a r t i c l e i n f o a b s t r a c t

Article history: This is a review of the current strengths and weaknesses of the various imaging modalities available for
Received 16 November 2014 the diagnosis of suspected non-massive Pulmonary Embolism (PE). Without careful consideration for the
Received in revised form 26 February 2015 clinical presentation, and the timely application of clinical decision support (CDS) methodology, the cur-
Accepted 23 March 2015
rent overutilization of imaging resources for this disease will continue. For a patient with a low clinical
risk profile and a negative D-dimer there is no reason to consider further workup with imaging; as the
Keywords:
negative predictive value in this scenario is the same as imaging. While the current efficacy and effective-
Pulmonary Embolism
ness data support the continued use of Computed Tomographic angiography (CTA) as the imaging golden
Patient outcomes
Computed tomographic angiography
standard for the diagnosis of PE; this test does have the unintended consequences of radiation exposure,
Magnetic resonance angiography possible overdiagnosis and overuse. There is a persistent lack of appreciation on the part of ordering
Nuclear medicine ventilation–perfusion physicians for the effectiveness of the alternatives to CTA (ventilation–perfusion imaging and contrast
scans enhanced magnetic resonance angiography) in these patients. Careful use of standardized protocols for
Venous thromboembolism patient triage and the application of CDS will allow for a better use of imaging resources.
© 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction with chest pain, dyspnea and/or hypoxemia. Moreover, analogous

1.1. Think before opening Pandora’s Box
In the Greek fable of Pandora, found in Hesiod’s treatise Works
and Days, there was an overwhelming desire on the part of Pan-
dora to “open a box” that her father said never to open [1]. This
seemingly innocent action leads to severe consequences for the
world. This fable is a metaphor for the current state of imaging for
Pulmonary Embolism (PE). While computed tomographic angiog-
raphy (CTA) has revolutionized our ability to rapidly diagnose PE,
as well as provide alternative diagnoses, it has also become the
Pandora’s Box of imaging; a rapid and highly specific test that is
difficult for clinicians to resist when faced with patients presenting
to Pandora’s Box, opening up the CT scanner for imaging of the
large number of patients with these nonspecific symptoms and
signs has also lead to undesirable consequences: increased cost,
ionizing radiation exposure and potential overdiagnosis. However,
it is often forgotten that in the Pandora myth something remained
in the opened box- “Hope.”Likewise, improved (simplified) clini-
cal risk stratification schemes to triage patients to determine those
best served by imaging provides hope that CTA will be used in a
more optimized manner. In addition, magnetic resonance imaging,
with continued advances, holds potential in offering an alternative
to CTA without radiation exposure.
1.2. Purpose

The purpose of this review is to summarize our current under-

∗ Corresponding author. Tel.: +1 608 263 8970; fax: +1 608 263 0876. standing of the strengths and weaknesses of imaging for the
E-mail address: mschiebler@uwhealth.org (M.L. Schiebler). diagnosis of acute PE and how these can be used as part of

http://dx.doi.org/10.1016/j.ejrad.2015.03.023
0720-048X/© 2015 Elsevier Ireland Ltd. All rights reserved.
 D. Levin et al. / European Journal of Radiology 84 (2015) 1202–1211
integrated pathways for care in a variety of patient populations.
A number of different diagnostic imaging strategies can be used,
which will depend not only on the availability of local imaging and
expertise, but also features specific to the patient. In particular, we
will compare the evidence for CT pulmonary angiography (CTA)
versus MR angiography.
1.3. Background
PE is a common clinical problem with an annual incidence of
4–21/10,000 people per year rising significantly to 1 in 100 patients
over 80 years of age. Untreated mortality is estimated at 23–87%
whereas prospective studies have identified a mortality at 3 months
from PE of 3–6% following therapy [2]. Although treatment is clearly
effective in the majority of patients, post mortem studies show that
less than half the patients who died as a result of PE were suspected
of having this condition pre-mortem. In the United Kingdom, PE
is the leading cause of maternal death in pregnancy. The fear of
missing a diagnosis of PE can act as a strong incentive to physicians
to over investigate patients.
It is equally important to exclude disease in suspected cases, in
order to eliminate the risks of inappropriate treatment with anti-
coagulants, as both fatal and non-fatal bleeding events occur in
significant numbers of patients using older and, to a lesser extent,
newer range of therapies available. This requires a careful approach
and recently a bleeding-risk strategy has been proposed.
There are a number of challenges physicians may face when
caring for patients with suspected or proven PE, and the potential
to cause harm due to incorrect diagnostic or treatment strategies
is high, these include: (A) the variable clinical presentations, (B)
the large choice of diagnostic tools, (C) the increasing numbers of
treatment options, (D) the variable natural history of this clinical
spectrum of disease that includes deep venous thrombosis (DVT),
PE and venous thromboembolism (VTE), (E) the range of specialists
involved in patient care and (F) possible bleeding complications of
anticoagulation [3].
Fortunately, there are many strategies that can be used to
mitigate the risk of this disorder in high risk patients through
prophylactic anticoagulation and venous compression stockings.
There are also many validated diagnostic algorithms and risk scores
to improve risk stratification. There is an increasing choice of
anticoagulants and there has been a steady improvement in our
understanding of the natural history of VTE. Of critical importance
for optimizing patient outcomes is to ensure that this evidence is
available to the physician managing the patient. This requires inte-
grated pathways (standardized protocols) for the at-risk patient in
both the community and hospital setting (Fig. 1).
Imaging has a key role in making the diagnosis of PE and in
risk stratification. However, the first and most crucial step is the
clinical assessment of the patient. The clinical presentation of PE
depends on a variety of factors including the size and the number
of emboli, the chronicity of the presentation, and the presence of
comorbidities [4]. When the diagnosis of PE is suspected, the use
of clinical decision rules (CDS) improves the outcome for patients
and reduces unnecessary imaging. A number of well validated sco-
ring systems, including the Wells, Simplified Wells and modified
Geneva scores, are recommended [5,6]. Where PE is deemed likely
the clinician should proceed immediately to imaging; whereas in
low likelihood patients, a D-dimer test can be performed to help
exclude the disease and imaging should only be performed if the
D-dimer test is positive.
After PE is confirmed, it is important to accurately phenotype
the event. This includes identifying whether it is a first or recur-
rent VTE event, whether it is provoked, such as following surgery,
where the risk of recurrence is very low following 3–6 months
of anticoagulation, or unprovoked, where the risk of recurrence
1203
following cessation of anticoagulation is over 20% at 3 years. The
hemodynamic effect of the clot burden on the right ventricle is also
important and determines short-term prognosis [7–9]. Patients
with PE are classified into three groups based on the presence of
hypotension (or shock) and the effects on the right heart: massive,
sub-massive and non-massive. Massive PE presents with hypoten-
sion or shock due to the rapid increase in pulmonary artery pressure
which then may result in acute right ventricular failure. For these
patients, mortality at 3 months is thought to approach 50% [10].
Those with sub-massive PE have no hypotension or shock, but have
features of right heart dysfunction, which requires specific assess-
ment and cannot be established based upon clinical parameters,
and have a 30-day mortality of over 20%. In contrast, patients with a
small peripheral PE (non-massive) will often present with dyspnea
(and/or pleuritic chest pain) and have an excellent prognosis.
In addition to establishing a diagnosis of PE, it is important
to risk stratify patients. Correct risk stratification triages patients
with massive PE to thrombolysis, but and can also identify patients
at low risk for death that may be suitable for treatment in an
outpatient setting (Fig. 1). In addition, patients with larger clot bur-
den are more likely to develop long-term complications, such as
pulmonary hypertension [11]. In one large study, chronic throm-
boembolic pulmonary hypertension (CTEPH) occurred as a delayed
complication of PE in 3.8% of patients after 2 years [12]. Patients
may also present acutely with established CTEPH, having features
of right ventricular dysfunction but be relatively well conditioned.
These patients may have a large volume of proximal clot and right
heart dilation on imaging investigations. The diagnosis of CTEPH
is often suggested by a long history (if elicited) and the absence
of clinical features, such as tachycardia and hypotension that
would have been expected had the vascular obstruction occurred
acutely.
2. Imaging of acute PE
2.1. Computed tomographic angiography (CTA)
Godwin et al. were the first to report the use of computed tomo-
graphic angiography (CTA) for the detection of PE [13]. Given the
limitations of the scanners at that time, the technique was not
widely utilized. As hardware improved, especially with the devel-
opment of multidetector scanners, CTA became increasingly used
for the evaluation of suspected PE, and rapidly became the primary
method of investigation.
2.1.1. Technique
The basic concept behind CTA for PE is to image rapidly during
the bolus administration of intravenous contrast. The technique
became de rigueur with the development of spiral CT. Remy-Jardin
et al. [14] acquired a 12 cm volume, reconstructed at 3 mm inter-
vals, during a 24 s breath-hold using an early generation spiral CT
scanner. Current protocols using high- pitch techniques allow for
the coverage of the thorax with 0.6 mm collimation in roughly one
second. This allows for image acquisition without breath-holding.
One of recent advances of pulmonary CTA has been the appli-
cation of dual energy CT (DECT) technology. With this technique,
simultaneous acquisition of data at different tube kilovoltage
potential (kVp), high energy (140 kVp) and low energy (80 or
100 kVp), allows for analysis of tissue components within each
voxel of volumetric CT data. Among several approaches to enhance
diagnosis or assessment of PE using DECT, the most focused is the
assessment of pulmonary blood volume (PBV). With application
of the material decomposition theory, DECT can be used to dif-
ferentiate the iodine component from lung parenchyma enhanced
with iodine contrast material. A recent animal study has shown
1204 D. Levin et al. / European Journal of Radiology 84 (2015) 1202–1211

Fig. 1. Triage flow chart of suspected pulmonary embolism adapted from the Sheffield Teaching Hospital Guideline for the treatment of Venous Thromboembolic Disease.
(Abbreviations: EKG – electrocardiogram, ABG – arterial blood gas, CXR – chest X-ray, CBC – complete blood count, SBP – systolic blood pressure, Hg – mm mercury blood
pressure, Rt Ht – right heart, CTA-PE – computed tomographic angiography, V/Q – nuclear medicine ventilation–perfusion scan, TTE - transthoracic echocardiogram, MRA –
pulmonary magnetic resonance angiography, +PE – imaging exam positive for pulmonary embolism, −PE – imaging exam negative for pulmonary embolism, Dx – diagnosis,
PESI score – pulmonary embolism severity score, TPA – tissue plasminogen activator, Out Pt – out patient, ICU – intensive care unit).

excellent correlation between PBV measured using DECT and
pulmonary blood flow measured using dynamic CT perfusion,
justifying the surrogate use of this method [15]. Using DECT angiog-
raphy, the loss of parenchymal perfusion distal to a vascular
occlusion can be visualized, in addition to the endolumenal throm-
bus (Fig. 2). There are several additional techniques to use DECT
information to enhance the visualization of lung vessels, including
automatic classification of lung vessels as either patent (contrast
filled) or occluded (without iodine material), and augmentation of
iodine contrast using low kVp images or monochromatic (monoen-
ergetic) images. This allows for a reduction in the volume of
administered iodinated contrast material.
2.1.2. Test Performance
There are several ways to evaluate the performance of CTA
in the detection of PE. Early efficacy studies compared spiral CT
to conventional pulmonary angiography [16]. Remy-Jardin et al.
reported sensitivities of 91% for central emboli, with positive pre-
dictive values of 100% and negative predictive values of 89% [16].
Importantly, CTA was associated with reduced interobserver dis-
cordance when compared to conventional angiography. However,
conventional angiography is not an ideal gold standard, particularly
in subsegmental PE [17].
An alternative approach is to evaluate outcomes (effectiveness)
in patients who remain untreated following a normal pulmonary
CTA. Swensen et al. [18] followed 993 patients in whom PE was
excluded using CTA for three months and demonstrated a cumu-
lative incidence of DVT or PE of 0.5%. Quiroz et al. performed a
meta-analysis of 15 studies, evaluating a total of 3500 patients, to
assess the validity of CTA for excluding PE using DVT and PE inci-
dence as end point [19]. They found an overall negative predictive
value (NPV) for subsequent VTE of 99.1%, which is similar to that
found for conventional angiography [19].
2.1.3. Interobserver variability
The interobserver variability of CTA for the diagnosis of large PE
is good, but for subsegmental PE (SSPE) considerable interobserver
variability exists. One retrospective study in 70 patients reported as
having isolated subsegmental PE demonstrated that only 51% (95%
C.I., 39–64%) were detected at review [20]. Thus, as with other diag-
nostic tests for PE, the technique is less than perfect for detecting
smaller PE.
In terms of DECT, initial clinical and experimental studies
showed high accuracy of perfused blood volume (PBV) imag-
ing and suggested additional detection of perfusion defects
caused by very small blood clots in peripheral arterial branches.
 D. Levin et al. / European Journal of Radiology 84 (2015) 1202–1211 1205

Fig. 2. (A) Weighted average image of dual energy CT angiogram (DECT) shows a suspected occlusive filling defect in the right lower lobe (arrow). (B) Calculated Pulmonary
Blood Volume (PBV) from deconvolution of the iodine concentration derived from the 80 kVp portion of the DECT, shows a perfusion defect (arrow), which is color coded
in blue for its lack of iodine, distal to the suspected occlusive subsegmental PE shown in Fig. 1A. Note the dorsal (red and green color coding) to ventral (lighter green and
blue) perfusion gradient in the normal left lung (bracket). (C) Post processing of non iodine containing structures in red marks the thrombosed subsegmental vessel segment
(arrow) allowing the clot to easily standout against the background lung and the normaly enhanced pulmonary arteries and veins.

Nevertheless, most of the recent studies using DECT have focused
on the assessment of embolism severity. Several studies have
shown that the extent of perfusion defect caused by acute PE
correlates well with other CT parameters of severity, such as
intravascular clot burden and RV dilatation, and clinical param-
eters. However, only a few studies have been published on the
prognostic value of PBV images in acute PE [21]. The benefit of
PBV images over the other CT parameters is that PBV volume can
be quantified automatically with minimal or no user input. The
drawbacks of the PBV image include that it is prone to beam hard-
ening and cardiac motion artifact and that perfusion impairment
can also be caused by a variety of parenchymal diseases. One recent
study has suggested that CTEPH can be differentiated from acute PE
using two-phase DECT scanning, by detecting additional delayed
parenchymal enhancement by systemic arterial collaterals [22].
2.1.4. Special considerations
2.1.4.1. Radiation dose. Given the clinical history of untreated PE,
the diagnostic benefit of CTA likely outweighs the stochastic
radiation risk. However, given the large number of CTA stud-
ies performed, efforts to reduce the effective radiation dose per
examination are appropriate [23]. Modern scanners provide many
different dose reduction strategies, these include: automatic tube
current modulation, peak kVp modulation, scan range adjustment,
special collimator design to prevent z-axis over-scanning, and itera-
tive reconstruction. DECT angiography can be performed with equal
or lower radiation dose and comparable image quality compared
to conventional CTA.
The risks of medical radiation are important to understand in the
context of imaging for Pulmonary Embolism. The glandular dose to
the female breast is an important factor to consider. These stochas-
tic risks have been modeled by Li et al. and have shown that a single
chest CT in a young woman of 20 years of age is likely to cause
approximately 4.7 extra cancers per million exams [24]. Interest-
ingly enough,Pijpe et al. have shown that in a group of patients
with the BRCA1/2 gene that the epidemiologic evidence points to a
dose response effect for an increase in malignancy from exposure
to medical radiation within this cohort of patients [25]. The use of
peripheral blood lymphocytes to determine the relative number of
phosphorylated histones (H2AX), before and after a CTA chest with
iodinated contrast, has shown a significant increase in the number
of these areas of radiation induced DNA damage after the CTA exam
[26]. These data indicate that minimization of patient exposure to
medical radiation is desirable and that its use in younger patients
should have a very clear indication.
2.1.4.2. Overutilization. The use of diagnostic imaging studies in
general has increased substantially in the past two decades and
the use of CT for the evaluation of suspected PE has increased to
an even greater extent. Prologo et al. [27], found a nearly four-fold
increase in the use of CTA for the evaluation of PE over the five year
period from 1997–1998 to 2002–2003. During this time, the rate
of positive studies declined from 27% to 12% [27]. The increase in
utilization of CTA was greater in the Emergency Department than
among hospital inpatients. Chandra et al. [28], reported a 27-fold
increase in the total number of CTA performed at a single institution
over the period from 2000 to 2010.
One factor behind the increased utilization of CTA may be the
lack of adherence to protocol recommendations for the use of CTA.
Adams et al. [29], found that adherence to the PIOPED II recommen-
dations was low. In their analysis, only 45% of patients seen in an
emergency setting had a CTA ordered on the basis of an appropriate
clinical likelihood or a positive D-dimer test. Diagnostic yield was
found to be significantly less in patients where CTA was ordered
outside of protocol recommendations [29].
2.1.5. Identification of alternative diagnoses
One of the reported benefits of CTA for the evaluation of
suspected PE is the identification of alternative diagnoses. Good-
man [30] argues that patients present with signs and symptoms
1206 D. Levin et al. / European Journal of Radiology 84 (2015) 1202–1211
requiring an explanation. Part of the increased utilization of
pulmonary CTA comes from the ability to identify alternative diag-
noses that may require immediate action. Additionally, a “negative”
study may have significant clinical importance in patients with
other comorbidities and conditions. However, the importance of
alternative diagnoses has been debated. Chandra et al. [28], found
that CTA provided an alternative diagnosis that was not previously
known or evident on chest radiographs in only 7.6% of patients.
Frequently, this alternative diagnosis is a possible pneumonia. Hall
et al. [31], in their series, found evidence of pneumonia in 11% of
patients and pleural effusions in 19% of patients undergoing pul-
monary CTA. Both of these were more likely than identifying a
PE. Incidental findings, such as mediastinal lymphadenopathy and
non-calcified pulmonary nodules, were also common [31].
2.1.6. The incidental PE
For any practicing thoracic imaging physician, an unexpected
finding of PE on a contrast enhanced CT is a frequent occurrence.
The corollary to this is that it is also easy to overlook PE in con-
trast enhanced examinations of the chest. The incidence of PE
in oncology outpatients in a tertiary cancer center during a 6-
year period was 2.87%. CNS, pancreatic, upper gastrointestinal, and
lung/pleural malignancies had a significantly higher risk for PE than
other malignancies, whereas hematologic and breast malignancies
had a significantly lower risk [32].
2.1.7. Assessment of risk from acute PE
Evidence of right heart dysfunction may be used to estimate
the risk of death in patients with acute PE. This is most frequently
assessed by comparing the diameters of the left and right ventricles
and by identifying bowing of the interventricular septum toward
the left ventricle. In a meta-analysis, Becattini et al. [33], found a
two-fold increase in the risk of death at 30 days and a greater than
four-fold increase in death at three months among patients with
right ventricular dilatation detected on the initial pulmonary CTA.
While this was variably measured among the studies reviewed,
most frequently a ratio of transverse diameters (RV/LV) > 1.0 was
used.
2.2. Contrast Enhanced Magnetic Resonance Angiography
(CE-MRA)
The lungs and its associated pulmonary vasculature have been
a difficult region for Magnetic Resonance Imaging (MRI) and Con-
trast Enhanced Magnetic Resonance Angiography (CE-MRA) to gain
any useful clinical utility. The reasons for this are multifactorial but
mainly relate to low proton density in normal lung parenchyma,
field inhomogeneities at tissue-air interfaces and the asynchronous
movement of heart and lungs. Historically CE-MRA for the detec-
tion of PE was tried and was found to be was problematic due to
the long breath hold times (30–60 s) required [34]. While there
were some early successes, these were difficult to replicate [35].
A subsequent study showed value of CE-MRA using a double
injection protocol in patients with indeterminate lung scintigra-
phy results. Recently, CE-MRA methods have been successful in
overcoming many of these problems using a single breath-hold
acquisition [36].
2.2.1. Technique
There have been incremental advances in MRI hardware and
software that have reduced the time needed to obtain adequate
images of the lung. The first major advance was the introduction
of parallel imaging, reducing breath-hold times [37]. Shorter echo
(TE) and repetition times (TR) along with novel ways of filling
k-space have further reduced imaging and reconstruction times
respectively [38]. These innovations have further accelerated the
acquisition of 3D data for time resolved perfusion imaging. In
addition, optimizing the contrast injection protocol with diluted
contrast agent improved consistency of opacification of the vascu-
lar tree. Lastly, a recent publication by Bannas et al. has limited the
impact of Gibbs ringing artifact for the potential “overdiagnosis” of
PE at CE-MRA [39]. The resolution of CE-MRA exams using current
methods is: 1.3 mm × 1.8 mm × 2.0 mm, which is then interpolated
to 0.7 mm × 0.7 mm × 1.0 mm by zero-filling [36]. This is a near
isotropic 3D data set obtained in 13–20 s breath-hold. For compar-
ison, current 64 slice CTA voxel sizes for a 1.25 mm slice thickness,
40 cm FOV with 512 × 512 reconstruction matrix, zero-filled to a
1024 × 1024 matrix is 0.39 mm × 0.39 mm × 1.25 mm, acquired in
less than 6 s. The MRA maximum intensity projection (MIP) recons-
tructions have less artifact on them as the data set is a sum of all of
the vessel and respiratory motion, while the CTA MIP reconstruct-
ions show multiple stair-step artifacts related to cardiac and vessel
motion.
2.2.2. MR perfusion
An added value of MRI over CTA is the ability to acquire
time resolved images without incurring any additional penalty of
increased radiation for each measurement. This is of particular
importance for perfusion imaging. In principal, performing sequen-
tial images of the chest with CTA to monitor contrast passage has
a large dose penalty and for that reason is not routinely used. As
expected, perfused lung shows a wedge-shaped signal intensity
changes over time while that lung downstream from an embolus
has a very different pattern of enhancement. This can vary from a
simple delay in the appearance of the peak enhancement (such as
one might find distal to a non-occlusive embolus) to an area of non-
enhancement (such as what one might find distal to an occlusive
embolus). These areas of altered perfusion can also be found on
routine contrast enhanced pulmonary MRA exams. These wedge
shaped defects in the enhancement of the lung parenchyma can
be very helpful secondary signs that point to an occlusive embo-
lus that might not be observed on MRA due to the fact that this
is a “black-on-black” perceptual event at MRA, because the lung
and adjacent bronchus has no signal intensity (black) next to the
adjacent embolus (black) which also has no signal intensity. This
does however result in a “cutoff” of the pulmonary artery at that
location.
2.2.3. Test performance
The results of PIOPED III have cast a long shadow over the utiliza-
tion of CE-MRA for the primary diagnosis of PE [40]. This is primarily
due to the lower sensitivity of CE-MRA (78%) when compared to the
gold standard of CTA [40]. However, there was some encouraging
data from that study [40]. First, CE-MRA was found to have a very
high specificity (99%) for PE [40]. Also, the combination of CE-MRA
and Magnetic Resonance Venography (MRV) was more sensitive
(92%) for the diagnosis of PE than CE-MRA alone [40]. The PIOPED
III study suffered from technical issues wherein 25% of exams were
considered to be technically inadequate in visualizing the sub-
segmental vessels [40]. More recent studies have demonstrated a
higher sensitivity (89.5%) and specificity (100%) for CE-MRA than
that reported in PIOPED III [41]. This same group has also shown
that CE-MRA is more limited in its ability to accurately find sub-
segmental pulmonary emboli [41]. This makes sense intuitively as
the pixel size (in plane resolution) of CTA exams is about 2× that of
CE-MRA exams. In a single center retrospective review of CE-MRA
at 1.5 Tesla (1.5 T)for the diagnosis of PE in patients from the Emer-
gency Department presenting with dyspnea, the 3 month follow up
of all patients with a negative MRA had a negative predictive value
(NPV) of 97% [36]. Kalb et al. showed a combined sensitivity of three
pulse sequences for the detection of PE of 84% [42]. Recently Zhang
et al. have prospectively studied 43 patients with both CE-MRA at
 D. Levin et al. / European Journal of Radiology 84 (2015) 1202–1211 1207

Fig. 3. (a) Dual Energy CXR (bone subtracted image) showing a large Hampton’s Hump in the right lower lobe (arrow). (b) FSE Axial image from the scout series for exam
planning (first acquired series) showing the increased T2 signal intensity of the Hampton’s hump (bracket) in the right lower lobe from pulmonary infarction. (c) Pulmonary
MRA in the coronal projection of what is a 3D data set showing the large interlobar PE (thin arrow) and the area of decreased perfusion in the Right Lower Lobe related to
the Hampton’s Hump of pulmonary infarction (fat open arrow). (d) Axial T1 SPGR Fat saturation image through the level of the interlobar bronchus and artery showing the
large PE (lightning bolt) and the interlobar bronchus (white arrow). These two findings comprise the “double bronchus” sign for PE on MRA.

3 Tesla (3 T) and CTA and determined the efficacy of CE-MRA at 3 T
for the diagnosis of PE [43]. They had a very select group of patients
that were all at high risk for PE: 1. Age >15 years old; 2. Nephrotic
syndrome; 3. Hypercoagulable state (hemoglobin >16 g/dL, pro-
thrombin time <12 s, and fibrinogen >400 mg/L); 4. Serum total
cholesterol level ≥10 mmol/L; 5. Not clinically symptomatic for
PE; 6. Serum creatinine less than 2 mg/dL; and 7. No con-
traindication to iodinated contrast material. In this highly
enriched (for PE) cohort of patients they observed perfect (100%)
values for sensitivity, specificity, NPV and PPV respectively
[43].
2.2.4. The case for CE-MRA
Not every symptomatic patient needs a CTA to exclude mean-
ingful PE. There will always be alternative imaging tests that can be
performed. CE- MRA is part of the tool box that any imager needs
to consider when advising physicians about the possible choices
for imaging exams in patients with suspected PE. The avoidance
of medical radiation is important for younger women and chil-
dren and CE-MRA may be a good alternative to CTA in this group
[24]. Also, for those patients that have iodinated contrast aller-
gies, CE-MRA may be considered along with ventilation–perfusion
(V/Q), in place of CTA. The case for the use of CE-MRA is
particularly strong for young women using oral contraception
(OCP) (Fig. 3).
3. Ventilation–perfusion imaging (V/Q)
The use of V/Q scanning has a long history and is a well-accepted
method for the diagnosis of PE. Gutte et al. demonstrated that V/Q
SPECT had a sensitivity of 100% and a specificity of 87%, while pla-
nar V/Q scintigraphy had a sensitivity of 64% and a specificity of
72% [44]. At issue with all V/Q scanning is what to do with those
patients that have an abnormal CXR to begin with and thus have
a higher likelihood for an indeterminate examination. While not
always appropriate using current best practice guidelines, at most
institutions, pulmonary CTA has replaced the use of V/Q scan-
ning in virtually all patients with clinically suspected PE due to
its increased speed and overall accuracy when compared to V/Q
scanning. Very recently, low dose CT has been combined with V/Q
SPECT and has improved the efficacy of SPECT V/Q for the detection
of PE [45].
4. Best use of Imaging for suspected acute PE: Opening
Pandora’s Box
The current ACR appropriateness® criteria for the initial evalu-
ation of, “Acute chest pain- Suspected PE,” was published in 2012
[46]. These appropriateness criteria are very helpful from the point
of view of exam efficacy based on a review of the literature and
are often needed to obtain reimbursement from Center for Medi-
care and Medicaid Services (CMS) and other third party providers.
However, they do not addr ess these two key questions: (1) “What is
the overall utility of these studies?” and, (2) “What is the warranty
period on a negative test?” Pulmonary DSA is weighted too high
-5 [46], as this test is reserved for massive PE that needs intravas-
cular thrombolysis and is not used for primary diagnosis anymore.
CE-MRA of the chest is rated too low at a value of “4 [46], as this
publication has not been updated to reflect the important strides
that CE-MRA of the chest has made in image quality, effective-
ness and accessibility for the acute patient. While the V/Q scan is
rated at value of 8, its overall utility in clinical practice has been
diminished because of speed and concerns over the large number
of “Indeterminant” tests.
1208 D. Levin et al. / European Journal of Radiology 84 (2015) 1202–1211

Table 1
Benefit versus cost for the evaluation of test effectiveness for the Triage of Suspected non-massive PE (acute dyspnea in the non-pregnant patient). This new scoring system
demands that the ordering physician take into account the clinical context as the most important value in determining whether or not imaging should be performed. Unlike
the ACR rating, which is based on efficacy testing for the presence of PE in a loosely defined clinical setting, this table simply breaks down the choices by the published
negative predictive value divided by the estimated cost (NPV/Cost) in the United States of America. The NPV/Cost value emphasizes the importance of clinical decision rules
and test effectiveness (NPV) before considering any imaging for PE. (Abbreviations: * multisite combination of data, Est – Estimated, mSv – milliSieverts, ACR – American
College of Radiology Appropriateness rating, RHC – right heart Catheterization, 24/7/365 – test availability for completion of a wet read for actionable results at any hour, of
any day, during the year, ϕ – MRA for PE should be considered at those sites with the requisite technical expertise for performing and interpreting this test, NPV – negative
predictive value, N – total number of patients in study, TTE – transthoracic echocardiography, TEE – transesophageal echocardiography.).

Test (author, year) Estimated cost in Estimated time to (–) Test result Radiation ACR 2011 NPV (95%C.I.) N NPV/cost
USD increments get actionable value dose range rating
(Stein, 2007) results (mSv)
24/7/365

Wells’ Score 1 <5 min <2 0 NR 96 595 96

(Yap, 2007)
Revised 1 <5 min ≤3 0 NR 92 300 92
Geneva
Score
(van Es, 2014)
D-dimer 25 <30 min <250 D- dimer 0 NR 94 204 3.76
(Wang, 2001) units
Negative D-dimer and low 25 <30 min < 500 ug/L 0 NR 99.9 (99.5–100) 3367* 4.0
or moderate clinical
probability (Torbicki,
2008)
CXR-portable (NA) 100 <20 min <1 NR NA NA NA
PA & Lat CXR (Greenspan 200 Normal 9 74, 73 680, 152 0.38
1982; Worsley 1993)
CXR-Dual Energy (NA) 200 <30 min Normal <1 NR NA NA NA
CTA chest (Mos, 2009; 1700 <30 min Normal 5–20 9 99.5, 98.2 993, 2020 0.06
Swensen, 2002)
CTA chest + CT venogram 3000 <30 min Normal 10–40 6 99.1, 97 425, 824 0.03
(Mos 2009; Darze 2012)
DECT chest (NA) 1700 <30 min Normal 5–10 NA NA NA
V/Q scan (Miniati, 2003) 900 <120 min Normal 2–5 8 99.6 (97.2–100) 390 0.1
V/Q SPECT (NA) 800 <120 min Normal 2–5 NA NA
CE-MRA␸ (Schiebler, 2014) 2000 <60 min Normal 0 4 97 (92–99) 167 0.05
CE-MRA + CE-MRV 3000 <60 min Normal 0 NA NA NA NA
venogram (NA)
NCE-MRA (NA) 2000 <60 min Normal 0 3 NA NA NA
TTE 1200 <60 min Normal 0 2 NA NA NA
(NA)
TEE (NA) 1700 <480 min Normal 0 2 NA NA NA
Duplex venous doppler of 600 <120 min Normal 0 7 97–99 1022 0.16
the LE (Vaccaro, 1990)
DSA of Pulmonary Arteries 6000 <240 min Normal 10–90 5 98.3 (97.3–99) 1050 0.016
and RHC (van Beek 1996)

4.1. Benefit versus costs of imaging tests
There are a range of test charges and levels of CMS reimburse-
ment that change depending on what part of the United States one
surveys. For those countries with socialized medicine, or those sites
in the United States participating in an Accountable Care Organi-
zation that are reimbursed on a capitated rate per patient in the
at-risk pool, these charges are less meaningful. For the purposes of
this review (Table 1) we have assigned estimated US dollar values
to the various tests based loosely on CMS reimbursement and data
from PIOPED II [47].
We have listed the various tests available for the work up of
suspected PE by their negative predictive value and estimated cost
(Table 1) [4,18,36,47–56]. Table 1 highlights the critical importance
of first using Clinical Decision Support (CDS) before a test is ordered.
Rather than simply considering the efficacy of which test to per-
form, in this analysis, the negative predictive value and cost of the
test is considered to be the most important feature to evaluate.
4.2. Overutilization
The use of CDS in the setting of possible PE has been shown to
decrease the utilization of imaging.[57] Raja et al. found that utiliza-
tion was cut by 20% after CDS implementation with an increase in
CTA exams positive for PE from 5.8% to 9.8% [57]. One impediment
to the adoption of CDS is lack of understanding of the improvement
in overall patient care that can be obtained by using these meth-
ods. As shown by Runyon et al. in a survey of 555 clinicians (80% in
Academic practice), 57% of all respondents indicated that >50% of
the time they used a Gestalt approach in determining the need for
imaging tests, rather than CDS [58].
There is a modest radiation dose associated with a CTA for PE,
which ranges from 1 to 10 mSv. However, it is important to recog-
nize that many patients will have multiple additional studies over
time to evaluate incidental findings or to evaluate for suspected PE
in the future. Takahashi and Yoon followed 300 patients initially
evaluated in the Emergency Department for PE using CTA [59]. Over
the next four years 900 subsequent CT studies were performed
in those patients for a mean cumulative dose estimate of 31 mSv
(range 7–297 mSv) [59]. Thus, an unintended consequence (open-
ing Pandora’s Box) of an initial CTA exam for PE is that additional
CTA follow-up examinations are performed.
4.3. Is it ok to not find all Pulmonary Emboli?
Yes, it is often the case that an untreated patient will do fine even
if there is a small PE present. When comparing imaging with CDS, a
CTA chest exam for PE has the same negative predictive value after
3 months of follow up as a Wells score of <2 and a negative D-dimer
(NPV = 99%) [47,60]. Mehta et al. in New Zealand have recently
 D. Levin et al. / European Journal of Radiology 84 (2015) 1202–1211
shown that patients with a single subsegmental PE (SSPE), along
with two negative lower extremity ultrasounds, performed ten
days apart, can be safely managed without anticoagulation [61]. The
Ottawa group has recently re-reviewed their data covering 4410
CTA exams and found that of the 18 patients with sub-segmental
PE (SSPE) not treated with anticoagulation (14 single SSPE and 4
multiple SSPE), not one suffered from a subsequent VTE in the 3
month follow up period [20].
4.4. The possibility for litigation requires practicing defensive
medicine
The counter argument to this evidence based practice is that
missing 1% of PE is still too high of a miss rate. As physicians, we
are held to an impossible standard of not missing any PE. This is
an unrealistic goal which is now the new de facto requirement
that is adhered to in trying prevent medical malpractice litigation
related to death from PE. In other words, there is no disincentive
for the “over-ordering” of tests, while there is a very large penalty
for not ordering a test that may have discovered treatable disease.
In support for finding and treating all possible PE (including SSPE),
a recent prospective analysis of 3728 patients by den Exter et al.
[62], found no difference between the risk factors for patients with
SSPE and patients with larger PE. For the SSPE group, they found
that there was no difference in the risk of VTE at follow up when
compared to those with larger embolic burdens [62]. Patients with
SSPE were at an increased risk for VTE at 3 months when compared
with those patients that were negative for PE [62]. This study sug-
gests that it is not safe to forgo anticoagulation therapy for any
patient with SSPE. One hypothesis is that this is due to a continuing
imbalance of the thrombosis–fibrinolysis system in these patients.
4.5. Oral contraception use increases the risk for PE
The use of oral contraception is an important risk factor for the
development of fatal PE that is not currently accounted for by any of
the CDS models (Wells score, Geneva score, Modified Wells score,
and Simplified Geneva score) [6,63]. This risk is larger for women of
less than forty years of age and is highest for those patients on OCP
formulations containing Drospirenone [63]. Parkin et al. showed
that women using OCP had a hazard ratio for death from PE that
was 9.6 times higher than women who did not use OCP [64]. While
V/Q scanning is a valid alternative, this group of patients is tailor
made for the use of CE-MRA as they are cooperative, potentially
vulnerable to medical radiation and are able to hold their breath
for the exam.
4.6. Pregnancy
Imaging for PE in pregnancy has been extensively reviewed in
the landmark paper by Leung et al. [65]. The use of Gadolinium
Based Contrast Agents (GBCAs) is not recommended given the pos-
sible teratogenicity of free Gadolinium (from the transmettalation
exchange of Ca++ for Gd+++ in the chelation molecule of the GBCA)
to the fetus. Duplex Doppler scanning of the lower extremities, V/Q
scanning (if the patient has a normal CXR) and CTA (if the patient
has an abnormal CXR) are the current tests recommended in this
specific setting [65]. The use of Non Contrast MRA for the diagnosis
of PE in pregancy is currently under investigation.
4.7. Overdiagnosis
CTA for the diagnosis of suspected PE has become one of the most
over used tests in diagnostic imaging and clear cut action needs to
be taken to address this issue. The age adjusted incidence of PE
has increased by 80% since the introduction of multidetector CT
1209
(MDCT). Despite the detection of more emboli, the mortality rate
from PE has not changed significantly [66]. However, the case fatal-
ity rate has decreased, suggesting that the emboli being detected
using MDCT are less lethal than those detected prior before its
widespread use [66]. Current CTA techniques allow for the detec-
tion of small filling defects, and subsegmental emboli are identified
with increasing frequency as scanner technology improves. In a
meta-analysis, Carrier et al. [67], found a 7% rate of detection of SSPE
with 4- and 16-slice MDCT. That rate increased to 15% for studies
that used 64-slice MDCT scanners [67]. The importance of an iso-
lated SSPE is not clear. There is evidence that some small emboli
may not require therapy. Patients who present with isolated SSPE
have a very low risk of recurrent PE whether or not they receive
anticoagulation therapy [68]. Despite the increase in detection of
emboli with later generations of MDCT scanners, the incidence of
VTE within 3 months following a negative CTA has not changed.
This empirical data suggests that isolated emboli – those that may
not have been detected with older scanners – are not clinically
significant.
5. Conclusion
We have discussed the relative benefits and shortcomings of
the primary non invasive imaging choices available for the diag-
nosis of PE. At the present time, CTA is the test of choice for the
evaluation of suspected PE. Certainly the use of V/Q scanning is
an important alternative to CTA that is currently being underuti-
lized. For selected patients, CE-MRA may be a good alternative test,
although, its widespread adoption has been hindered by its limited
availability in the Emergency Department setting and decreased
sensitivity.
The primary drivers for the continued use of CTA are its avail-
ability, speed, high accuracy, and ability to identify alternative
diagnoses. This has led to its near universal adoption. However,
there are significant issues that have accompanied this choice to
open “Pandora’s Box” – chiefly overutilization and overdiagnosis.
The issue of overutilization is important. Multiple studies have
shown that utilization can be reduced with the use of validated
clinical protocols and CDS tools. The issue of overdiagnosis is less
clear cut. There are two opposing sets of data. The first is the long
held view that PE is associated with substantial mortality when not
diagnosed and treated. The second is the understanding that the
increased numbers of emboli detected have not affected the overall
mortality rate for PE. It is increasingly apparent that many smaller
emboli likely do not warrant therapy and that their detection is
of limited clinical importance. This issue is rapidly evolving and
imaging will play an important role in our understanding the nat-
ural history of an imbalance in the thrombosis–fibrinolysis system
and its effect on the clinical spectrum of VTE.
Using current imaging technology, it is simply not possible to
find all pulmonary emboli. As physicians, we must be brave enough
to use the current best evidence to guide our practice patterns, rather
than responding to the fear of missing an extremely small portion of
treatable disease.
Conflict of interest
None.
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