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Contrast echocardiography in Canada:
Canadian Cardiovascular Society/
Canadian Society of Echocardiography position paper
George Honos (chair) MD FRCPC FACC1, Robert Amyot MD FRCPC2, Jonathan Choy MD FRCPC3,
Howard Leong-Poi MD FRCPC4, Greg Schnell MD FRCPC5, Eric Yu MD FRCPC6
G Honos, R Amyot, J Choy, H Leong-Poi, G Schnell, E Yu.
Échocardiographie de contraste au Canada :
Contrast echocardiography in Canada: Canadian Cardiovascular
Énoncé de position de la Société canadienne de
Society/Canadian Society of Echocardiography position paper.
Can J Cardiol 2007;23(5):351-356.
cardiologie / Société canadienne
As an adjunct to transthoracic, transesophageal and stress echocardio-graphy, contrast echocardiography (CE) improves the diagnostic accu-
À titre de mesure d’appoint aux échocardiographies transthoraciques,
racy of technically suboptimal studies when used in conjunction with
trans-œsophagiennes et de stress, l’échocardiographie de contraste (ÉC)
améliore la précision diagnostique des examens suboptimaux sur le plan
Intravenous ultrasound contrast agents are indicated for left ventricu-
technique lorsqu’elle est utilisée en conjonction avec une imagerie
lar (LV) opacification and improvement of LV endocardial border
delineation in patients with suboptimal acoustic windows.
Les agents de contraste intraveineux sont indiqués avec l’ÉC pour opacifier
Demonstrated benefits of CE include improvement in the accuracy of
le ventricule gauche et améliorer la visibilité du rebord endocardique VG
LV measurements, regional wall motion assessment, evaluation of
chez les patients qui présentent des fenêtres acoustiques suboptimales. Les
noncompaction cardiomyopathy, thrombus detection, Doppler signal
avantages avérés de l’ÉC sont notamment qu’elle améliore la précision desmesures VG, l’évaluation du mouvement pariétal régional, l’évaluation de
enhancement and conjunctive use with stress echocardiography.
la cardiomyopathie sans compaction, le dépistage des thrombi,
Studies have shown the value of CE in the assessment and quantifica-
l’amplification du signal Doppler et l’utilisation concomitante de
tion of myocardial perfusion, and recent clinical trials have suggested
l’échocardiographie de stress. Les études ont montré l’utilité de l’ÉC dans
a role for contrast perfusion imaging in the stratification of patients
l’évaluation et la quantification de la perfusion myocardique et selon de
with suspected coronary artery disease.
récents essais cliniques, l’imagerie de perfusion avec agent de contraste
While it adds some time and cost to the echocardiographic study, CE
pourrait faciliter la stratification des patients chez qui on soupçonne une
frequently obviates the need for additional specialized, expensive and
less accessible cardiac investigations, and allows for prompt and opti-
Si elle prend plus de temps et coûte plus cher, l’échocardiographie de
mal subsequent patient management. Despite its proven advantages,
contraste permet par contre souvent d’éviter le recours à d’autres épreuves
CE is presently underused in Canada, and this situation will, unfortu-
cardiaques spécialisées qui se révèlent coûteuses et moins accessibles, d’où
nately, not improve until several barriers to its use are overcome.
un traitement plus rapide et optimum des patients. Malgré ses avantages
Resolving these important hurdles is vital to the future of CE and to
éprouvés, l’ÉC est actuellement sous-utilisée au Canada et cette situation
its eventual implementation into clinical practice of promising
risque fort malheureusement de ne pas s’améliorer tant que certains
contrast-based diagnostic and therapeutic applications, including the
obstacles à son utilisation ne seront pas surmontés. Et il faudra aplanir ces
assessment of perfusion by myocardial CE.
importantes difficultés si l’on veut assurer l’avenir de l’ÉC comme outild’évaluation de la perfusion myocardique et assister éventuellement à son
Key Words: Contrast; Echocardiography; Imaging; Perfusion
utilisation à grande échelle dans la pratique clinique, comme n’importequelle autre technique diagnostique et thérapeutique prometteuse à based’agents de contraste.
Intravenous ultrasound contrast agents are indicated for left
contrast perfusion imaging in the stratification of patients
ventricular opacification (LVO) and improvement of LV
with suspected coronary artery disease (CAD) (9,10).
endocardial border delineation in patients with suboptimal
While the injection of a contrast agent often improves
acoustic windows. Benefits of contrast echocardiography (CE)
study diagnostic quality, the use of CE in Canada is still quite
have been demonstrated for accuracy of LV measurements (1),
limited. Time constraints, financial concerns, and a lack of
regional wall motion assessment (2), evaluation of noncom-
equipment and expertise are some of the many challenges that
paction cardiomyopathy (3), thrombus detection (4), Doppler
have prevented more widespread use of CE in the past, under-
signal enhancement (5) and conjunctive use with stress
scoring the importance of developing criteria for the appropri-
echocardiography (6). Studies have shown the value of CE in
ate use of this simple and useful technique. The present
the assessment and quantification of myocardial perfusion
document reviews the basic principles and clinical applica-
(7,8), and recent clinical trials have suggested a role for
tions of CE and provides the Canadian cardiology community
1Sir Mortimer B Davis Jewish General Hospital; 2Hôpital du Sacré-Coeur, Montreal, Quebec; 3University of Alberta Hospital, Edmonton, Alberta;
4St Michael’s Hospital, Toronto, Ontario; 5Foothills General Hospital, Calgary, Alberta; 6University Health Network, Toronto, Ontario
Correspondence and reprints: Dr George Honos, Sir Mortimer B Davis Jewish General Hospital, 3755 Côte Ste-Catherine, E-206, Montreal,
Quebec H3T 1E2. Telephone 514-340-8283, fax 514-340-7534, e-mail firstname.lastname@example.org
Received for publication February 12, 2007. Accepted February 27, 2007
2007 Pulsus Group Inc. All rights reserved
Copyright Pulsus Group Inc – Do not copy
Honos et al
generation, air-filled agents (16). These newer agents also
Echocardiographic contrast agents
encapsulate the gas within lipid shells to further enhance
microbubble stability in the circulation (Table 1).
Harmonic imaging, which is available on most ultrasound sys-
tems currently in clinical use, was first developed specifically for
CE (17). The intent of harmonic imaging was to take advan-
tage of the unique physical properties of contrast microbubbles
exposed to an ultrasound field. When bubbles are insonated,
they oscillate within the acoustic field, going through rapid suc-
cessions of compression and expansion. The amplitude of the
bubble volume change is maximal at a specific frequency,
termed resonant frequency. The resulting backscattered signal
therefore includes frequencies that are multiples (harmonics) of
the incident (fundamental) frequency. In standard harmonic
imaging, only the second harmonic echoes are displayed and
the remaining frequencies are filtered out (18). It was then
observed that cardiac tissues, such as the endocardium-blood
pool boundary, also generate harmonic signals, while many arti-
facts do not. The use of second harmonic imaging, therefore,results in substantial improvement in two-dimensional image
*In clinical use in Canada; †Formerly known as Bracco Diagnostics Inc;
quality, even in the absence of any contrast injection.
Undergoing phase III testing; §Undergoing phase II testing. PESDA
Perfluorocarbon (PFC)-exposed sonicated dextrose albumin; SF6 Sulphurhexafluoride
The mechanical index (MI) is an estimate of the ultrasound
output power and is defined as the peak negative acoustic pres-
with some guidance for the implementation of CE in local
sure at the focus of the ultrasound beam, divided by the square
echocardiography laboratories based on the best available sci-
root of the incident frequency (19). MI is user-adjustable and
its value appears onscreen on most commercially availableultrasound systems. Many echocardiographic platforms offer
different contrast presets with an MI optimized for LVO and
Enhancement of the acoustic signal of blood during echocar-
diography was first described in 1968 (11), when it was noted
At a high MI, microbubbles are susceptible to destruction
that saline injected into the aortic root produced strong echoes
by insonation. Therefore, a lower MI is desired during contrast
within the aortic lumen. This contrast effect was attributed to
imaging to prolong the effect of the agent and optimize the
the accidental introduction of small air bubbles into the blood-
enhancement of the blood-myocardium interface. However,
stream with fluid injections. These air bubbles strikingly
the ability to generate strong acoustic signals by microbubble
increase the backscatter because of their high impedance to
destruction has implications for myocardial CE (MCE). Early
ultrasound propagation compared with blood. However, air
attempts to assess perfusion using high MI harmonic imaging
bubbles present in agitated saline administered intravenously
failed because microbubbles were continually destroyed while
do not cross the pulmonary circulation because the larger bub-
entering the myocardial microvasculature on insonation at the
bles are trapped by the microcirculation, while microbubbles
high frame rates used in continuous imaging. Intermittent
small enough to pass through the pulmonary capillary bed
imaging was introduced to overcome this problem. Imaging
(smaller than 8 µm) collapse within a few seconds before reach-
with this modality is performed at very low frame rates, trig-
ing the left heart cavities due to surface tension, surrounding
gered according to the electrocardiogram. This allows the
pressure and gas diffusion from bubbles into the blood (12,13).
replenishment of microbubble contrast agent into the
Early applications of CE were therefore limited to using agitated
myocardium in between destructive imaging frames, and
saline to detect intracardiac and intrapulmonary shunts, con-
enables the qualitative and quantitative (investigational)
firm needle placement during pericardiocentesis, and enhance
assessment of myocardial perfusion. With intermittent imag-
right-sided Doppler signals and two-dimensional images.
ing, delayed and incomplete replenishment implies reduced
Agitated saline CE is still widely used in these clinical settings
in the modern-day echocardiography laboratory.
To overcome the instability of air-filled microbubbles, and
Newer imaging techniques
to allow them to cross the pulmonary capillary bed and reach
Other than harmonic imaging, specific modalities have been
the left heart, two main strategies were initially adopted.
developed to selectively enhance the microbubble signal, and
Substances with surfactant-like properties to reduce surface
abolish background noise and tissue signal. These techniques
tension (14), as well as a protein shell to encapsulate the bub-
use low acoustic power to minimize microbubble destruction
bles and limit outward gas diffusion, were included in some for-
and prolong the contrast effect, and also maximize the
mulations (15). More recently, high-molecular-weight gases
microbubble signal intensity to noise ratio. Such ultralow MI
(mainly fluorocarbons) with low solubility in blood have been
(0.1 to 0.2) technologies are referred to as real-time perfusion
used to yield microbubbles with greater stability than the first
imaging because they allow assessment of tissue perfusion
Copyright Pulsus Group Inc – Do not copy
CCS/CSE position paper on contrast echocardiography
during real-time continuous imaging. These newer contrast
stimulation. This qualitative analysis of segmental contractility
imaging techniques specifically take advantage of the nonlin-
is limited by inadequate image quality. Therefore, optimal
ear response of microbubbles to an ultrasound field. A unique
endocardial delineation of all LV segments at rest and during
ultrasound signature from the contrast backscattered signal is
stress is of utmost importance to maximize diagnostic accuracy
generated by the asymmetrical oscillations of microbubbles,
and improve interobserver agreement (33). Image acquisition
which can expand more than they can be compressed. By send-
at peak stress inherently carries additional challenges over
ing sequences of ultrasound pulses of alternating phase and/or
baseline recording. Image degradation commonly takes place
intensity, the system suppresses the linear backscattered echoes
from rest to maximal stress because of the limited time to scan
from tissue. On the contrary, the successive nonlinear signals
in different incidences in the contexts of patient discomfort,
received from microbubbles do not cancel out when added,
tachycardia, hyperventilation, increased cardiac translation,
and are selectively amplified and displayed. These modalities
and sometimes significant ischemia, which have to be
are very sensitive for detecting contrast signal while virtually
eliminating the surrounding tissue echoes. Real-time perfusion
Stress echocardiography in conjunction with LVO has been
imaging limits microbubble disruption by the use of a low MI
studied mostly with dobutamine testing (6,26,34-37). In several
and avoids the need for intermittent triggered imaging.
trials, contrast use consistently improved endocardial depic-
Therefore, wall motion can be assessed in real time without
tion and confidence of interpretation during stress echocardio-
interruption of image acquisition (16). The great potential of
graphy. However, the diagnostic accuracy of stress
these approaches is their ability to acquire cardiac systolic
echocardiography with LVO compared with noncontrast har-
function and myocardial perfusion information simultaneously.
monic imaging stress echocardiography has not been well stud-ied. Some investigators have provided indirect evidence
LV FUNCTION ASSESSMENT
suggesting superior stress echocardiography performance in the
Accurate determination of LV ejection fraction (LVEF) is
detection of CAD with contrast. For example, LVO, during
important in the clinical management of patients with cardio-
dobutamine stress echocardiography in patients with subopti-
vascular disease. For example, LVEF predicts the risk of adverse
mal acoustic windows, has shown sensitivity and specificity
outcomes in patients with congestive heart failure, as well as
similar to noncontrast examinations in subjects with adequate
those postmyocardial infarction and following revascularization
images (34). In the largest trial of stress echocardiography with
(20-24). Several techniques have been used for the determina-
contrast (6), 300 consecutive outpatients underwent dobuta-
tion of LV volumes and LVEF, among them, echocardiography,
mine testing using both noncontrast harmonic imaging and
cineventriculography, radionuclide-ventriculography and mag-
LVO. Although the subjects were not selected on the basis of
netic resonance imaging (MRI). Although echocardiography is
having a poor acoustic window, contrast use improved image
the most frequently used modality in clinical practice, it has
quality and confidence of interpretation both at rest and at
gained little acceptance in clinical trials, because prior studies
peak stress. Moreover, LVO prevented the deterioration in
have indicated that conventional noncontrast echocardiogra-
image quality and confidence of interpretation from baseline
phy may have significant variability compared with accepted
to maximal stress that was observed with noncontrast images.
gold standards, with resultant low interobserver agreement, and
Nevertheless, the most important benefits were observed in
moderate reproducibility and accuracy to define LVEF. The
the subset of patients with suboptimal images, and the general
main reasons for the compromise in reproducibility and accu-
consensus supports the use of LVO during stress echocardiogra-
racy, aside from geometric assumptions, lie with the inadequate
discrimination of the endocardial border. CE provides betterendocardial border delineation than nonenhanced echocardio-
The advent of newer myocardial contrast agents that safely tra-
CE has been demonstrated to significantly improve agree-
verse the pulmonary circulation has permitted the intravenous
ment in the measurements of LV volumes and LVEF using cur-
administration of contrast to assess not only LV wall motion,
rent reference standards, including cineventriculography,
but also the myocardial microcirculation. These agents remain
radionuclide ventriculography, electron beam computed
entirely within the vascular space, have similar rheology to red
tomography and MRI (1,27-30). The enhanced accuracy of CE
blood cells and are hemodynamically inert. During a constant
has been demonstrated in several single-centre and multicentre
intravenous infusion of microbubbles, a steady state is achieved
studies, with significant reductions in intra- and interobserver
within the capillary bed. The ultrasound signal returned from
variability when contrast is used in the assessment of ventricu-
the bubbles within the myocardium at a steady state can be
lar function, volumes and EF (1,27,28-30). The interobserver
detected using modern ultrasound imaging modalities and is
variability for CE has been demonstrated to reach the same
proportional to the number of intact capillaries or myocardial
level as that for MRI (1). Ultrasound technologies, including
blood volume. Destruction of microbubbles using a high-energy
the automatic quantification of LV structure and function using
pulse of ultrasound and observation of the subsequent replen-
a variety of edge detection and blood pool algorithms, have
ishment of microbubbles into the microcirculation permits
been greatly facilitated and improved with echocardiographic
evaluation of myocardial tissue perfusion (38). Using these
contrast agents, and have been shown to correlate well with
principles, techniques have been developed to quantify
current reference standards (31,32).
myocardial perfusion and have been validated experimentallyby radiolabelled microspheres, and clinically against coronary
LVO and stress echocardiography
Doppler flow wires and positron emission tomography imaging.
The diagnosis and stratification of significant CAD by stress
The excellent spatial resolution and the temporal ability of
echocardiography depends on the identification of regional
MCE to assess the rate of myocardial blood flow make it an
wall motion deterioration with exercise or pharmacological
ideal tool to evaluate the adequacy of myocardial perfusion.
Copyright Pulsus Group Inc – Do not copy
Honos et al
MCE has been clinically shown to reliably identify the pres-
and interobserver agreement for the assessment of resting
ence or absence of myocardial reperfusion following primary
regional wall motion, to reduce interobserver variability and
percutaneous coronary intervention (the ‘no-reflow’ phenom-
enhance the reproducibility of stress echocardiography studies,
enon) (39), predict subsequent LV function post-MI (40),
to help define altered cardiac anatomy by improving the
determine myocardial viability after ischemic injury (41), and
echocardiographic detection rates of myocardial rupture,
assess infarct-related artery patency and the degree of collateral
pseudoaneurysms, intracardiac thrombi, aortic dissection, LV
support to the infarcted territory (42). Multiple studies have
noncompaction and apical hypertrophic cardiomyopathy, and
also used MCE in conjunction with dobutamine or vasodilator
to enhance left-sided Doppler velocity signals in the assess-
(adenosine or dipyridamole) stress to detect CAD with a sen-
ment of intracardiac pressures and transvalvular gradients.
sitivity and specificity comparable with that of nuclear tech-
Ultrasound contrast agents have also been used during trans-
niques (43-45). Two studies have demonstrated the
esophageal echocardiography in aortic dissection assessment
incremental prognostic value of MCE over routine clinical
and left atrial appendage thrombus detection.
assessment in risk-stratifying patients who present to the emer-
Despite improvements in ultrasound imaging techniques,
gency room with chest pain syndromes (46,47). Finally, Basic
including the widespread availability of harmonic imaging, an
et al (48) recently demonstrated that MCE was able to accu-
estimated 10% of resting echocardiograms and 30% of stress
rately classify patients at risk for cardiac disease, and provided
echocardiograms remain diagnostically suboptimal. In these
prognostic information comparable with validated nuclear
circumstances, the use of CE improves diagnostic accuracy and
may contribute to a cost-effective pattern of care. This is
Despite the safety (49) and potential utility of MCE, the
achieved through the impact of the reduced downstream repet-
initial enthusiasm over the use of MCE for perfusion imaging
itive testing in patients with an initially nondiagnostic
has not translated into routine clinical use, because several
echocardiogram, a reduced rate of false-positive and false-
outstanding issues remain. It is important to note that MCE is
negative echocardiograms as a result of improved image qual-
a technically challenging modality, and requires an experi-
ity and increased laboratory efficiency in evaluation of
enced operator and optimal acoustic windows to obtain accu-
labour-intensive, difficult-to-image patients. In a study involv-
rate results. Interpretation of images to reliably differentiate
ing multiple Canadian centres, Tardif et al (51) studied the
perfusion defects from imaging artifacts is very user-dependent.
impact of contrast stress echocardiography on resource use in
An early multicentre study (50) of the use of MCE in routine
the management of patients with suspected CAD, comparing
practice by novice users demonstrated poor sensitivity com-
it with standard stress nuclear perfusion imaging. The authors
pared with nuclear techniques for the detection of CAD.
found that contrast stress echocardiography had a similar suc-
While phase III trials of a contrast agent proving the accuracy
cess rate to nuclear perfusion imaging in diagnosing CAD, but
of MCE for the detection of CAD have been performed, most
had a 28% lower cost, along with the potential for additional
results are still unpublished, and currently, no contrast agent
cost savings through the elimination of additional tests due to
has been approved for use in perfusion imaging. Other unre-
false-positive nuclear perfusion scans. Castello et al (52)
solved issues include the optimal method of analysis – online
showed that a ‘sonographer-driven’ CE protocol for LV assess-
qualitative versus offline quantitative analysis of perfusion
ment was feasible, decreased the decision time for contrast
studies, optimal imaging techniques for perfusion assessment,
injection, and significantly improved LV global and regional
real-time versus intermittent imaging modalities and the opti-
wall motion visualization in technically difficult patients.
mal mode of contrast administration (constant infusion versus
Despite the overwhelming evidence of its benefit, CE remains
bolus). These shortcomings have limited the adoption of this
highly underused in Canada. Barriers to the greater use of CE
technique for the assessment of myocardial perfusion.
include the requirement of insertion of an intravenous access
Currently, MCE should be considered an experimental tech-
for contrast injection, lack of budget for the cost of the con-
nique, with clinical use limited to experienced centres alone.
trast agent, the need for additional scanning time, lack of
However, the development of newer contrast agents, contin-
physician experience with CE and the absence of physician
ued refinements in ultrasound imaging modalities, optimiza-
reimbursement in most regions of the country.
tion of online analysis, and successful completion of large,
The most promising future clinical application of CE is the
multicentre studies of MCE perfusion imaging demonstrating
noninvasive assessment of myocardial perfusion. Potential
its diagnostic and prognostic use will be important steps in
advantages of MCE over other available methods for assess-
ment of perfusion, such as nuclear single-photon emissioncomputed tomography and positron emission tomography
PRESENT AND FUTURE
techniques include the simultaneous assessment of perfusion
and regional wall motion in real-time, with good spatial and
Currently, ultrasound contrast agents are approved for use in
temporal resolution; the ability to quantify myocardial blood
Canada to improve image quality in suboptimal echocardio-
flow and flow reserve; portability, allowing the performance of
grams by opacifying the LV cavity and improving endocardial
studies at the bedside, in the emergency room, coronary or
border delineation. These ultrasound contrast agents have
intensive care unit and the operating room; and the use of a
been proven to be safe and effective in numerous clinical stud-
non-nephrotoxic, nonradioactive and safe contrast agent.
ies (1-10), they are easy to use and they can be used with vir-
Finally, research continues into future novel and exciting
tually all currently available echocardiographic systems.
diagnostic and therapeutic applications for CE. These include
During transthoracic echocardiography, these agents have
molecular imaging of pathophysiological molecular and cellu-
been shown in clinical trials to improve the qualitative assess-
lar processes, such as thrombosis, endothelial dysfunction,
ment of global LV systolic function, to improve the accuracy
inflammation (53) and angiogenesis (54), using contrast
LV volumes and LVEF quantification, to improve the accuracy
ultrasound and ‘site-targeted’ microbubbles, as well as the use
Copyright Pulsus Group Inc – Do not copy
CCS/CSE position paper on contrast echocardiography
of ultrasound-mediated destruction of designer ‘carrier’
14. Schlief R, Staks T, Mahler M, et al. Successful opacification of the
microbubble agents for the site-specific delivery of drugs, lig-
left heart chambers on echocardiographic examination afterintravenous injection of a new saccharide based contrast agent.
ands and genes for therapeutic applications (55).
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new transpulmonary contrast agent: Initial multicenter clinical
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esophageal echocardiography and stress echocardiography, CE,
contrast after intravenous injection of sonicated dextrose albumin
when used in conjunction with harmonic imaging, improves
microbubbles containing high molecular weight, less soluble gases.
the diagnostic accuracy of technically suboptimal studies due
to poor acoustic windows. While adding some time and cost to
17. Burns PN, Powers JE, Fritzsch T. Harmonic imaging: A new
imaging and Doppler method for contrast enhanced ultrasound.
the echocardiographic study, CE frequently obviates the need
for additional specialized, expensive and less accessible cardiac
18. Porter TR, Xie F, Kricsfeld D, Armbruster RW. Improved
investigations, and allows for prompt and optimal subsequent
myocardial contrast with second harmonic transient ultrasound
patient management. Despite its proven advantages, CE is
response imaging in humans using intravenous perfluorocarbon-
presently underused in Canada, and this situation will, unfor-
exposed sonicated dextrose albumin. J Am Coll Cardiol1996;27:1497-501.
tunately, not improve until several barriers to its use have been
19. Becher H, PN Burns. Contrast agents for echocardiography:
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Principles and instrumentation. In: Becher H, Burns PN, eds.
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The Ottawa County Board of Commissioners held their regularly scheduled meeting at 9:00 AM with the following members present: Gary Wyrick, Chairman, John Clarke and Russell Earls. First Assistant District Attorney Ben Loring was also in attendance. Notice of the meeting was posted at the south door of the Ottawa County Courthouse at 4:39 PM on August 1, 2013. Commissioners’ Meeting Agendas a
Processos de subjetivação e novos arranjos urbanos O artigo aborda uma linha de pesquisa ainda incipiente na Psicologia: os processos de subjetivação e o espaço urbano. Discorre sobre a tradição de se compreender a subjetividade conquanto interioridade, e dissociada dos processos sociais, propondo, com base em Foucault, uma compreensão da subjetivação como processo conecta