GUIDELINES AND STANDARDSClinical Applications of Ultrasonic Enhancing
Agents in Echocardiography: 2018 American
Society of Echocardiography Guidelines Update
Thomas R. Porter, MD, FASE (Chair), Sharon L. Mulvagh, MD, FASE (Co-Chair),
Sahar S. Abdelmoneim, MBBCH, MSc, MS, FASE, Harald Becher, MD, PhD,
J. Todd Belcik, BS, ACS, RDCS, FASE, Michelle Bierig, MPH, ACS, RDCS, FASE,
Jonathan Choy, MD, MBA, FASE, Nicola Gaibazzi, MD, PhD, Linda D. Gillam, MD, MPH, FASE,
Rajesh Janardhanan, MD, MRCP, FASE, Shelby Kutty, MD, PhD, MHCM, FASE,
Howard Leong-Poi, MD, FASE, Jonathan R. Lindner, MD, FASE, Michael L. Main, MD, FASE,
Wilson Mathias, Jr., MD, Margaret M. Park, BS, ACS, RDCS, RVT, FASE, Roxy Senior, MD, DM,
and Flordeliza Villanueva, MD, Omaha, Nebraska; Rochester, Minnesota; Edmonton, Alberta, Canada; Portland,
Oregon; Fort Myers, Florida; Parma, Italy; Morristown, New Jersey; Tucson, Arizona; Toronto, Ontario, Canada;
Kansas City, Missouri; S~
a o Paulo, Brazil; Cleveland, Ohio; London, United Kingdom; and Pittsburgh, Pennsylvania
This document is endorsed by the following American Society of Echocardiography International AlliancePartners: the Argentinian Federation of Cardiology, the British Society of Echocardiography, the Canadian Societyof Echocardiography, the Chinese Society of Echocardiography, the Echocardiography Section of the Cuban Societyof Cardiology, the Indian Academy of Echocardiography, the Indian Association of Cardiovascular Thoracic
Anaesthesiologists, the Iranian Society of Echocardiography, the Japanese Society of Echocardiography, the Korean
Society of Echocardiography, the Saudi Arabian Society of Echocardiography, and the Vietnamese Society of
Echocardiography.
Keywords: Echocardiography, Contrast, Guidelines, Imaging
TABLE OF CONTENTS

I. Introduction 242
II. Comparing UEAs 246
III. Recommendations for Imaging of UEAs

IV. Clinical Applications 247
IV.A. Update on Quantification of LV Volumes, LVEF, and RWM
246

From the University of Nebraska Medical Center, Omaha, Nebraska (T.R.P., S.K.); theMayo Clinic, Rochester, Minnesota (S.L.M., S.S.A.); the Alberta Heart Institute andUniversity of Alberta, Edmonton, Alberta, Canada (H.B., J.C.); Oregon Health &Science University, Portland, Oregon (J.T.B., J.R.L.); Lee Health, Fort Myers,
Florida (M.B.); Parma University Hospital, Parma, Italy (N.G.); Morristown Medical
Center, Morristown, New Jersey (L.D.G.); Banner University Medical Center,
Tucson, Arizona (R.J.); St. Michael’s Hospital, Toronto, Ontario, Canada (H.L.-P.);Saint Luke’s Mid America Heart Institute, Kansas City, Missouri (M.L.M.); the Heart~o Paulo School of Medicine, Sa~o Paulo, Brazil (W.M.);
Institute, The University of Sa
The Cleveland Clinic Heart and Vascular Institute, Cleveland, Ohio (M.M.P.); Royal
Brompton Hospital and Imperial College, London, United Kingdom (R.S.); and the
University of Pittsburgh, Pittsburgh, Pennsylvania (F.V.).
The following authors reported no actual or potential conflicts of interest in relation tothis document: Sahar S. Abdelmoneim, MBBCH, MSc, MS, FASE, Michelle Bierig,
MPH, ACS, RDCS, FASE, Linda D. Gillam, MD, FASE, Shelby Kutty, MD, PhD,
MHCM, FASE, Wilson Mathias, Jr., MD, and Flordeliza Villanueva, MD. The following
authors reported relationships with one or more commercial interests: Thomas R.
Porter, MD, FASE, has received educational support from Bracco Imaging and isa speaker at Bracco Imaging educational programs. He has received prior grant support from Lantheus Medical and GE Healthcare. He has received equipment support
from Philips Healthcare. Sharon L. Mulvagh, MD, FASE, has served as a consultant
for Bracco Diagnostics and has received investigator-initiated research grants fromGE Healthcare, Lantheus Medical Imaging, and Bracco Diagnostics. Harald Becher,
MD, PhD, has received research support (software), a research grant, and an honorarium for satellite symposia and courses from Bracco and research support (software) from Siemens and Philips. J. Todd Belcik, BS, ACS, RDCS, FASE, haspresented talks on behalf of Bracco. Jonathan Choy, MD, MBA, FASE, has served

IV.B. Update on Intracardiac Abnormalities

247

249

as a course director and speaker and has received an unrestricted educational grantfrom Philips Healthcare, has served as a consultant for Bracco Imaging, and was on
the advisory board for Aspen Canada. Nicola Gaibazzi, MD, PhD, has served as alecturer and consultant and has participated in sponsored studies for Bracco Imaging. Rajesh Janardhanan MD, MRCP, FASE, has served on the speakers bureau forLantheus. Howard Leong-Poi, MD, FASE, has served on the speakers bureau forLantheus and as a site investigator for a clinical trial run for Bracco Imaging. Jonathan R. Lindner, MD, FASE, has received an investigator-initiated grant from GE
Healthcare. Michael L. Main, MD, FASE, has received research grants from Bracco
Imaging and Boston Scientific and has served as a consultant for Boston Scientific.
Margaret M. Park, BS, ACS, RDCS, RVT, FASE, has served on the speakers bureau
for Lantheus Medical and was a Sonographer Contrast Task Force member for
Bracco Imaging. Roxy Senior, MD, DM, has received speaking fees from Philips
Healthcare, Bracco Imaging, and Lantheus Medical Imaging.
Reprint requests: American Society of Echocardiography, Meridian Corporate Center,
2530 Meridian Parkway, Suite 450, Durham, NC 27713 (E-mail: ase@asecho.org).
Attention ASE Members:
Visit www.aseuniversity.org to earn free continuing medical education credit
through an online activity related to this article. Certificates are available for immediate access upon successful completion of the activity. Nonmembers will need to join
the ASE to access this great member benefit!
0894-7317/$36.00
Copyright 2018 by the American Society of Echocardiography.
https://doi.org/10.1016/j.echo.2017.11.013

241

242 Porter et al

Journal of the American Society of Echocardiography
March 2018

V. Update on Safety and Indications for UEAs in Adults
263
VI. Echocardiography Laboratory Implementation of Contrast Agent Use
VI.A. Physicians 264

Abbreviations

2D = Two-dimensional

264

VI.B. Sonographers 264
VII. Emerging Applications 265
VII.A. Sonothrombolysis 265

3D = Three-dimensional
ASE = American Society of Echocardiography

VII.B. Molecular Imaging

CAD = Coronary artery disease

265

VII.C. Targeted Drug and Gene Delivery

CHD = Congenital heart disease

266

VII.D. Flow Augmentation with Diagnostic UTMD
VIII. Cost-Effectiveness of UEAs 267
VIII.A. Reducing Costs per Patient
267

CMRI = Cardiac magnetic resonance imaging
COR = Class of recommendation

267

VIII.B. Improving Positive Predictive Value 268
VIII.C. Improving the Emergent Evaluation of a Patient
268
IX. Summary of Recommendations for UEA Use for Echocardiography and
Additional Resources268

CPT = Current Procedural Terminology
CT = Computed tomography
DSE = Dobutamine stress echocardiography
DUS = Diagnostic ultrasound
ECG = Electrocardiography

I. INTRODUCTION

ED = Emergency department

The use of ultrasound enhancing agents (UEAs) has become an integral component of echocardiography practice. Since the 2008
American Society of Echocardiography (ASE) consensus statement
on clinical applications of ultrasound contrast agents,1 there havebeen several important developments that require the document
be revised into a guidelines paper.

FDA = US Food and Drug Administration
ICU = Intensive care unit
IV = Intravenous
LOE = Level of evidence
LV = Left ventricular
LVEF = Left ventricular ejection fraction
LVO = Left ventricular opacification
MBV = Microvascular blood volume
MCE = Myocardial contrast echocardiography
MI = Mechanical index
MP = Myocardial perfusion
OR = Odds ratio
PAD = Peripheral arterial disease
RCT = Randomized controlled trial
RTMCE = Real-time myocardial contrast echocardiography
RWM = Regional wall motion
SPECT = Single-photon emission computed tomography
STEMI = ST-segment elevation myocardial infarction
TEE = Transesophageal echocardiography
TTE = Transthoracic echocardiography
UEA = Ultrasound enhancing agent
UTMD = Ultrasound-targeted microbubble destruction
VLMI = Very low mechanical index

IV.C. Stress Echocardiography

252

IV.D. Vascular Imaging: Carotid, Femoral, Aortic, and Endografts

258

IV.E. Contrast Echocardiography in Critical and Emergency Settings

259

IV.F. Use of Contrast Agents in Congenital Heart Disease and Pediatric
Echocardiography 262

1. The term ultrasound contrast agents, describing a class of products comprising
microbubbles to enhance ultrasound signals,2-5 was replaced with the lessconflicting term ultrasound enhancing agent. Although the Writing Group
understands the need for this terminology in helping patients and referring
physicians distinguish these substances from iodinated contrast agents or
gadolinium chelates, it was considered equally acceptable to refer to theseagents as contrast agents and the imaging techniques as contrast
echocardiography or myocardial contrast echocardiography (MCE).
2. The Intersocietal Accreditation Commission has required that policies be inplace for UEA use (section 1.6.2.4B, updated June 1, 2017) in specific clinical settings in which UEAs are required.6
3. The safety of UEAs has been documented in several different clinical scenarios (stress echocardiography, pulmonary hypertension, intracardiac
shunting) as well as in emergency department (ED), critical care, and pediatric settings.5 Propensity-matched studies have not only documented safety
but also demonstrated the potential value and importance of early UEA use
in improving patient outcomes (Table 1). These large single- and multicenterstudies have led to changes in the US Food and Drug Administration (FDA)
boxed warnings regarding UEA use in pulmonary hypertension, critical caresettings, and more recently, known or suspected right-to-left shunts.
4. Numerous clinical trials have demonstrated the safety and efficacy of UEAs
in new stress echocardiography settings (dipyridamole, adenosine, regadenoson, bicycle, and treadmill), as well as in different resting conditions inwhich regional wall motion (RWM) and perfusion information provide significant incremental value in predicting patient outcomes (Table 2).
5. The use of myocardial perfusion (MP) imaging with UEAs has increased,
specifically in the setting of stress echocardiography, chest pain evaluationin the ED, and in the evaluation of intracardiac masses.25,34,35 The
American Medical Association Current Procedural Terminology (CPT)
Panel approved a category III (‘‘emerging technology’’) CPT code(+0439T) for ‘‘myocardial contrast perfusion echocardiography; at rest orwith stress, for assessment of myocardial ischemia or viability’’ (effective
July 1, 2016) for the use of perfusion imaging as an add-on to the followingbase CPT codes: 93306, 93307, 93308, 93350, and 93351. Although thiscategory III code is not reimbursed by the Centers for Medicare andMedicaid Services in the United States, approval of this code acknowledges
the significant incremental value of MP with UEAs in several clinical settings.

StudyDesign7

UEA

Total patients

UEA patientsControl patients

Inpatient/outpatient

Rest/stress

Outcomes

Aggeli et al. (2008)

Prospective

Sonovue

5,250

5,250

NA

NR

StressNo deaths or myocardial
infarctions

Gabriel et al. (2008)8

Retrospective

Definity or
Optison*

9,798

4,786

5,012

95% OutpatientsStressNo increased rate of SAEs or
mortality at 24 h in UEA patients

Herzog et al. (2008)9

Retrospective

Definity or
Optison

16,02516,025

NA

Both

Both

No short-term mortality; SAEs in
0.031%

Kusnetzky et al. (2008)10

Retrospective

Definity

18,671

6,196

12,475InpatientsRest

No increased mortality in UEA
patients

Main et al. (2008)11

Retrospective

Definity

4,300,966

58,2544,242,712

InpatientsRest

No increased mortality in UEA
patients

Shaikh et al. (2008)12

Retrospective

Definity or
Optison

5,069

2,914

2,155

Both

StressNo increased risk for SAEs in UEA
patients

Wei et al. (2008)13

Retrospective

Definity or
Optison78,38378,383

NA

Both

Both

Severe allergic reactions in 0.01%
and anaphylactoid reactions in
0.006%

Abdelmoneim et al. (2009)14

Retrospective

Definity or
Optison26,774

10,792

15,982

Both

StressNo increased short- or long-term
mortality in UEA patients

Anantharam et al. (2009)15

Retrospective

Definity or
Lumason†

3,704

1,150

2,554

Both

StressNo increased SAEs in UEA
patients

Dolan et al. (2009)16

Retrospective

Definity or
Optison66,22042,40823,812NR

Both

No increased mortality in UEA
patients

Abdelmoneim et al. (2010)17

Retrospective

Definity or
Optison

16,434

6,164

10,270Both

StressNo increased risk for myocardial
infarction or mortality in UEA
patients with pulmonary
hypertension

Exuzides et al. (2010)18

Retrospective

Optison14,5002,900

11,600InpatientsRest

No increased mortality in UEA
patients

Goldberg et al. (2012)19

Retrospective

Definity

96,705

2,518

94,187Both

Both

No increased mortality in UEA
patients

Weiss et al. (2012)20

Prospective

Definity

1,053

1,053

NA

NR

Both

No deaths or SAEs

Wever-Pinzon et al. (2012)21

Retrospective

Definity

1,513

1,513

NA

InpatientsBoth

No deaths or SAE attributed to
UEA in pulmonary hypertension
patients

Platts et al. (2013)22

Retrospective

Definity

5,956

5,956

NA

Both

Both

No increased mortality in UEA
patients

Main et al. (2014)23

Retrospective

Definity

32,434

16,217

16,217

Inpatients

Rest

Lower mortality in UEA patients

Wei et al. (2014)24

Prospective

Optison

1,039

1,039

NA

OutpatientsBoth

No deaths or SAEs

Porter et al 243

NA, Not applicable; NR, not reported; SAE, serious adverse event.
Modified with permission from Muskula et al.25*Definity is marketed as Luminity in Europe.
†
Lumason is marketed as SonoVue in Europe.

Journal of the American Society of Echocardiography
Volume 31 Number 3

Table 1 Large studies (>1,000 patients) published since 2008 that evaluated UEA safety244 Porter et al

Table 2 Smaller studies (<1,000 patients) published since 2009 that evaluated UEA safety
Study

DesignKurt et al.
(2009)26

Prospective

Senior et al.
(2013)27

UEA

Total patients

UEA patients

Inpatient/outpatient

Definity

632

632

NA

545 inpatient, 87
outpatient

Prospective

Sonovue

630

628

NA

Main et al.
(2013)28

Prospective

Optison

33

30

NA

Wei et al.
(2012)29

Prospective

Definity

32

32

Kutty et al.
(2016)30

Retrospective

Definity

113

Fine et al.
(2014)31

Retrospective

Definity,
OptisonBennett et al.
(2016)32

Retrospective

Kalra et al.
(2014)33

Retrospective

Modality

OutcomesRest

1 serious AE, 5
minor AEs (backpain)*

Stress1 serious AE, 16
minor AEs, 2.5%
(nausea,headache)†Outpatient

Rest (PASP> 35 mm Hg)

No serious AEs

16 with PASP
< 35 mm Hg

Outpatient

Rest (16 with
PASP >
35 mm Hg)

No serious AEs, 1
mild AE (backpain, headache)

113

140

Outpatient

Rest and stress

13 minor AEs(<1 min induration, no
treatment)

251

10

NA

Inpatient

LVAD patients

No complications
related to UEA, no
AEs, no change indeviceparameters

Perflutren,
Definity,
Optison

1,996

4

NA

Inpatient

ECMO patients

No complications
related to UEA, no
AEs, no change indeviceparameters

Definity,
Optison39,020UEA
patients

418 withright-to-leftshunts‡

NA

NA

Rest

No primary AEs, 1
minor AE (backpain) in the shunt
group

AE, Adverse event; ECMO, extracorporeal membrane oxygenation; LVAD, LV assist device.
*Death after 5 hours of UEA administration; patient experienced a large anterior wall myocardial infarction after knee replacement with hypotension, recurrent ventricular tachycardia within
the 24 hours before echocardiography.
†
A 69-year-old woman with suspected myocarditis developed hypersensitivity-like symptoms and asystole for 30 sec (symptom-free recovery within 57 min).
‡Left-to-right shunts excluded.

Journal of the American Society of Echocardiography
March 2018

Control patients

Journal of the American Society of Echocardiography
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Porter et al 245

Table 3 The three commercially available UEAs
Name

Manufacturer/vial contents

Mean diameter

Shell

Gas

Contraindications

Lumason (sulfur
hexafluoride lipid-type
A microspheres)

Bracco Diagnostics, 5 mL 1.5–2.5 mm (maximum
20 mm, 99% #10 mm)

Phospholipid

SulfurAllergy to sulfur
Hexafluoride
hexafluoride

Definity (perflutren lipid
microsphere)

Lantheus Medical
Imaging, 1.5 mL

1.1–3.3 mm (maximum
20 mm, 98% <10 mm)

Phospholipid

Perflutren

Allergy to perflutren

Optison (perflutren
protein type-A
microspheres)

GE Healthcare, 3.0 mL

3.0–4.5 mm (maximum
32 mm, 95% <10 mm)

Human albumin Perflutren

Allergy to perflutren/
blood products

Table 4 Location and description of VLMI imaging software on commercially available echocardiographic scanners

Manufacturer

Platform andportability*

Location and name ofenhanced imaging
software on front end

Specific pulse sequence scheme
used (dominant nonlinear activity
detected)

High-MI ‘‘flash’’impulse location
on front end

Frequency/MI
recommended for
VLMI imaging

Philips

iE33
Not portable

Contrast key
On/off
LVO and low-MI
choices

Touch screen/
flash label

Amplitude modulation andpulse inversion(fundamental and harmonic)<2.0 MHz/MI < 0.2 (GEN or
PEN setting)PhilipsEpiq
Not portable

Contrast key
On/offLow-MI and LVO
choices

Touch screen/
flash label

Amplitude modulation andpulse inversion(fundamental and harmonic)<2.0 MHz/MI < 0.2 (GEN or
PEN setting)Philips

CX50
Portable

Contrast key
On/off
LVO choiceControl panel

Amplitude modulation(harmonic)<2.0 MHz/MI < 0.3

GEVivid E95
Not portable

Advanced
contrast
optionTouch screen/
flash label

Pulse inversion 1.5/3.0 and1.6/3.2 MHz and 1.7/
3.4 MHz (harmonic)
Amplitude modulation
2.1 and 2.4 MHz (fundamental
and harmonic)

1.5–1.7 MHz/MI < 0.2

Not available; need
to use ‘‘color
Doppler’’ knob

Pulse inversion and alternating
polarity/amplitude(fundamental and harmonic)

2.0 MHz/MI < 0.2

2.1–2.4 MHz/MI < 0.2

Siemens

SC2000Not portable

Toshiba

Aplio i900
Not portable

Touch screen/
CHI label

Control panel

Pulse subtraction (amplitude
modulation; harmonic)

h3.5/MI < 0.2 (PEN setting)Toshiba

Aplio 500
Not portable

Touch screen/
low label

Touch screen/
flash label

Pulse subtraction (amplitude
modulation; harmonic)

h2.8–h3.6/MI < 0.2

EsaoteMyLabEightNot portable

Contrast key
On/off
LVO choice

Touch screen/
flash label

Phase cancellation

PEN frequency/MI < 0.2

EsaoteMyLabSeven
Not portable

Contrast key
On/off
LVO choice

Touch screen/
flash label

Phase cancellation

1.5 MHz/MI < 0.2

EsaoteMyLabAlpha
Portable

Contrast key
On/off
LVO choice

Touch screen/
flash label

Contrast tuned imaging

1.5 MHz/MI < 0.2

CHI, Contrast Harmonic Imaging; GEN, general harmonic frequency setting; LVO, left ventricular opacification; MI, mechanical index; PEN, lower
fundamental frequency for harmonic imaging; VLMI, very low mechanical index (<0.2).
*Portable: defined as does not require wheels.

6. A critical mass of data have been published that demonstrates the beneficial
effect of UEAs on early outcomes in critically ill patients and the costeffectiveness of UEAs in patients with suboptimal windows in a wide variety of clinical settings.5,25

7. The FDA in the United States has approved new UEAs (Table 3). New
agents have been approved in other North American and South Americancountries. Ultrasound manufacturers have also revised their left ventricularopacification (LVO) and low–mechanical index (MI) settings for optimal

246 Porter et alenhancement.36 Specific instrumentation guidelines are now provided to
optimize left ventricular (LV) RWM and perfusion analysis (Table 4).

In recognition of the large volume of patients enrolled in prospective randomized studies, meta-analyses, registry data, and multicentercomparative effectiveness studies during rest and stress imaging, theWriting Group advises a class of recommendation (COR) and levelof evidence (LOE) on diagnostic strategies using UEAs. The recommendations made are according to the updated 2015 American
College of Cardiology/American Heart Association clinical practiceguidelines37 as follows:
COR
Class I (strong): Benefits are much greater than risks. The procedure should be performed.
Class IIa (moderate): Benefits are greater than risks, and theprocedure can be useful if performed.
Class IIb (weak): Benefits are slightly greater than risks, andthe procedure might be reasonable to perform.
Class III: The procedures offers no benefit or is harmful if performed.
LOE
Level A: High-quality evidence from more than one randomized controlled trial (RCT), a meta-analysis of high-quality RCTs,
or one or more RCTs corroborated by high-quality registry data
Level B-R: Moderate-quality evidence from one or more RCTs
or a meta-analysis of moderate-quality RCTs
Level B-NR: Moderate-quality evidence from one or morewell-designed nonrandomized trials, observational studies, or
registry studies or meta-analysis of such studies
Level C-LD: Randomized or nonrandomized observational orregistry studies with limitations in design or execution or a metaanalysis of such studies
Level C-EO: Consensus based on clinical experience
This update focuses on the new data that have been published andhow these data, when combined with the 2008 consensus statementand 2014 ASE contrast sonography guidelines,1,38 have led to specificrecommendations for UEA use in different clinical settings.

Key Points Regarding Current FDA Labeling of
UEA Use
1. The only FDA-approved use for UEAs in cardiovascular disease is for LVO. However,given significant scientific literature support, other off-label uses of UEAs (such as
MP, pediatric and vascular applications, and use during stress echocardiography)
are recommended in the present document according to the 2015 clinical practiceguidelines.37
The approved indications for use of ultrasound enhancing agents are governed byeach country and societal endorsement of this document does not imply otherwise.

Journal of the American Society of Echocardiography
March 2018

Lumason is approved throughout North America, New Zealand,
Europe, Brazil, and Asia.5 The range of bubble sizes permits passage
through the pulmonary circulation (1.1–4.5 mm in diameter). All containa high–molecular weight gas that improves their persistence because of
reduced solubility and diffusivity. Both Optison and Definity contain perflutren (octofluoropropane) gas, with the main difference being the flexible shell composition. The Optison shell is made up of human serum
albumin, whereas Definity uses a phospholipid shell. Lumason consistsof a sulfur hexafluoride gas core with a phospholipid shell (Table 3).
The specific fatty acid chain length and charge, as well as the compositionand length of the polyethylene glycol spacer, differ between Lumasonand Definity.3,4 Optison and Definity require refrigeration before use,
whereas Lumason is stored as a dry powder without refrigeration.
Preparation requirements for each of the agents differ: Definity requires
activation with a mechanical agitator, Optison requires a resuspensionof the bubbles by hand, and Lumason requires hand agitation.
Although Optison and Definity have been given as 10% and 3% to
5% diluted infusions in normal saline (Appendix),38 Lumason has been
primarily used in the United States as small 0.5-mL bolus injections followed by slow 5- to 10-mL saline flushes to avoid LV cavity shadowing.
Because the Lumason vial contains 5 mL, these bolus injections can be
repeated as needed to maintain homogenous cavity opacification.
There are other less widely available or developing UEAs. Sonazoid
is a microbubble with a perfluorobutane gas core in a phosphatidylserine shell that received regulatory approval in 2007 for imaging of liverand breast tumors in Japan and South Korea. In 2014, it was approvedfor focal liver lesion imaging in Norway.4
Intravenous (IV) UEAs are currently approved in the United States by
the FDA to enhance LVO in adults, although Lumason has also been
approved for pediatric use and for liver imaging. Although not specificallyapproved for stress testing, UEAs have been shown to improve the detection of RWM abnormalities at rest and during stress testing.38 All three
approved UEAs have been shown to have excellent safety profiles.34

Key Points Regarding Currently Available Commercial UEAs
1. All currently approved commercial UEAs contain a high–molecular weight gas encapsulated in a flexible shell.
2. All are able to traverse pulmonary and systemic capillary beds, with a size range of 1.1
to 4.5 mm.
3. UEA persistence in the circulation is determined by microbubble size, gas composition (diffusivity and solubility), pharmacokinetics, and shell properties.
4. Three UEAs (Optison, Definity, and Lumason) are approved for use by the FDA for theindication of LVO; all other applications in cardiovascular disease are off-label uses.
Lumason also has approval for adult and pediatric liver imaging, as well as evaluationfor vesicoureteral reflux.

III. RECOMMENDATIONS FOR IMAGING OF UEAs
II. COMPARING UEAs
Unlike red blood cells, which are poor scatterers of ultrasound, the microbubbles that compose UEAs are compressible and are of different density.
This unique physical characteristic of microbubbles is important in understanding the behavior microbubbles exhibit when exposed to ultrasoundenergy. Currently there are three commercially available UEAs worldwide for cardiac imaging: Optison, Definity (Luminity in Europe), andLumason (SonoVue outside the United States). Optison is available
only in the United States and Europe, whereas Definity is marketed in
the United States, Canada, Europe, Australia, and parts of Asia.

The signals obtained from UEAs are dependent on the MI of the transmitted ultrasound. The MI is directly related to the peak negative pressure and inversely related to the square root of the transmitted
frequency. At a very low MI (VLMI) of <0.2, microbubbles begin tooscillate in an asymmetric manner, as the expansion phase is larger
than the compression phase, generating an acoustic signal that is
nonlinear in nature. A further increase in amplitude of the transmit
wave may cause discontinuities in the microbubble shell as the oscillations become more exaggerated, effectively releasing the free gas todissolve into the circulation. Additionally, gas can be driven out during
compression of the microbubble, known as acoustically driven diffusion.

Journal of the American Society of Echocardiography
Volume 31 Number 3

The nonlinear acoustic signal distinction is essential to allow effective differentiation of surrounding tissue signal from microbubble signal.25,35
As per the 2014 ASE contrast sonography guidelines,38 VLMI represents multipulse cancelation sequences that are most effective at MI
values <0.2, low MI represents harmonic imaging techniques that areused at MI values <0.3, intermediate MI represents harmonic imaging
techniques used at MIs of 0.3 to 0.5, and high MI is any MI that exceeds
0.5. Real-time VLMI techniques are available on nearly all commerciallyavailable ultrasound imaging systems. These pulse sequence schemes
permit the enhanced detection of microbubbles within the LV cavity
and myocardium and thus permit improved RWM and perfusion analysis. The pulse sequence diagrams of available multipulse VLMI imaging
techniques were published in Table 1 and Figure 1 of the 2014 ASE
contrast sonography guidelines.38 Pulse inversion (or phase inversion)
is a tissue cancelation technique that delivers ultrasound pulses of alternating polarity (phase). Although pulse inversion provides excellent suppression of surrounding noncardiac tissue and results in high resolution
by receiving only even-order harmonics, there is significant ultrasoundsignal attenuation, especially in basal myocardial segments of apicalviews in part because of filtering at higher frequencies. Power modulation (or amplitude modulation) detects fundamental and/or harmonic
nonlinear activity almost exclusively from microbubbles when used at
an MI < 0.2. This technique is also a multipulse cancelation technique,which varies the power, or amplitude, of each pulse, rather than the polarity. For example, at an MI of 0.05, both microbubbles and tissue
respond in a linear fashion to the ultrasound pulse, whereas at twice
this power (0.1), there is still a linear response from tissue but a nonlinear
response from microbubbles. The linear responses from the twodifferent pulses (the twice-amplified 0.05-MI response and the 0.1-MI
response) can be subtracted from each other, thereby displaying only
nonlinear behavior from the microbubbles. Although an increase incontrast enhancement is produced, this sequence scheme theoreticallyhas reduced resolution and image quality compared with pulse or phase
inversion imaging (which detects only higher frequency harmonic responses). Manufacturers have also combined these multipulse techniques by using both interpulse phase and amplitude modulation,
which although more complex has the purpose of further enhancing
nonlinear activity from microbubbles at a VLMI and canceling out thelinear responses from surrounding tissue. The advantage of the VLMI
imaging techniques, compared with B-mode low-MI harmonic imaging,is that there is better tissue cancelation, greater signal-to-noise ratio(sensitivity for detecting agent), and less microbubble destruction
because of the lower MI required.25 The overall clinical effect of
VLMI imaging techniques is to provide high spatial and reasonable temporal resolution that permits the simultaneous assessment of MP andwall motion, which is especially important in detecting coronary arterydisease (CAD; Videos 1 and 2; available at www.onlinejase.com).
Because they detect the nonlinear activity at the fundamental
frequency, power modulation and interpulse phase and amplitude
modulation pulse sequence schemes have less attenuation and better
microbubble contrast signal, resulting in improved apical and basal
segment visualization (Videos 3 and 4; available at www.onlinejase.
com). Specific instructions on optimizing image quality are given in
Table 2 of the 2014 sonographer update.38
Continuous intermediate (MIs of 0.3 of 0.5) or high-MI imaging
should be avoided because it causes destruction of microbubbles
and creates swirling artifacts. However, brief (five to 15 frames)
high-MI impulses (MIs of 0.8 to 1.2), which have been termed ‘‘flash
impulses,’’ can be used during VLMI imaging to clear contrast fromthe myocardium and enhance the delineation of endocardial borders.
As discussed in detail later, the rate of myocardial contrast replenish-

Porter et al 247

ment following the high-MI flash impulse has been used in combination with the plateau myocardial contrast intensity to assess MP.35,36
As outlined in the 2008 ASE consensus statement1 and 2014 ASE
guidelines for sonographers,38 Doppler enhancement of left- andright-sided Doppler signals can be achieved with UEAs, and this has
been useful for both adult and pediatric applications. Although there
are no new clinical studies formally evaluating this, the guidelines
committee continues to strongly recommend their use for enhancement of tricuspid regurgitant peak velocity jet detection (for right ventricular pressure estimates) and peak velocity measurements in
valvular stenosis evaluation. This is particularly relevant when the
UEAs are being used for imaging indications, especially because thethreshold for the detection of microbubbles by Doppler is lower
than that for imaging indications. When performing these measurements, the Doppler gain signals should be lowered from unenhanced
echocardiography settings, to a level that reduces ‘‘microbubble noise’’and improves the resolution of the Doppler profile. As emphasized in
the 2008 guidelines, the most distinctly enhancing spectra should bemeasured at a lowered gain setting to reduce blooming artifact.

Key Points and Recommendations
1. VLMI multipulse imaging techniques with or without brief high-MI (flash) impulses
to clear myocardial contrast should be used to image UEAs for RWM analysis (Video 1;
available at www.onlinejase.com) and quantification of LV ejection fraction (LVEF;
COR IIa, LOE B-R).
2. VLMI multipulse imaging techniques can also be useful for detecting MP (Videos 2–4;
available at www.onlinejase.com) using brief high-MI flash impulses to clear myocardial contrast and subsequently analyzing myocardial replenishment kinetics andplateau intensity (COR IIa, LOE B-R).
3. Doppler-enhanced signals of tricuspid regurgitant jets can be obtained, especially if
UEAs are being used for other imaging indications, and the jet was not visualized
adequately without contrast. This also applies to enhancement of Doppler spectrum
related to valvular stenosis, if needed. (COR I, LOE C-EO).
4. Manufacturers should provide users with information on the contrast-specificalgorithms available on their systems and how to readily access them. This should
include information on how to apply brief high-MI impulses (MI > 0.5) to clear
myocardial contrast and enhance endocardial border delineation with these pulse
sequence schemes. Table 4 displays the front-end location for VLMI imaging presetson the most recent versions of commercially available systems.

IV. CLINICAL APPLICATIONS
Since the 2008 ASE consensus statement,1 numerous publications
have reinforced existing applications or emphasized new applications
for ultrasound enhancement.16,18,23,26,27,39-68 This section will
provide an update on these specific clinical applications andrecommendations for their use.
IV.A. Update on Quantification of LV Volumes, LVEF, andRWM
According to the recent ASE/European Association of Cardiovascular
Imaging recommendations for LV chamber quantification, volumetricmeasurements should be based on tracings at the interface of the compacted myocardium and the LV cavity.69 However, trabeculations in
the apical region, as well as artifacts from adjacent lung tissue andnoise, can make it difficult to track this interface. After injection of ultrasound contrast agent, the opacified blood in the left ventricle fills thespaces among the LV trabeculations up to the compacted myocardium, allowing more accurate and reproducible tracings to be performed. All three contrast agents commercially available for LVO
have been extensively evaluated in large multicenter trials.2-4
LV Volumes. Defining normal values for LV size is important for prognosis in a spectrum of clinical diagnoses, including cardiomyopathy and248 Porter et al

Journal of the American Society of Echocardiography
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Figure 1 Differences in end-diastolic and end-systolic volumes observed in the same patient without contrast (top) and with UEAs
and low-MI imaging (bottom). Top row, left to right: Precontrast LV quantification of end-diastolic volume (306 mL) and end-systolicvolume (246 mL) for estimation of LVEF. Bottom row, left to right: Postcontrast LV quantification of end-diastolic volume (391 mL) andend-systolic volume (308 mL) for estimation of LVEF. A marked increase in volume size is noted after contrast.
valvular heart disease. Quantification of LV volumes is not a straightforward task and can depend on many factors, including populations studied
and imaging methods. Current ASE guidelines for cardiac chamber quantification provide recommended standards for reporting LVinternal diameters derived from the parasternal long-axis view, LV volumes by a biplane
method, and normalization to body surface area69; use of UEAs is advised
if this information cannot be readily obtained because of the poor qualityof endocardial visualization. LV internal dimension measurements may
underestimate the degree of LV enlargement compared with volume
determination by biplane contrast.70 Furthermore, unenhanced twodimensional (2D) echocardiography may underestimate LV volumes
because of foreshortening, exclusion of the portion of the left ventricle
within noncompacted trabecular surfaces, and inadequate visualizationof the endocardium. Use of UEAs may overcome these technical errors
by allowing the true longitudinal axis of the left ventricle to be measured,as well as enabling accurate tracing of endocardial borders by detection of
intratrabecular blood volume and clear delineation of the endocardial
border (Figure 1), resulting in a closer correlation with cardiac magnetic
resonance imaging (CMRI). LV volumes measured with unenhanced
echocardiography are also consistently smaller than those derived from
CMRI.40 In a recent multicenter study, end-diastolic volume measurements determined by enhanced echocardiography were significantly
larger than those without UEAs, irrespective of 2D or threedimensional (3D) echocardiographic techniques.40 However, there are
currently no established values for normal LV volumes in enhanced echocardiography, as enhanced studies in large populations without cardiac
disease or indications for contrast echocardiography are not feasible.
An early study examining baseline prechemotherapy echocardiogramson female patients with breast cancer classified 51% of contrast-

enhanced end-diastolic volume as abnormal, even though LV dimensions
were within the normal range by unenhanced 2D volume measurements.70 To account for this change in the normal range when using
UEAs for volume measurements, the authors proposed an enddiastolic volume upper limit cutoff of 83 mL/m2 for women and
98 mL/m2 for men.70 Using 62 SDs from the mean of enhanced volumes as normal also resulted in better agreement with CMRI than thatof noncontrast volumes. The Writing Group emphasizes the need forlarger prospective studies to define ranges for LV volumes observedwith UEAs and VLMI imaging.
Left Ventricular Ejection Fraction. The quantitative assessmentof LVEF becomes particularly important when patients are considered
for a defibrillator or cardiac resynchronization therapy, as well as in thefollow-up of cardiotoxicity from chemotherapeutic agents or the evaluation of patients with valve disease for intervention (e.g., aortic andmitral regurgitation). In these circumstances, reproducibility is of critical importance. Several studies have demonstrated that whencomparing unenhanced with enhanced cardiac ultrasound, and using
CMRI as the gold standard, the accuracy of determination of LVEF was
improved with UEA. Multicenter studies have confirmed that in comparison with unenhanced echocardiography, interobserver variability
was significantly reduced with UEAs, resulting in similar intraclass correlation coefficients as seen with CMRI.40,71 Although unenhanced
3D echocardiography has improved the reproducibility andreliability of serial ejection fraction measurements (as in the case ofcancer chemotherapy), the use of UEAs in this setting has notfurther improved test-retest variability.72 However, VLMI imaging
techniques have not been available for 3D acquisitions.

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Regional Wall Motion. Analysis of RWM is subject to significant
interobserver variability. Inherently, wall motion is a subjective assessment without a gold standard and is in part dependent on image quality, highlighting the importance of being able to accurately detect theendocardium throughout systole. It is also important to note that visual wall motion assessment relies on evaluation of wall thickening,
and thus both the endocardium and epicardium must be identified.
A multicenter study has demonstrated that interobserver agreementfor RWM was highest in patients who underwent enhanced echocardiography compared with unenhanced echocardiography and
CMRI.73 This same group of investigators found that UEAs significantly improved the agreement for RWM over nonenhanced echocardiography compared with CMRI.40 In this study, 3D-enhanced
echocardiography did not show any incremental value over 2Denhanced echocardiography in the detection of RWM abnormalities.
Similarly, the use of echocardiographic enhancement during stresshas been shown to improve visualization of LV segments, interpretation confidence, sensitivity, and specificity in technically challenging
and obese patients.58 Although the Writing Group does not recommend UEA use where the heart cannot be imaged because of chest
deformity or lung hyperexpansion, UEAs should be used for RWM
analysis whenever the appropriate views can be obtained but endocardial border delineation is inadequate for interpretation.

Porter et al 249

delineate the perfusion territory of each perforator (section G.ii).
Other clinical studies have been published that highlight these specificapplications and support broader guidelines for UEA use.
Intracardiac Thrombi. Intracardiac thrombi pose serious clinicalrisks, including systemic embolization with potential catastrophic consequences; likewise, treatment with antithrombotic agents can also
impose significant risk, and their use must be appropriately justified.
Therefore, accurate detection and diagnostic management of cardiac
thrombi is essential. Despite advances in other imaging modalities,
echocardiography remains the initial tool for diagnosis and risk stratification in patients predisposed to developing cardiac thrombi. The
use of UEAs facilitates LV thrombus detection by providing opacification within the cardiac chambers to demonstrate the ‘‘filling defect’’appearance of an intracardiac thrombus (Video 5; available atwww.onlinejase.com). Furthermore, perfusion echocardiography
can provide an assessment of the tissue characteristics of identified
LV masses by differentiating an avascular thrombus from a tumor, resulting in improved diagnostic performance of echocardiography.38
Although delayed enhancement CMRI has the highest sensitivity
and specificity for detection of LV thrombi, performance of echocardiography with a UEA is a more clinically feasible initial test. However,
CMRI should be considered when a UEA with VLMI fails to detect an
intracardiac thrombus but clinical suspicion persists.

Key Points and Recommendations
1. As per 2008 ASE guidelines, for routine resting echocardiographic studies, UEAs
should be used when two or more LV segments cannot be visualized adequately forthe assessment of LV function (LVEF and RWM assessment) and/or in settings inwhich the study indication requires accurate analysis of RWM. (COR I, LOE A).
2. A brief (5- to 10-frame) high-MI (0.8–1.2) ‘‘flash’’ impulse can be used with VLMI imaging to clear myocardium of contrast and improve endocardial border delineationfor volume and ejection fraction measurements (COR IIa, LOE C-EO).
3. Ultrasound enhancement should be used in all patients in whom quantitative assessment of LVEF is important to prognosis or management of the clinical condition.
VLMI and low-MI harmonic imaging techniques should be used to provide optimal
LVO (COR I, LOE B-R).
4. LV volumes obtained by enhanced echocardiography are typically larger than thosemeasured without UEAs, and therefore 2015 ASE chamber quantification guidelines
should be applied with caution when determining normal ranges. Although thenormal range for LVEF does not appear to be different, new reference ranges forend-diastolic and end-systolic LV volumes when using UEAs should be established.
5. As per section III of the 2014 ASE guidelines for sonographers,38 a continuous infusion or a low volume (#0.5 mL) bolus injection with slow (10–20 sec) saline flush
is recommended along with VLMI imaging to minimize apical microbubble destruction and basal segment attenuation.

IV.B. Update on Intracardiac Abnormalities
There are specific areas in which prior guideline documents have recommended UEAs for intracardiac abnormalities. The 2016 ASE
guidelines for the use of echocardiography in evaluation for a cardiac
source of embolism recommend the use of UEAs ‘‘to assist in borderdefinition and check for vascularization’’ of intracardiac thrombi or
masses and consider as ‘‘potentially useful’’ the application of UEAs
to aid in detection of left atrial and appendage thrombi (discussed
later) and differentiation of avascular thrombi from vascular tumors.74
The 2011 ASE clinical recommendations for multimodality cardiovascular imaging of patients with hypertrophic cardiomyopathy affirm
that transthoracic echocardiography (TTE) combined with the IV injection of a UEA should be performed in patients with hypertrophic
cardiomyopathy with suspected apical hypertrophy, to define theextent of hypertrophy and to diagnose associated potential complications of apical aneurysms and thrombi.75 This document also outlines
the specific protocol for septal perforator injections of diluted UEAs to

Intracardiac Masses. Two-dimensional echocardiography is usually the primary initial diagnostic imaging modality offering realtime, high spatial and temporal resolution evaluation of cardiac
masses. Although numerous echocardiographic criteria have beendeveloped to define cardiac masses, diagnostic errors and misclassifications can lead to unnecessary surgery or inappropriate anticoagulation.1 The judicious use of UEAs to characterize cardiac masses andintegrate all the information to establish etiologies may potentiallyavoid these diagnostic errors. Intracardiac masses can be a normal
variant of cardiac structure such as a false chord, accessory papillarymuscle, or heavy trabeculation or can be pathologic such as
thrombus, vegetation, or tumor. Any suspicious cardiac mass, when
not clearly evident on baseline images, can be confirmed or refuted
after injection of IV UEAs for better delineation of structures.76 Just
as with unenhanced echocardiography, off-axis images and longer
loop acquisitions may be required to identify and characterize intracardiac thrombi or masses.
Echocardiographic perfusion imaging using VLMI withintermittent-flash (high-MI) technique has been demonstrated tocharacterize vascularity of cardiac masses and assist with the differentiation of malignant, highly vascular tumors from benign tumors or
thrombi.76 This characterization is supported by the qualitative andquantitative differences between the levels of perfusion (enhancement) in various types of cardiac masses and comparison with adjacent myocardium. The qualitative approach includes the visualinspection of rate of contrast replenishment within the mass following
a high-MI impulse and descriptively categorized as lack of enhancement, partial or incomplete enhancement, or complete enhancement.77 Most malignancies have abnormal neovascularization that
supplies rapidly growing tumor cells, often in the form of highly
concentrated, dilated vessels.77 Thus, complete enhancement or hyperenhancement of the tumor (compared with the surrounding
myocardium) supports the existence of a highly vascular tumor,
which is most often malignant.77 Stromal tumors, such as myxomas,
have a poor blood supply and appear partially enhanced (Video 5,
Figure 2; available at www.onlinejase.com), while thrombi or papillary

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Figure 2 Modified apical four-chamber images of intracardiac masses in patients receiving continuous UEA infusion. All images wereobtained at plateau intensity before a high-MI impulse. The left panel exhibits no enhancement, consistent with thrombus. The middle
panel exhibits a small amount of enhancement (less than myocardial) and was a myxoma. The mass in the right ventricle in the rightpanel was hypervascular (similar to myocardial plateau enhancement) and was a metastatic renal cancer (see Video 5; available atwww.onlinejase.com).

Figure 3 Apical four-chamber end-systolic images of a patient with apical hypertrophic cardiomyopathy. Unenhanced images (left)
fail to delineate endocardial border, but VLMI images during a continuous infusion of a UEA (right) demonstrated apical hypertrophy in
October 2014. Over approximately 2 years, VLMI imaging detected the interval development of an apical aneurysm. The patient subsequently had an implantable defibrillator placed.
fibroelastoma are generally avascular and show no enhancement.78
The level of enhancement has been shown to correlate with the pathologic diagnosis or with resolution of the mass after anticoagulant

therapy.77 However, potential pitfalls exist that may contribute to
the appearance of partial enhancement of avascular structures in
the far field. Therefore, it is recommended that perfusion imaging

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Porter et al 251

Figure 4 Apical four- and two-chamber (A4C and A2C) views at end-diastole in a patient with unexplained cardiomyopathy. VLMI imaging
demonstrated LV cavity and myocardial opacification, but real-time B-mode harmonic imaging at a slightly higher MI (middle) resulted in
destruction of trabecular myocardial microbubbles and better delineation of the noncompacted layer (arrows). The noncompaction thickness in this intermediate-MI real-time harmonic imaging mode correlated closely with that seen at magnetic resonance imaging (right).
be done in views that allow near-field visualization of microbubble
replenishment following high-MI impulses. Several investigations
since the 2008 ASE contrast document1 have confirmed the differences in maximum acoustic intensity and mass-replenishing velocity
following high-MI impulses during VLMI for various pathologies.79,80
Apical Abnormalities in Patients with Hypertrophic
Cardiomyopathy. The apical variant is present in about 7% of patients with hypertrophic cardiomyopathy but may not be detected byroutine TTE, because of incomplete visualization of the apex. When apical hypertrophic cardiomyopathy is suspected but not clearly documented or excluded, contrast studies should be performed. If apical
hypertrophic cardiomyopathy is present, the characteristic spade-likeappearance of the LV cavity in diastole, with marked apical myocardialwall thickening, is clearly evident on enhanced images.1 Complications
associated with apical hypertrophy can also be readily visualized, such asapical aneurysm formation and thrombi (Figure 3, Video 6; available atwww.onlinejase.com). The presence of an apical aneurysm has recently
been associated with adverse outcomes, including arrhythmic eventsand thromboembolism.81 However, some pitfalls can be encountered,leading to false-negative echocardiographic findings, as is the case insmaller apical aneurysms, or if contrast-specific imaging machine settings are not optimized, as was reported in a recent study comparing
enhanced echocardiography with CMRI.82 Because VLMI imaging
permits better apical delineation, it is recommended that UEAs be
routinely used with VLMI imaging in evaluating patients with hypertrophic cardiomyopathy (Video 6; available at www.onlinejase.com).
Adjustment of the transmit focus to an apical position may reducescan line density and UEA destruction, further improving apical image
resolution.
Noncompaction Cardiomyopathy. Noncompaction of the
myocardium is an uncommon but increasingly recognized abnormality that can lead to heart failure, arrhythmias, cardioembolic events,
and death. It is due to alterations of myocardial structure with thickened, hypokinetic segments that consist of two layers: a thin, com-pacted subepicardial myocardium and a thicker, noncompacted
subendocardial myocardium. Enhanced echocardiographic studies
may be helpful in identifying the characteristic deep intertrabecular
recesses by showing microbubble-filled intracavitary blood between
prominent LV trabeculations when LV noncompaction is suspected
but inadequately seen by conventional 2D imaging (Figure 4). It
may be useful to use an MI that is somewhat higher than VLMI
(e.g., increase to 0.3–0.4) to better distinguish the myocardial trabeculations in the noncompacted myocardium from UEA presence within
the deep recesses.1,38 This higher MI at real-time frame rates destroys
the low-velocity microbubbles within the trabecular myocardium
before they can replenish, while the higher velocity intertrabecular
microbubbles in the LV cavity can replenish, permitting better delineation of the noncompacted layer (Figure 4).
Post–Myocardial Infarction Complications. LV aneurysm, anoften asymptomatic complication of a prior myocardial infarction,
is a common apical LV abnormality. True aneurysms are characterized by thin walls and a dilated apex, which may be akinetic ordyskinetic and involve the full thickness of the ventricular wall.
These findings are usually seen easily on unenhanced echocardiographic imaging. However, if the apex is not completely visualized,
an apical aneurysm may go undetected until a UEA is used. LV
pseudoaneurysm, free wall rupture, and post–myocardial infarction
ventricular septal defects pose life-threatening risks to patients andcan usually be detected by unenhanced echocardiography.
However, patients may have suboptimal studies because of anatomy
or position, or both, and clinical conditions (e.g., being supine andintubated in the critical care unit) that limit the attainment of an
optimal view of the apex. UEAs may be essential in establishingthe diagnosis, as well as detecting further associated complications,such as LV thrombus.1
Right Ventricular Assessment. Although agitated-salineenhancing agents can be used to visualize abnormalities in the rightsided chambers, the contrast effect is of short duration. When

252 Porter et al

persistent enhancement of the right ventricular endocardial borders isnecessary, commercially available UEAs have been used to show
various abnormalities of right ventricular morphology, including focal
RWM abnormalities, tumors, and thrombi. The UEAs can also be used
to distinguish these abnormalities from normal structures, such as
prominent trabeculations or the moderator band.1 In this setting, parasternal views, or a modified apical four-chamber window of rightventricle, may be optimal to place the right ventricle into the nearfield.
Atria and Left Atrial Appendage. UEAs have also been used toshow anatomic features of the atria, especially the left atrial
appendage, more clearly and can be useful in differentiating thrombi
from artifacts, dense spontaneous echocardiographic contrast, or
normal anatomic structures.83 Differentiation of artifacts fromthrombus is especially important in the setting of precardioversion
transesophageal echocardiography (TEE). A prospective study of
100 patients undergoing precardioversion TEE demonstrated that
UEAs provided improved identification of left atrial appendage filling
defects and differentiation from artifacts, resulting in an increased
level of confidence for thrombus exclusion before cardioversion.83
Moreover, in another prospective case-control comparison study of
180 patients in atrial fibrillation undergoing cardioversion, no embolic
events occurred in the group that was imaged with UEAs during precardioversion TEE, while three events occurred in a control group.
The authors concluded that in patients with atrial fibrillation plannedfor cardioversion, contrast enhancement renders transesophageal
echocardiographic images more interpretable, facilitates the exclusionof atrial thrombi, and may reduce the rate of embolic adverse
events.84 Specific MI settings were not provided in these studies,but it is likely that at frequencies used in TEE, an MI < 0.5 and harmonic mode will be optimal for UEA delineation.

Key Points and Recommendations for the Use of
UEAs in Detecting LV Cavity Abnormalities andIntracardiac Masses
1. Ultrasound enhancement should be used in patients in whom LV thrombus cannot
be ruled in or out with noncontrast echocardiography (COR I, LOE B-NR).
2. Ultrasound enhancement should be considered in patients in whom structural abnormalities of the left ventricle (noncompaction cardiomyopathy, apical hypertrophy
and aneurysms) cannot be adequately assessed with noncontrast echocardiography(COR IIa, LOE B-NR).
3. Ultrasound enhancement should be used for ruling in or out an LV pseudoaneurysm(COR I, LOE B-NR).
4. Ultrasound enhancement with VLMI imaging should be used in the differential diagnosis of cardiac masses by assessing the vascularity of the mass (COR IIa, LOE B-NR).
5. Ultrasound enhancement should be considered during TEE whenever the atrial
appendage has significant spontaneous contrast or cannot be adequately visualizedwith unenhanced imaging (COR IIa, LOE B-NR).

IV.C. Stress Echocardiography
Left Ventricular Opacification. LVO with low-MI harmonic imaging has been demonstrated to be integral in the achievement of
more accurate and efficient stress echocardiographic testing.85 The
use of UEAs during both exercise and dobutamine stress echocardiography (DSE) improves sensitivity, specificity, and diagnostic accuracy to a greater extent in patients with suboptimal versus optimal
imaging windows.1 This improvement in accuracy has been attributed to the ability to visualize all regional wall segments, making it

Journal of the American Society of Echocardiography
March 2018equivalent to the accuracy of optimal unenhanced studies in which
all segments can be visualized.16 In 839 consecutive patients undergoing stress echocardiography, the addition of UEAs with VLMI imaging during stress echocardiography improved endocardial borderdetection at rest and peak stress, yielding 99.3% efficacy in achieving
diagnostic study quality,86 thereby improving reproducibility andreader confidence in interpretation. This has translated into a significant impact on accuracy, especially when the unenhanced image
confidence was low or there were more than two segments notwell visualized without contrast.85
Decision algorithms in which contrast imaging enhancement isused when two or more segments are not adequately visualized,
beginning at rest and repeated at peak stress, produce a cost savings
with abnormal testing predicting mortality and adverse events.
Compared with exercise electrocardiography (ECG) and nuclear
testing, UEA use results in fewer downstream tests, which correlateswith significantly lower costs.68
Although the VLMI multipulse sequence schemes were available
on most manufacturing systems as detailed in the 2008 ASE
consensus statement,1 only recently have manufacturers begun using
them for LVO. The VLMI techniques were initially designed for MP
assessment, but their sensitivity for microbubble detection and complete apical cavity opacification without swirling artifact has improved
stress LVO imaging. Both multicenter and prospective single-centerstudies have demonstrated the effectiveness of VLMI imaging todetect RWM abnormalities.16,45,66 In addition to enhanced
sensitivity and apical delineation, the VLMI techniques detect
subendocardial wall thickening abnormalities that may otherwise go
undetected if one were examining transmural wall thickening during
demand stress.42,66 The combination of LVO and subepicardial
layer enhancement during replenishment following high-MI impulses
helps delineate the subendocardium and analysis of wall thickening
just at this location (Figure 5, Video 7; available at www.onlinejase.
com). The integration of UEAs with VLMI imaging for the evaluationof wall thickening and ischemia into the routine evaluation of patientswith left bundle branch block during DSE has been shown to improvethe detection of CAD and independently predict mortality and cardiovascular events.67
On the basis of these studies, it is apparent that UEAs improve thediagnostic accuracy of RWM analysis at rest and during stress imaging. VLMI imaging appears to be optimal for RWM analysis, in thatthe added perfusion data assist in the differentiation of subtle wall
thickening abnormalities due to subendocardial ischemia. This appears to be helpful in all coronary artery territories and may be especially helpful in segments that are frequently difficult to visualize(Figure 6, Videos 4 and 7; available at www.onlinejase.com).
Because disease in a coronary artery territory may affect only one
segment in any particular apical or parasternal view, the Writing
Group recommends that UEAs be used for LVO whenever any
segment cannot be adequately visualized.
Perfusion Imaging during Inotropic or Exercise Stress. MP
imaging has been used in a variety of circumstances for the assessmentof myocardial ischemia and viability. VLMI imaging with IV infusions or
small bolus injections of UEAs has been used to examine myocardial
blood flow and volume at frame rates of 20 to 30 Hz. This has beentermed real-time MCE (RTMCE). Brief high-MI impulses are administered to clear myocardial contrast, following which replenishment isanalyzed on the end-systolic images (Videos 8 and 9; available atwww.onlinejase.com). This technique has been performed clinicallyJournal of the American Society of Echocardiography
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Porter et al 253

Figure 5 Subendocardial perfusion defect and subendocardial wall thickening abnormality (arrows) that is not seen when contrast was
opacifying only the LV cavity and not the subepicardium (left). During myocardial contrast replenishment, the subendocardial perfusion
defect (arrows) delineates the subendocardial wall thickening abnormality (see Video 7; available at www.onlinejase.com).

Figure 6 End-diastolic (ED; left), and end-systolic (ES; right) in the apical two-chamber view, demonstrating how only VLMI imaging
with UEAs can completely delineate a basal to mid inferior wall thickening abnormality. Because VLMI imaging is done with power
modulation, fundamental nonlinear responses are detected, resulting in less basal segment attenuation compared with low-MI imaging (middle) which are attenuated because they are harmonic frequency signals. See Video 4, available at www.onlinejase.com.
in thousands of patients during dobutamine stress or with treadmill orbicycle exercise.16,42,45,46,49,57,65,66
In the setting of DSE, perfusion analysis has improved CAD detection compared with wall motion analysis alone. The improvement appears to be related to the ischemic cascade, in which perfusion
abnormalities have been shown to occur before wall motion abnormalities during demand ischemia.34 As discussed in the previous

section, another factor leading to improved sensitivity with VLMI imaging is the detection of subendocardial wall thickening abnormalities
when using perfusion enhancement (Figure 5). This has been evident
primarily in DSE,42,45,66 where transmural wall thickening may
appear normal despite the existence of a subendocardial wall
thickening abnormality unmasked by the subendocardial perfusion
defect (Video 7; available at www.onlinejase.com).

254 Porter et al

The 20- to 30-Hz frame rates with VLMI imaging have permitted sonographers and physicians trained in basic echocardiography to adapt tothis technique, whether they are using UEAs to enhance RWM analysis,
assess global systolic function, or analyze perfusion. The higher spatial
resolution of perfusion echocardiography, compared with radionuclide
imaging or positron emission tomography, has permitted improved
detection of ischemia at rest and during stress. It may also be useful inpatient populations with resting nonischemic wall motion abnormalities
such as ventricular paced rhythms or left bundle branch block.48 Adding
perfusion information to RWM analysis has resulted in better defining
the extent of CAD that exists34 and is better than RWM analysis alone
in identifying those at risk for subsequent cardiac events.45
Perfusion abnormalities during demand stress have been correlatedwith fractional flow reserve measurements using invasive hemodynamics in patients with intermediate angiographic stenosis between
50% and 80% in diameter.65 Here the correlations are not good andreflect differences in what the two techniques are measuring.
Fractional flow reserve is determined by measuring a pressure gradientacross a given stenosis during hyperemic stress in the catheterization laboratory and does not take into account the impact of capillary resistance,
which has been shown to be the major regulator of coronary blood flow
during stress.87 Because RTMCE measures capillary blood velocity andblood volume, stress-induced abnormalities may exist before detectionof significant hyperemic pressure changes across a stenosis in the 50%
to 80% range. These differences appear to be clinically relevant,65 andfurther investigation into their prognostic significance is needed.
Since the publication of the 2008 ASE contrast document,1 the incremental value of MP imaging over wall motion analysis alone in predicting patient outcomes has been demonstrated with bicycle
exercise echocardiography,46 treadmill exercise echocardiography,45
and DSE.16,45 This includes RCTs comparing conventional stressechocardiography (in which UEAs were used only for the current
FDA-approved indication) with RTMCE. In each of these settings, delayed replenishment of contrast during a continuous infusion of microbubbles was seen in a significant percentage of patients in theabsence of RWM abnormalities and appeared to be independently
predictive of subsequent death and nonfatal myocardial infarction.
Perfusion Imaging during Vasodilator Stress. Since the publication of the last 2008 ASE consensus statement regarding the use of
UEAs in the context of echocardiography,1 many pertinent studies
have reported on feasibility, safety, diagnostic and prognostic accuracyof RTMCE in the assessment of MP imaging, specifically during vasodilator stress echocardiography, strengthening the evidence toward theuse of such vasodilator stress modality in conjunction with
RTMCE.27,39,41,43,47,48,50-53,55,56,64 Vasodilator stress perfusion
imaging appears to provide equivalent information for detection of
CAD compared with inotropic stress, with advantages of rapid
performance and possibly better image quality due to the lower heart
rate (often not exceeding 100 beats/min) and less translational cardiac
movement (Figure 7). However, conventional detection of stressinduced RWM abnormalities may in some cases be less sensitive
because the mode of stress does not depend on myocardial oxygen demand. Several vasodilators have been used in studies with RTMCE,
namely, adenosine,16,43,47,50,51 dipyridamole,26,27,41,43,48,52,53,55 and,more recently, regadenoson.54,64 Adenosine and dipyridamole are
the most commonly used vasodilators for perfusion imaging. Bothagents act nonselectively directly or indirectly to activate all four
adenosine receptor subtypes (A1, A2A, A2B, and A3). This can resultin chest pain, mild dyspnea, hypotension, bronchospasm, and, rarely,
reversible atrioventricular nodal block. Regadenoson is a potent

Journal of the American Society of Echocardiography
March 2018selective A2A agonist, administered as a 400-mg IV bolus, with rapid
onset of action (within 30 sec) and adequate duration of action toallow sufficient time for image acquisition (up to 4 min) with lesssevere side effects, and it may evolve to be one of the vasodilators ofchoice for perfusion imaging (Figure 8). Information from perfusion
data is equivalent for all these vasodilators, and therefore the choicefor each can be tailored on the basis of local availability, cost, side effects,
and perceived practical advantages or disadvantages.
Some vasodilator stressors can be used at different dosages, depending on whether only perfusion or also wall motion stress information is desired. For example, dipyridamole may be administeredover 4 min to a total dose of 0.56 mg/kg to achieve perfusion assessment, while a longer infusion and a higher dose are required to accurately detect RWM abnormalities with this technique.
Large multicenter trials comparing RTMCE with single-photon emission computed tomography (SPECT) using the above pure vasodilatory
dose of dipyridamole for the detection of CAD have been performed.27,41 The first such trial showed equivalent sensitivity andspecificity for the detection of CAD, but in the latter trial, which waslarger with all images read blindly at other centers, and when using
coronary angiography as a reference standard, the sensitivity of MCE
was superior to that of SPECT. The basis of superior sensitivity
appears to be that (1) MCE has better spatial resolution comparedwith SPECT,48 and (2) vasodilator SPECT assesses only capillary blood
volume, while MCE detects both capillary blood volume and capillary
velocity,88 the latter being a more sensitive marker of CAD.
Preliminary retrospective studies examining the prognostic power ofvasodilator stress RTMCE have demonstrated enhanced predictive
value compared with SPECT.39 For simultaneous evaluation of perfusion and function during vasodilator stress, a high dose of vasodilator(0.84 mg/kg over a 6-min infusion) is required. High-dose dipyridamole(with or without atropine coadministration) for RWM assessment forthe diagnosis and prognosis of CAD has been well established on the basis of more than two decades of published studies, encompassing several
thousands of patients (mostly European studies). Thus, when using
RTMCE for simultaneous assessment of perfusion and function, experience with high-dose dipyridamole predominates. In this setting, it has
consistently been shown that perfusion analysis improves overall accuracy for CAD detection compared with RWM analysis alone, with aneven greater diagnostic benefit for the detection of angiographically intermediate (50%–70%) stenosis. The accuracy benefit is due mainly to
an increase in sensitivity. Similar to demand stress, the improved sensitivity appears to be related to the ischemic cascade.6 Furthermore, in specific patient populations with resting nonischemic wall motion
abnormalities, such as left bundle branch block,48 RTMCE has permitted
improved detection of ischemia compared with radionuclide imaging
and thus may be particularly useful in this setting, as well as in paced
rhythm. Adenosine and regadenoson are both very potent vasodilators,
and their accuracy in the induction of ischemia-related RWM abnormalities for the detection of CAD appears to be similar.47,54
From a prognosis standpoint, single-center studies have clearly
demonstrated the incremental value of dipyridamole55,67,71 and, in
one study, adenosine89 MP imaging over RWM analysis alone in
the prediction of combined cardiac end points. In one study following>1,000 contemporary patients for >2 years, hard cardiac events(death or myocardial infarction) could also be better predicted thanwith RWM assessment alone.55,67 In each of these settings, delayed
replenishment of contrast during slow bolus or continuous infusionof UEAs was seen in a significant percentage of patients in theabsence of RWM abnormalities and appeared to have independent
prognostic value for prediction of subsequent death and nonfatal

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Figure 7 Demonstration of inducible anterolateral and apical perfusion defects (arrows) during dipyridamole stress RTMCE (bottom
middle). The top row panels demonstrate the delay in replenishment in these segments following the high-MI flash impulse (top second). The corresponding angiogram (bottom left and right) demonstrates angiographic lesions in the left anterior descending and left
circumflex coronary artery territories (arrows). See Video 10, available at www.onlinejase.com.

Figure 8 Demonstration of an inducible basal to mid inferior subendocardial perfusion defect at 0 to 2 and 2 to 4 min (arrows)
following a 400-mg regadenoson bolus. REG, Imaging within 2 minutes of regadenoson bolus; REG1, imaging at 2-4 minutes after
regadenoson bolus; REG2, imaging at 4-6 minutes after regadenoson bolus.
myocardial infarction. Five-year follow-up data in >1,300 patients
following high-dose dipyridamole perfusion stress echocardiography
have demonstrated that incremental prognostic information is obtained when combining MP with RWM analysis.90
When using vasodilator stress, the use of high-MI flash-replenishment technique is essential and likely more important than during demand stress, when perfusion defects may more easily become

apparent even when not taking advantage of such flashreplenishment technique, because of significantly increased oxygen
consumption. RTMCE using vasodilator stress has been evaluatedwith quantitative techniques, allowing the determination of myocardial blood flow and its stress/rest ratio (blood flow reserve) and has
been found comparable with alternative techniques, although there
is some controversy regarding the feasibility of this technique.43,44,51

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Figure 9 Illustration of myocardial contrast echocardiographic perfusion imaging sequence. The first image after the destructive
pulse series illustrates complete elimination of contrast signal from the myocardium. Subsequent end-systolic frames (tn) demonstrate progressive increase in myocardial intensity due to replenishment of microbubbles into the myocardial microcirculation.
The graph illustrates the kinetic modeling used to derive the red blood cell flux rate (FluxRBC) from the rate constant and the MBV
from the plateau intensity (A). Post-Destr, End systolic image immediately after a high mechanical index impulse.
Visual qualitative analysis is more readily learned and less labor
intensive (Figures 7 and 8, Video 10; available at www.onlinejase.
com). The following rule of thumb permits interpretation: resting
replenishment with a 2D echocardiographic transducer should bewithin 5 sec following a high-MI flash impulse and within 2 sec during
stress (Videos 6 and 7; available at www.onlinejase.com).
Perfusion Quantification. When performing myocardial contrast
echocardiographic perfusion imaging, there are situations in which
the presence of perfusion in a binary ‘‘yes or no’’ fashion is sufficient,
as when assessing the efficacy of reperfusion therapy for myocardial
infarction or when evaluating the presence of myocardial viability.
For these applications, one needs only to spatially evaluate the presence or absence of an intact microvasculature.91,92 Quantitative
assessments of myocardial blood flow and blood volume with MCE
have been performed with bolus injections and continuous
infusions of UEAs. Techniques for measuring the first pass ofcontrast agents after rapid bolus injection are used with other forms
of noninvasive imaging and have been applied to MCE.93
However, this approach is not recommended for MCE, because it
is not possible to (1) image the entire heart during the first pass ofcontrast or (2) adequately account for bolus spreading during
venous-to-systemic transit. Accordingly, perfusion imaging approaches have been developed specifically for MCE that are basedon measuring the two main parametric elements of perfusion: (1)the number of microvascular units actively perfused at any time
(microvascular blood volume [MBV]) and (2) the flux rate of blood
through these microvascular units.94 The measurement of these parameters relies on the unique ability to influence microbubble
contrast integrity with ultrasound energy.94,95 High-MI impulsesthat are >0.8 destroy microbubbles within the microcirculation,
thereby eliminating their signal enhancement. The localized timeintensity analysis of microvascular reentry of microbubbles can beused to assess the rate and extent of microbubble signal replenishment, reflecting microvascular flux rate and MBV, respectively(Figure 9). It is recommended that this procedure be performed using(1) continuous infusions of microbubbles to allow a stable steady-state
concentration of microbubbles in the blood pool, (2) only a few highpower ‘‘flash’’ frames (to avoid influencing blood pool concentration),and (3) only end-systolic frames for analysis (to eliminate signal fromlarge intramyocardial vessels).96,97 It is recognized by the Writing
Group that small bolus injections of UEAs with slow saline flushes
also can create a period of time following each injection during
which steady state kinetics apply and have been effectively used inclinical studies to examine signal replenishment and MBV.53,55
Background-subtracted intensity data can be fit to an exponential
equation: y = A(1e bt), where y is the video intensity at any
time t after the ‘‘flash’’ impulse, A is the plateau signal intensity

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Figure 10 An example of a distal septal, apical, and distal lateral perfusion defect detected at end-systole, which is primarily evident
during the replenishment phase following the high-MI flash impulse. (A) Immediate post-high MI impulse. (B,C) Early and late replenishment phases. At plateau intensity (D) at 5 sec following the high-MI flash impulse, the defect is no longer apparent. The basal
anterolateral segment is most likely exhibiting attenuation.
reflecting relative MBV, and the rate constant b (sec 1) reflects theflux rate of microbubbles through the microcirculation.94 The product of blood volume and blood velocity (A  b) provides a semiquantitative index of myocardial blood flow, whereas absolute blood flow
can be derived by normalizing the A value to the blood pool signal toderive absolute MBV.
Quantitative analysis of blood flow or flow reserve has been validated against positron emission tomography, quantitative coronary
angiography, Doppler flow wire, and SPECT.51,98-100 It is generally
recognized that the b value has better discriminatory value fordetecting ischemia than the A value because of greater likelihood
for artifacts when measuring A value (e.g., attenuation) and earlier
perturbation of b in the course of disease (Figure 10).101 Full quantitative assessment of MP with parametric mathematical analysis
described above generally involves drawing large regions of interest
that are based on either major coronary artery perfusion territories
or recommended myocardial segmentation models. An important
limitation is that a small area of severe ischemia within a segment
may result in identical quantitative data as a larger region of moremodest ischemia. Accordingly, it is recommended that quantitative
data be accompanied by a qualitative assessment of the spatial extent
of perfusion abnormalities, in terms of both the number of segments
involved and the transmural versus subendocardial localization offlow abnormality.
Studies that have used quantitative or semiquantitative stress-rest
MCE for the detection of CAD have demonstrated good diagnostic
performance compared with angiography or other noninvasive stressimaging,100-102 with a meta-analysis demonstrating sensitivity andspecificity both in excess of 80%.43 For patients with heart failure
with reduced LVEF, quantitative MCE has been shown to be able
to differentiate ischemic from nonischemic etiology.103 Quantitative
MCE also provides prognostic information in patients with ischemic
heart disease with known or suspected CAD and normal LV functionthat is superior to that of qualitative perfusion analysis89 and has beenused for the evaluation of microvascular dysfunction in nonischemic
and hypertensive cardiomyopathy, stress cardiomyopathy, and in patients with chest pain and positive stress testing but no obstructive
CAD on coronary angiography.62,104-106
For the detection of CAD, a plateau intensity ratio (stress/rest) has
not been useful for disease detection, but a b ratio or A  b ratio $ 2
appeared to have consistent predictive value in differentiating normal
from abnormal myocardial blood flow reserve.43 It is unknown
whether this has predictive value in detecting microvascular abnormalities that are not due to epicardial CAD.

Key Points and Recommendations for Stress Echocardiographic Imaging with UEAs
1. UEAs should be used whenever adequate segmental visualization within any coronary artery territory cannot be achieved with resting unenhanced echocardiography(COR I, LOE A).
2. VLMI imaging is the preferred imaging mode and should be used with intermittent
flash high-MI impulses (five to 15 frames at an MI of 0.8–1.0) to achieve homogeneous LVO and analysis of RWM (COR IIa, LOE B-R).
3. Continuous 3 to 5 mL/min infusions of dilute UEAs (3%–5% for Definity, 10% for Optison) or small bolus injections (0.1–0.2 mL for Definity, 0.3–0.5 mL for Lumason or
Optison) with slow 5- to 10-mL saline flushes over 10 sec should be used to reduce
acoustic shadowing and permit steady-state concentrations of microbubbles during
image acquisition (COR I, LOE EO).

Recommendations 4 to 7 pertain to those individuals
who have received recommended training in perfusion imaging techniques with UEAs
4. Although perfusion imaging with UEAs is off label, the detection of myocardialischemia and viability can be enhanced when used in the correct setting by trained
personnel.
5. If performing MP imaging, VLMI perfusion imaging should be used during demandstress using real-time high-MI flash replenishment technique for simultaneous perfusion and wall motion assessment (COR IIa, LOE B-R).
6. Perfusion analysis combined with RWM analysis using RTMCE should be consideredduring DSE to maximize the sensitivity and accuracy of the study for the detection of
CAD and prediction of clinical outcome (COR IIa, LOE B-R).
7. Standard (0.56 mg/kg) or high-dose (0.84 mg/kg dipyridamole) vasodilator stress
RTMCE should assess both MP and RWM to maximize sensitivity for the detectionof CAD (COR IIa, LOE B-NR).
8. Adenosine and regadenoson stress should be performed with RTMCE to analyze both
RWM and MP to maximize test sensitivity and specificity (COR IIa, LOE B-NR).
9. When homogeneous myocardial contrast is observed following an IV infusion or
small, repetitive bolus doses of IV UEA, a flash high-MI impulse should be designed
and adjusted to clear myocardium of contrast signals without excessive cavity microbubble destruction. The high-MI impulse should be 0.8 to 1.2. The number of flash
frames should be adjusted to clear myocardial contrast while minimizing cavity
destruction.
10. The replenishment for a 2D imaging plane should be uniform and within 5 sec underresting conditions and within 2 sec in a constant imaging plane during any form ofstress imaging. Figure 11 demonstrates normal resting and demand stress replenishment following high-MI impulses. Figures 12 and 13 are examples of inducible MP
defects in different coronary artery territories during dobutamine stress.
11. Quantitative MCE appears to have additional value over visual analysis in detecting
myocardial blood flow abnormalities due to significant CAD but requires dedicatedsoftware capable of analyzing myocardial replenishment kinetics at end-systole
following brief high-MI impulses. It is not recommended for clinical application until
usable and readily available software is available on commercially available systems.
The Writing Group recommends that all vendors develop quantitative software on
their systems for analyzing replenishment rates and plateau intensities following
high-MI impulses within any chosen region of interest.

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Figure 11 An example of stress end-systolic perfusion assessment during dobutamine stress RTMCE. Note that visual replenishment at end-systole occurs within 2 sec, which in this case is the third cardiac cycle after the high-MI impulse. Note a small subsegmental amount of basal inferior and basal anterior attenuation.

Figure 12 An example of a stress-induced perfusion defect in the left circumflex coronary artery territory (arrows). Note that endsystolic replenishment within the basal to mid inferolateral segments in the apical long-axis window is normal under resting conditions
but delayed (arrows) during dobutamine stress imaging.

Figure 13 An example of a stress-induced perfusion defect in the left anterior descending coronary artery (LAD) territory (arrows).
Note that end-systolic replenishment within the LAD territory in the apical four-chamber window is normal under resting conditions
but delayed in the LAD territory (arrows) during dobutamine stress imaging.
IV.D. Vascular Imaging: Carotid, Femoral, Aortic, andEndografts
The use of UEAs for vascular imaging continues to grow rapidly (Table 5),
including imaging of the carotid arteries, peripheral arteries, aorta, vasculargrafts, and endovascular grafts.107,108 Similar to cardiac applications,microbubbles can act as blood pool–enhancing agents to allow better
visualization of vascular structure and flow (by B-mode grayscale
imaging and color and spectral Doppler techniques), as well as
perfusion in the context of imaging the vasa vasorum, atherosclerotic
plaque neovascularization, and peripheral muscle perfusion.

Carotid Artery. In the majority of cases, UEAs are not required forstandard ultrasound imaging of the carotid artery to determine stenosis severity. However, when ultrasound imaging is suboptimal,
contrast opacification of the carotid artery lumen may be useful tobetter delineate plaques and ulcerations and help determine lesion
severity. Specifically, UEAs are useful in select cases to differentiate
a severely stenotic lesion from complete carotid occlusion(Video 11; available at www.onlinejase.com), thus affecting patientmanagement.109,110 Data continue to emerge on the utility of
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Table 5 Current and emerging vascular applications
Carotid artery

Luminal opacification to better delineate plaque characteristics, including ulceration and luminal patency(absence of complete occlusion)Femoral artery

Identification of flow into femoral artery pseudoaneurysms and guidance of percutaneous thrombin occlusion

Evaluation of the vasa vasorum and carotid plaque neovascularization (emerging)
PAD

Quantification of skeletal muscle perfusion and flow reserve in patients with PAD (emerging)

Aortic pathology and grafts

Identification of intimal flap in cases of suspected aortic dissection, and delineation of true and false
lumen; identification of graft leaks/pseudoaneurysms

Aortic endovascular grafts

Detection of endoleaks after endovascular aortic repair (emerging)

neovascularization (Figure 14, Video 12; available at www.onlinejase.
com), which may reflect plaque instability and vulnerability.111
Although studies have shown good correlations between contrast
signal intensity within plaque and subsequent histologic examination,112,113 robust prospective studies evaluating the prognostic
implications of plaque neovascularization by contrast ultrasound areneeded before more routine use can be recommended.
Femoral Artery and Peripheral Arterial Disease. UEA use has
been limited in femoral arteries and peripheral arterial disease (PAD).
Ultrasound enhancement has been shown to be useful in cases of iatrogenic femoral artery pseudoaneurysm to delineate flow and guidepercutaneous thrombin occlusion.114 Similar to MP imaging by
MCE, UEAs can also be used to assess skeletal muscle perfusionand flow reserve in the setting of chronic PAD.115 Given the paucityof techniques to assess tissue perfusion in PAD, enhanced ultrasoundis poised to become the mainstay technique to assess limb perfusionin patients.
Aortic Pathology and Grafts. Endovascular technology has progressed over the past two decades, with equivalent outcomes fromendovascular aortic repair compared with open repair for many patients who require an intervention for an abdominal aortic aneurysm.
Post–endovascular aortic repair surveillance includes monitoring forendoleaks, the most common complication of this procedure.
Endoleaks can result in high pressure within the aneurysm sac, potentially leading to expansion and rupture. Although computed tomography (CT) remains the gold standard for endoleak detection,
Doppler ultrasound has advantages, including lack of nephrotoxic
contrast agents and ionizing radiation,116 as well as the potential tononinvasively monitor in real time interventional radiologic therapeutic procedures to treat the endoleaks. UEAs are now emerging as a
viable alternative to CT, whereby microbubbles detected within theresidual aneurysm sac during contrast administration are indicativeof an endoleak (Figure 15, Video 13; available at www.onlinejase.
com). Studies have demonstrated high sensitivity and specificity forthe detection of endoleaks, with contrast-enhanced ultrasound performing comparably with CT for the detection and classification of
endoleaks.116-118
Although CT and TEE are the most common diagnostic modalities
to detect type A aortic dissection, contrast enhancement of the aorta
can aid in distinguishing a true intimal flap from linear artifact on both
TTE and TEE. In patients with aortic dissection, contrast enhancement
can also help delineate the true and false lumens (Video 14; availableat www.onlinejase.com). The initial bolus of contrast needs to be
imaged during the first pass to delineate the differential flow in thetrue and false lumens, with avoidance of attenuation from too large
or too rapid an IV injection of contrast.

Key Points and Recommendations for UEA Use in
Vascular Applications
1. Although the use of UEAs is off label for this purpose, there are numerous recent anddeveloping vascular applications.
2. UEAs are recommended with low-MI ultrasound imaging of endovascular grafts todetect and classify any suspected endoleak (COR IIa, LOE B-NR).
3. Contrast ultrasound with VLMI imaging has the capability of assessing carotid arterystenosis severity and presence of plaque vascularity. Prospective studies are needed todetermine the predictive value of these imaging techniques.
4. Contrast ultrasound has been used to assess limb skeletal muscle blood flow reserve inpatients with diabetes and chronic PAD. Further studies are needed to determine thepredictive value of this technique compared with ankle-brachial indices and CT of theperipheral vasculature.

IV.E. Contrast Echocardiography in Critical andEmergency Settings
Critical Care Settings. As detailed below, the FDA in the UnitedStates imposed a black-box warning and multiple disease-state contraindications to UEA administration in 2007, contemporaneouswith the publication of the ASE consensus statement on the clinicalapplications of ultrasonic contrast agents in echocardiography.1
These disease-state contraindications (acute myocardial infarctionor acute coronary syndromes, worsening or decompensated heart
failure, serious ventricular arrhythmias, or patients at high risk for arrhythmias on the basis of QT-interval prolongation, as well as respiratory failure, severe emphysema, pulmonary emboli, or otherconditions that may cause pulmonary hypertension) essentially precluded contrast echocardiography in the vast majority of intensive
care unit (ICU) patients. In one study of >58,000 hospitalized patients undergoing contrast echocardiography, 67% carried one ormore of these diagnoses.11 Although these disease-state contraindications were subsequently rescinded by the FDA, current prescribing
information for each of the commercially available ultrasoundcontrast agents warns that the risk for serious cardiopulmonary reactions may be increased in patients with these diagnoses.1-3 However,
echocardiography is frequently technically difficult in ICU patients
given patient-related factors including mechanical ventilation,wound dressings, and difficulty in patient positioning, underscoring
the particular need for UEAs in this patient population. Althoughprevious studies documented that UEAs improve image quality in
ICU patients with baseline technically difficult studies, outcomesdata were lacking in this patient population when the 2008
consensus statement1 was published.
Following the FDA black-box warning in 2007, two echocardiographic outcomes studies were designed in collaboration between
the FDA and UEA manufacturers. In the first of these, 2,900

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Figure 14 An example of carotid B-mode ultrasound images and contrast-enhanced low-MI harmonic images side by side in a patient with calcific carotid plaque (large arrow) (A) and minimal plaque neovascularization (thin white arrows). The second patient (B)has more extensive adventitial plaque neovascularization extending into the intima (white arrows). See Video 12, available at www.
onlinejase.com.
ference, it is possible that earlier and more accurate diagnostic testingin these critically ill patients resulted in earlier provision of lifesaving
medical therapy.
Data from a study by Kurt et al.26 support this contention. A
consecutive cohort of 632 patients with technically difficult echocardiographic examinations also underwent second examinations with
UEAs. UEA use reduced the technically difficult study rate from
86.7% to 9.8% and resulted in conversion to a diagnostic-quality
echocardiogram in virtually all of the studied patients. This resulted
in a significant management change (avoidance of downstream diagnostic testing, an important medication change, or both) in 35.6% of
patients. This effect was largest in patients in the surgical ICU(n = 102), in which UEA use resulted in significant managementchanges in 63% of patients. Although the benefits of UEAs in the critical care studies were primarily in improving regional and global LV
systolic function analysis, additional information that can be obtainedin patients with difficult windows include enhanced Doppler signals
across valves for pressure gradient estimations and detection andcharacterization of any intracardiac masses.1,38
Figure 15 Short-axis view of the iliac bifurcation (white arrows)
in a 74-year-old man status post aortic stent grafting for an
abdominal aortic aneurysm. Ultrasound contrast agent–enhanced images demonstrate a type 2 endoleak (yellow arrow)located inferiorly and posteriorly at the graft bifurcation. The
remainder of the aneurysm sac appears filled with organizedthrombus. See Video 14, available at www.onlinejase.com.

critically ill patients who underwent TTE with Optison were
propensity-matched with 11,600 patients undergoing unenhanced
echocardiography.18 There was no difference in short-term mortality
between the two groups (odds ratio [OR], 1.18; 95% CI, 0.82–1.71;
P = .37). In a second, larger study, 16,217 critically ill patients who underwent contrast echocardiography with Definity were propensitymatched with 16,217 patients undergoing unenhanced echocardiography.23 At 48 hours, mortality was significantly lower in the contrast
echocardiography arm (1.7% vs 2.5%; OR, 0.66; 95% CI, 0.54–0.80). Although there is no direct evidence that performance ofcontrast echocardiography played a causative role in this mortality dif-

Echocardiography in the ED. Most patients presenting to the EDwith chest pain do not manifest electrocardiographic ST-segment
elevation, and many patients with acute myocardial infarction do
not describe typical angina-quality chest discomfort. Additionally,
conventional cardiac biomarker assessment has low sensitivity for
detection of myocardial necrosis in the early hours of acute myocardial infarction. Given these limitations, echocardiographic assessmentof wall thickening and MP (Figure 16) has been suggested as an
adjunct to the traditional evaluation of patients presenting to the
ED with suspected myocardial ischemia,119 and echocardiography
is endorsed for this indication in the 2011 appropriate use criteria
for echocardiography.120 Studies published before the 2008 ASE
consensus statement1 demonstrated a significant incremental diagnostic value of UEAs (assessment of both regional function andMP) in patients presenting to the ED with chest pain, as well as
enhanced short-, intermediate-, and long-term prognostic value,even in the absence of cardiac biomarker data.120 More recently,
Wei et al.59 studied 1,166 patients who presented to the ED with prolonged chest pain. A risk model was developed in these patients incorporating ECG, RWM by echocardiography, and echocardiographic

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Figure 16 End-systolic frames obtained during myocardial contrast echocardiography in the apical four-chamber (top) and twochamber (bottom) views in a patient with prior coronary bypass grafting who presented with chest pain and nondiagnostic ECG.
The imaging planes were obtained immediately after high-MI impulses (left) and either early or late after microbubble replenishment.
Early refill images illustrating delayed microbubble replenishment that is relatively less in the endocardial anterior, apical, and distallateral regions (arrows). Nearly complete replenishment is seen in the late refill images (>4 sec after high-MI impulse). The bypass graft
to the left anterior descending coronary artery was subsequently found to be occluded.
MP assessment and then validated in a subsequent consecutive seriesof 720 patients. Abnormal RWM with normal MP (OR, 3.5; 95% CI,
1.8–6.5; P < .001) and abnormal RWM with abnormal MP (OR, 9.6;
95% CI, 5.8–16.0; P < .001) were superior to electrocardiographic
ST-segment abnormalities (OR, 2.9; 95% CI, 1.7–4.8; P < .001) in
predicting nonfatal myocardial infarction or cardiac death.
Additionally, Wyrick et al.60 evaluated the cost-effectiveness of MCE
in 957 patients presenting to the ED with suspected myocardialischemia and nondiagnostic ECG. Although 67% of these patientswere admitted to the hospital using traditional clinical criteria (history,
physical examination, ECG, and cardiac biomarkers) with an averagehospitalization cost of $5,000, the authors estimated a potential $900
per patient savings with incorporation of MCE data. Five hundred
twenty-three patients had normal findings on MCE and, given their subsequent very low cardiac event rate (0.6%), could have been dismissed
directly from the ED, reducing the overall admission rate by 45%.
Assessment of Microvascular Obstruction Following STSegment Elevation Myocardial Infarction. MCE has beenused to evaluate resting microvascular flow following the emergent
management of ST-segment elevation myocardial infarction(STEMI).56,121 Even following successful early recanalization of theinfarct vessel, a persistent resting microvascular perfusion defectwithin the infarct territory has been shown to provide independent
predictive value with regard to adverse LV remodeling andrecurrent cardiac events (death and recurrent infarction) following
STEMI. Although data are limited, it appears that VLMI imaging

with UEAs permits the simultaneous assessment of two
prognostically important measures before hospital discharge in postSTEMI patients: the assessment of LV systolic function and the degreeof microvascular obstruction. Although angiographic recanalization
with normalized epicardial flow has been achieved with contemporary percutaneous interventional techniques, microvascular obstruction may still be present in a significant percentage of patients andis prognostically important (Figure 17).

Key Points and Recommendations for UEA Use in
Critical Care and Emergency Settings
1. Given a demonstrated impact on patient management and an association with mortality reduction, UEAs are recommended in all technically difficult ICU and ED patients to more quickly and accurately diagnose potentially life-threatening
conditions and to reduce the need for downstream diagnostic testing. Contrast echocardiography should not be withheld on the basis of any particular diagnosis or comorbidity (COR I, LOE B-NR).
2. In patients presenting to the ED with suspected myocardial ischemia (and nondiagnostic ECG), regional function assessment with UEAs adds incremental diagnostic
and prognostic value (over traditional clinical and electrocardiographic evaluation)and may reduce health care costs (COR I, LOE B-NR).
3. In patients presenting to the ED with suspected myocardial ischemia (and nondiagnostic ECG), MP assessment with UEAs adds incremental diagnostic and prognostic
value (over traditional clinical, electrocardiographic, and regional function assessment) and may reduce health care costs. This technique should be considered at centers with sonographer and physician expertise in performance and interpretation of
MP echocardiography (COR IIa, LOE B-NR).
4. MCE with VLMI imaging may be used in post-STEMI patients to evaluate for LV systolic function, intracavitary thrombi, and microvascular flow within the infarct territory at institutions with sonographer and physician expertise in performance andinterpretation of MP echocardiography (COR IIa, LOE B-NR).

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Figure 17 An example of persistent microvascular obstruction after angiographically successful percutaneous coronary angioplasty (PCI)of the left anterior descending coronary artery (LAD) (A,B). During the UEA infusion 24 hours after the successful PCI, there was still a large
microvascular defect in the LAD territory noted in the apical four-chamber (A4C) (C) and long-axis (ALA) (D) windows (arrows).

IV.F. Use of Contrast Agents in Congenital Heart Disease
and Pediatric Echocardiography
Despite extensive use and proven benefits in adults, there is limited
pediatric experience with UEAs. Furthermore, the FDA has not
approved any of the commercially available UEAs for pediatric cardiac imaging (although Lumason is approved for pediatric liver imaging). Relatively small studies of UEAs have reported clinical benefits inchildren and adolescents undergoing TTE.30,122,123 It has been shownthat UEAs improve visualization of segmental wall motion in both theleft and right ventricles in patients with congenital heart disease(CHD), leading to better quantification of ventricular function atrest and during physiologic or pharmacologic stress. Enhancementof Doppler signals using UEAs is beneficial for quantification ofright ventricular systolic pressure in patients with CHD. As in
adults, UEAs with RTMCE can provide right ventricular and LV MP
information simultaneous with wall motion analysis.30,56,122,123
Contrary to common perception, older children can be technicallychallenging to image using TTE. Patients with CHD pose additional challenges due to acoustic window limitations from previous cardiac operations, chest wall issues, and alterations in cardiac geometry. UEA use
both at rest and during stress echocardiography is likely to increase in
the pediatric population (even for only LVO) because of increasing fre-quency of difficult ultrasound windows in adolescents and young adults
due to prior surgical procedures and obesity, increasing number of surgical procedures involving coronary artery manipulation being performed in patients with CHD, the increasing need for evaluation ofischemia in the follow-up of acquired heart disease (e.g., Kawasaki disease), and the important need for non-radiation-exposure techniques.30
In patients with CHD, intracardiac communications are usuallyclosed at the time of surgical repair, so the presence of a right-toleft shunt is rare. However, in the presence of a communication,right-to-left shunting may occur with pulmonary hypertension, rightventricular dysfunction, or diminished right ventricular compliance.
It may be seen with biventricular or single ventricular CHD, but theactual site of right-to-left shunting may not be convincingly visualized,
because of technical reasons. The magnitude of shunting through an
intracardiac communication may also vary depending on loading conditions and streaming. Although the right-to-left shunting contraindication has recently been removed, the original intent of the FDA
warning was with regard to significantly large right-to-left shunting,38
as may be seen in some severe types of CHD. Despite removal of thiswarning, the Writing Group recommends further studies to document
the safety of UEAs in this specific patient population. As discussed
below, at the time of writing this document, there are no prospective

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completed trials that have evaluated the safety of UEAs in the pediatric population. A phase 3 multicenter clinical evaluation of safety andefficacy of Lumason in pediatric echocardiography (ClinicalTrials.gov
identifier NCT02282163) is currently under way. Increased clinicaluse in pediatrics is likely in the near future with greater experienceand safety data.
It is unclear at this point what UEA use rates will eventually be forpediatrics once agents are approved, but one would expect increased
use because of the increased frequency of pediatric patients surviving
early surgical repairs for CHD and the increasing prevalence ofobesity. The Writing Group’s recommendation for training, as withadult training, would require performing 50 supervised UEA studies
in the presence of a level III–trained cardiologist in echocardiography,
who is experienced in UEA applications. The lower age limit in current UEA studies in pediatric populations is 5 years. There are no
studies to date regarding safety in those under age 5.

Key Points and Recommendations Regarding UEA
Use in Pediatric Imaging
1. The use of UEAs in children and adolescents is off label but appears safe in those
5 years and older and should be considered if Doppler signals are inadequate (see section A.1.v of the 2008 ASE consensus document) or regional LV or right ventricularwall motion analysis is not feasible with standard tissue harmonic imaging. VLMI imaging techniques should be used to optimally enhance images (COR IIa, LOE B-NR).
2. The use of UEAs is safe in pediatric and adult patients with patent foramen ovale andsmall right-to-left shunts. Further safety studies are needed in children and adults
with large right-to-left shunts.

V. UPDATE ON SAFETY AND INDICATIONS FOR UEAs IN
ADULTS
Table 1 (studies exceeding 1,000 patients) and Table 2 (smaller,
focused studies) demonstrates the large body of literature that has
been published since 2008.7-10,12-17,19-24,28-34,60,123,124 Thesestudies include UEA use in a variety of settings: inpatients,
outpatients, and critically ill patients, during rest imaging andeither exercise or pharmacologic stress echocardiography. Most of
the studies are retrospective by design, and the majority involvethe use of either Definity or Optison. The total population ofsubjects receiving UEAs in Table 1 exceeds 250,000 and includes
patients undergoing stress echocardiography, patients in criticalcare settings, and patients with pulmonary hypertension. Overall,there were no reported deaths and no increases in the myocardial
infarction rate or mortality in comparison with the control population. Table 2 lists smaller studies published since 2009, which evaluated UEA safety with <1,000 enrolled subjects. The safety,
precautions, and benefits of UEAs in critically ill patients on mechanical circulatory support devices have been retrospectively reviewed
in two single-center reports.31,32 With regard to specific patient
populations, there are no safety data published in pregnant
patients or children <5 years of age.
Since 2016, all three UEA manufacturers have announced that
the FDA has removed the contraindication for UEA use in patientswith known or suspected right-to-left, bidirectional, or transient
right-to-left cardiac shunts. Currently, Optison is contraindicatedin patients with known or suspected hypersensitivity to perflutren,
blood, blood products, or albumin (Table 3). Definity is contraindicated in patients with known or suspected hypersensitivity to perflutren (Table 3).

Porter et al 263

In October 2014, a third UEA, Lumason, was approved by the FDA
for use in adults with suboptimal echocardiograms to opacify the LV
chamber and to improve the delineation of the LV endocardial
border.4 In March 2016, Bracco Diagnostics also announced that
the FDA had approved Lumason for use in ultrasonography of theliver for characterization of focal liver lesions in both adult and pediatric patients. Although restricted to liver imaging, this action madeLumason the first ultrasound contrast agent the FDA approved foruse in the pediatric population. Lumason also gained FDA approval
for use in the evaluation of suspected or known vesicoureteral reflux
in pediatric patients. Safety was based on evaluation of published literature involving use of Lumason in >900 pediatric patients. Nonfatal
anaphylaxis was reported in one pediatric patient.3 Currently,
Lumason is contraindicated in patients with histories of hypersensitivity reactions to sulfur hexafluoride lipid microsphere components or
to any of the inactive ingredients in Lumason.
These recent FDA changes follow other safety label alterations
that were made from 2008 to 2011 for both Optison andDefinity, as described in the 2014 ASE contrast sonographer guidelines update.38 All studies have demonstrated that life-threatening
reactions with UEAs are extremely rare, approximately one in
10,000. It is advised by the ASE, and mandated by theIntersocietal Accreditation Commission,5 that a policy be in placefor early identification and rapid response to these acute and severereactions. All personnel, including sonographers, registered nurses,
exercise physiologists, and physicians, should be familiar with theearly identification of an allergic reaction and the appropriate treatment. The ASE and the Intersocietal Accreditation Commission
recommend that a policy be in place before the use of any contrast
agent and that personnel be well trained in its implementation.
Allergy kits should be available and easily accessible in all areas
where UEAs are in use and should be frequently logged for expiration dates. Auto-injectable epinephrine (available as EpiPen; Mylan
Specialty, Basking Ridge, NJ) is the most important component ofthese kits and can be lifesaving in the case of anaphylactic shock.
Most contrast-related reactions occur immediately or within the first
30 min after UEA use. Anaphylactoid reactions, presumed to be a
type I hypersensitivity reaction known as complement activation–
related pseudoallergy, and characterized by skin erythema, urticaria,
rash, dyspnea, throat tightness, flushing, and difficulty swallowing
and/or anaphylactic shock, have been reported at a very low incidence, with serious reactions reported at less than one in 10,000.1
A low incidence of temporary back pain seems to be linked toDefinity and usually resolves spontaneously within a short period
without treatment,1 the causes of which are not entirely understood
but may be related to retention of lipid microbubbles within glomerular capillaries. This retention is significantly less with albumin microbubbles such as Optison.24

Recommendations Regarding the Safety of UEAs
1. Abundant literature (see Tables 1 and 2) exists supporting the safety of UEA use in
nonpregnant adults. These are supported by FDA modifications in the black-box
warning since the 2008 ASE contrast consensus statement (Table 6).
2. Although anaphylactoid reactions are rare, laboratories that routinely use UEAs
should have policies in place for emergent resuscitation of patients who may experience serious side effects.
3. UEAs can safely be used in patients with pulmonary hypertension and with right-toleft shunts (COR I, LOE B-NR).
4. No safety data exist for the use of UEAs in pregnancy or children <5 years of age. UEA
use is therefore not recommended in these groups until safety data emerge.

264 Porter et al

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Table 6 FDA product label changes, 2007 to 2017
Year

Change

Notes

2007

FDA issues black-box warning

Although actual causality was never proved, because of the deaths of a few patients with atemporal association with UCA use, the FDA issued a black-box warning and added a
new contraindication for patients with PH and unstable CPD and required themonitoring of all patients for 30 min after UCA use.

2008Black-box warning lessened
limitations for monitoring

After review of a series of publications from the ultrasound community confirming thesafety of UCAs, the FDA modified the ‘‘contraindication’’ of use in PH and unstable CPD
to warnings and limited the monitoring to only those patients with PH and unstable CVD.
References: postmarketing safety studies released: Kusnetzky et al.,10 Main et al.,11 andWei et al.24

2011

Definity, black-box warning removalof monitoring, stress testing

Definity label changes after FDA review of data from the risk modifications studies
included removal of the requirement for monitoring of patients with PH and unstable
CPD after use of Definity, and the statement regarding the efficacy and safety of Definity
had not been established in stress testing.
References: Abdelmoneim et al.17 (PH safety), Gabriel et al.,8 Shaikh et al.,12 and Dolan
et al.16 (stress testing safety)

2012

Optison, black-box warning removalof monitoring, stress testing

Optison label changes similar to Definity (2011). FDA removes the need for monitoring ofpatients with PH and unstable CPD and the statement regarding the efficacy and safetyof Optison not established in stress testing.
References: Abdelmoneim et al.,17 Wever Pinzon et al.21 in PH

2014

FDA approval of Lumason for use
in the United States

October 2014: Lumason is approved by the FDA for cardiac use in adults for LVO andendocardial border detection.

2016–2017Black-box warning removal of
shunts as contraindication

March 2016: Lumason receives FDA approval for use in ultrasonography of liver lesions inboth adult and pediatric patients.
October 2016: Optison label change removing shunt contraindication and use in
intra-arterial injection to warnings only.
December 2016: Lumason label removal of the contraindication for cardiac shunts.
Addition of FDA approval for use in the evaluation of vesicoureteral reflux in pediatricpatients.
Definity label change to removal of the contraindication for use in patients with known orsuspected right-to-left, bidirectional, or transient right-to-left cardiac shunts to warning.
References: Kalra et al.33 and Parker et al.124 (safety in use with shunts)

CPD, Cardiopulmonary disease; CVD, cardiovascular disease; PH, pulmonary hypertension; UCA, ultrasound contrast agent.

VI. ECHOCARDIOGRAPHY LABORATORY
IMPLEMENTATION OF CONTRAST AGENT USE
Physicians
Current training standards for echocardiography are described indetail in the COCATS 5 Task Force 4 document, published in2015.125 Physicians who wish to acquire skills for perfusion imaging
should obtain additional training at a high-volume center with special
expertise in the assessment of MP.1,38,126 Standards for advanced
echocardiographic training are currently being written and will be
published in the near future.
Physicians trained in focused ultrasound are often confronted withdifficult cardiac windows when making bedside assessments of RWM
and ejection fraction. Specific training on the use of UEA andinterpretation of these echocardiograms by physicians is needed.
Recommendations and standards on such training will be the scopeof future multisociety documents.
SonographersPreviously published 2014 ASE guidelines for cardiac sonographers in theperformance of contrast echocardiography support sonographer training
in IV insertions for the purpose of UEA administration in hospitals andclinic settings, to improve echocardiographic quality with increased efficiency.38 Personnel qualified to start an IV line and administer contrast
will vary by center according to local hospital policies. At the majorityof centers in North America, the IV start and contrast administration
will be performed by a registered nurse, medicine technician or phlebotomist, or fellow in training, whereas some sites have extended this responsibility to sonographers.38 The training of sonographers in IV line insertionand contrast administration requires hospital approval, knowledge of sterile technique and venous anatomy, and awareness of associated risks.
Although serious side effects are exceedingly rare, there should always
be a physician present on site when contrast is administered. Twosingle-center studies in Europe and Canada have demonstrated
improved efficiency with sonographer-driven contrast echocardiographic
protocols through reductions in time to decision for contrast use and time
to administration of contrast, resulting in potential cost savings.127,128 This
also underscores that training in the recognition of need for UEA must bea standard component of sonographer education, complemented byechocardiography laboratory implementation of standing orders for
UEA administration.

Recommendations
1. Physicians wishing to perform contrast echocardiography independently should
receive supervised training and interpretations by a level III–trained person. Perfusion imaging training requires specific training and performance and interpretationof additional rest and stress perfusion studies (COR I, LOE C-EO).
2. Sonographers should be trained in the establishment of IV lines and contrast administration, to improve operational efficiency in the echocardiography laboratory. It is
recommended that this skill be included in the sonography school curriculum (COR
I, LOE C-EO).

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Porter et al 265

Table 7 Emerging applications of UEAs
Microbubbles required

Ultrasound instrumentation required

Specific applications

Thrombolysis

Commercially available/targetedIntermittent diagnostic high-MI
impulses

Acute coronary syndromes,
ischemic stroke

Molecular imaging

Targeted/phosphatidyl serine–
bearing commercial
microbubbles*

High-MI imaging after blood poolclearance

Ischemic memory imaging
Plaque inflammation
Early plaque formation
Myocarditis/transplant rejection

Targeted drug/gene delivery

Commercially available/targetedIntermittent diagnostic high-MI
impulses following bolus
injection

DNA/RNA delivery foratherosclerosis, limb ischemia,
myocardial regeneration,
antiangiogenesis in targeted
tumor therapy

Diagnostic ultrasound–induced
inertial cavitation

Commercially available

Intermittent diagnostic high-MI
impulses

Improved downstream skeletal
muscle perfusion in ischemic
limbs (sickle-cell disease)
Improved microvascular outcome
in acute coronary syndromesDNA, Deoxyribonucleic acid; RNA, ribonucleic acid.
*Sonazoid is the only commercially available microbubble with phosphatidyl serine on the shell.

VII. EMERGING APPLICATIONSEmerging applications are detailed in Table 7.
VII.A. Sonothrombolysis
The potential for intermittent high-MI impulses from a diagnostictransducer to dissolve intravascular thrombi was first demonstrated
in a canine model of arteriovenous graft thrombosis, in which intermittent high-MI impulses (all <1.9) were applied when low-MI imaging detected microbubbles within the graft.129 The high-MI impulses
were shown to induce inertial cavitation within the graft, resulting in
fluid jets, which have been shown to mechanically erode
thrombus.130 Recanalization with the guided high-MI impulses wasachieved without any adjunctive fibrinolytic, antithrombotic, or antiplatelet agents, suggesting that the cavitation and radiation effects ofhigh-MI impulses observed in in vitro studies were sufficient todissolve thrombi. This study prompted subsequent investigations
that examined the efficacy of diagnostic high-MI impulses in restoring
microvascular and epicardial blood flow in porcine models of acute
STEMI.131,132 Because epicardial vessels are not easily visualizedwith diagnostic ultrasound (DUS), these studies used VLMI imagingof the microvasculature to guide the timing of the high-MI impulses.
Even with transthoracic attenuation, these studies demonstrated thatintermittent high-MI impulses from a DUS transducer could increase
the epicardial recanalization rates from 36% seen with a half dose oftissue plasminogen activator alone to 83% with DUS high-MI impulses and microbubbles combined with a half dose of tissue plasminogen activator. Also, ST-segment resolution (indicating microvascularrecanalization) was seen with DUS high-MI impulses even when
epicardial recanalization was not observed, indicating that vasoactive
mediators were playing a role in restoring microvascular flow, in addition to epicardial thrombus dissolution. Subsequent studies inischemic peripheral vessel occlusion have confirmed that high-MI
DUS impulses can induce nitric oxide release, resulting in restorationof microvascular flow, even in the presence of an upstream vessel occlusion.133 Preliminary clinical studies in patients with acute STEMI

have demonstrated that the guided high-MI diagnostic impulses (3msec pulse duration) are sufficient to improve early epicardial recanalization rates and restore microvascular flow (Figure 18) withcommercially available IV microbubbles.134 Ongoing studies will
examine the safety and efficacy of this DUS targeted sonothrombolytic technique in acute coronary syndromes as well as in ischemic
stroke.

VII.B. Molecular Imaging
Although UEAs are composed of microbubbles that act as free intravascular tracers, ligands can be attached to their surface that cause
them to attach to dysfunctional endothelium. These can be imaged
with contrast-specific imaging protocols for both diagnostic and therapeutic purposes. A common approach is to pair a novel site-targeted
imaging probe with conventional approaches to noninvasive contrast
imaging.135 Although clinical translation has been slow, molecular imaging has the potential to improve outcomes or efficiency of carethrough early diagnosis of disease and guided selection of therapy.
Molecular imaging has also been used in preclinical research to assess
on-target and off-target effects of new therapies and to identify new
pathways for intervention.
Molecular imaging with targeted contrast ultrasound relies on theselective retention at sites of disease of any one of several different
types of acoustically active targeted imaging molecules, ranging insize from a few hundred nanometers to several micrometers. The
use of microbubbles that have undergone modification of their shell
has been the most common approach on the basis of the relative
simplicity of agent preparation, the high degree of signal generation
provided during conventional contrast imaging, and the rapid clearance from the circulation after IV injection. The latter issue is important because discrimination of signal from retained agent is usuallyaccomplished by imaging after time is allowed for clearance ofthe freely circulating nonattached population of microbubbles.
Because most acoustically active contrast agents are confined to
the vascular compartment, UEAs have been targeted primarily to266 Porter et al

Journal of the American Society of Echocardiography
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Figure 18 A patient with an anterior STEMI treated with repeated high-MI diagnostic impulses during a dilute UEA infusion before
percutaneous coronary intervention (PCI). The top row depicts apical microvascular obstruction (arrow) in the apical two-chamberview on the initial images obtained as the patient arrived to the ED. A brief (10- to 20-min) period of intermittent high-MI impulses
was applied in each apical view during UEA infusion before reaching the cardiac catheterization laboratory, resulting in resolutionof the apical defect (lower row, middle panel) and angiographic recanalization on the initial projections obtained before stent placement in the left anterior descending coronary artery (bottom row, right panel).

events that occur within the blood pool or at the blood pool–endothelium interface.136
One of two strategies has accomplished targeting of ultrasoundagents. A simple approach has been to select certain microbubble
shell constituents that facilitate their attachment to either leukocytes
or activated endothelium in regions of disease. Lipid-shelled microbubbles bearing phosphatidylserine have been shown to be particularly effective in this regard and have recently been shown toprovide a simple approach for noninvasive detection of recent
myocardial ischemia.137 At the time of this publication, none of theseagents is available in the United States or Europe. Sonazoid (aphosphatidylserine-bearing microbubble) is available for noncardiac
imaging in Japan.
More specific targeting is achieved by conjugating ligands (generally at the end of a molecular spacer arm) to the microbubble surface
in densities of up to several thousand per square micrometer of surface area. The combination of ligand/target density and bond kinetics
must be sufficient to withstand vascular shear forces.138 Microbubbles
targeted to endothelial adhesion molecules and other activatedendothelial markers (vascular cell adhesion molecule–1, intercellular adhesion molecule–1, selectins, integrins) have been used
to detect preatherogenic potential or plaque inflammatory

phenotype.139-143 Some of these agents have also been used toimage myocardial ischemia, transplant rejection, myocarditis, andangiogenesis.144-151 Microbubbles targeted to fibrin, plateletcomponents of the coagulation system (glycoprotein IIb/IIIa,
glycoprotein Ib), and von Willebrand factor have been used to
identify either cavitary or arterial thrombus, microthrombi, or
plaque prothrombotic and proinflammatory potential.141,152,153
Microbubbles targeted to specific subsets of monocytes have also
been used for imaging of ischemia-related vascular remodeling.148
Targeted microbubbles have also been used in preclinical research
for augmentation of ultrasound-based therapies such as targeted delivery of stem cells or genes (plasmid complementary deoxyribonucleic acid) or enhancement of sonothrombolysis.154-156
VII.C. Targeted Drug and Gene Delivery
Targeted gene and drug delivery can be facilitated noninvasively by
the ultrasonic destruction of intravenously administered carrier microbubble UEAs, most frequently termed ultrasound-targeted microbubble destruction (UTMD). Although ultrasound energy alone canfacilitate gene transfection by sonoporation (cavitation-induced transient pore formation or altered permeability) and by active cell

Journal of the American Society of Echocardiography
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Porter et al 267

Table 8 Comparison of information obtained from a real-time myocardial contrast echocardiographic stress study and a stresssingle-photon emission computed tomographic study
Procedure

Resolution

Prognostic data?

Stress EF?

Rest EF

Diastolic function

Costs*

Radiation exposure0

Stress RTMCE

3 mm

Yes

Yes

Yes

Yes

$309.36

Stress SPECT

10 mm

Yes

No

Yes

No

$1,600.74

15.6 mSv187

EF, Ejection fraction.
*Global and technical Medicare reimbursement information using CPT code 78452 for single-photon emission computed tomographic multiple
myocardial perfusion and CPT codes 93351 and 93352 for stress TTE with exercise and use of contrast at stress.

uptake, the addition of microbubbles lowers the threshold for acoustic
cavitation and markedly increases transfection efficiency, particularly
when genes or nucleic acids are incorporated or charge-coupleddirectly to the microbubble surface.156-159 Delivery and transfection
occur by several mechanisms, including transient pore formation
and active calcium-mediated cell uptake, both of which are likely aresult of cavitation-related shear forces, microjets, shock waves, andpressure-related cell deformation.160,161
UTMD delivery can be optimized by the use of triggered DUS toallow replenishment of the tissue with carrier microbubbles between destructive pulses and creating an ideal acoustic environment
for inertial cavitation (high acoustic power or MI, lower transmit frequency).162 As carrier microbubbles are purely intravascular, transfection and delivery occur predominantly to the vascularendothelium of the insonified tissue but can produce extravasculartransfection and delivery as well. From a safety perspective, studies
have shown that high levels of transfection can occur at acousticpressures just less than those that produce adverse bioeffects156
and that minimal to no remote transfection occurs outside thearea insonified by the ultrasound beam,163-165 demonstrating thetargeted nature of delivery by UTMD. Furthermore, many ofthese preclinical studies have used the diagnostic high-MI impulses
available on commercially available transducers to achieve UTMD
and targeted drug delivery.
Although the initial in vivo study of UTMD for gene delivery usedrecombinant adenovirus,166 the vast majority of subsequent studies
have used plasmid deoxyribonucleic acid, with more recent studies using other nucleic acids such as small interfering ribonucleic acid167 andmicro–ribonucleic acid.168 To date, studies of UTMD for therapeutic
applications have been confined to preclinical studies in a wide varietyof animal models of disease, including cardiovascular, cancer, hepatic,
renal, and cerebral diseases. Within cardiovascular diseases, UTMD ofmany different therapeutic genes has been applied successfully tomodels of acute myocardial infarction,169 chronic myocardial infarction
and ischemic cardiomyopathy,170 dilated cardiomyopathy,171-173 andPAD,174 as well as to animal models of type 1 diabetes to restore endocrine pancreatic function.175 Given the modest transfection efficiency,
the beneficial effects of UTMD are most prominent when either transfecting a paracrine factor or transfecting a gene that has a significant effect even when the majority of cells are not transfected.171,176 A
comprehensive review of UTMD for gene and drug delivery for
cardiovascular applications is beyond the scope of this document.
However, several excellent reviews have been published within thepast few years.177,178 Although UTMD has potential advantages overother gene delivery techniques, including its noninvasive nature thatallows multigene therapy,169,170 ongoing work is focusing on
improving transfection efficiency using newer vectors that prolongtransfection or promote chromosomal insertion.

VII.D. Flow Augmentation with Diagnostic UTMD
As stated above, diagnostic high-MI impulses induce inertial cavitationof UEAs in vivo. In addition to the thrombolytic effects, this cavitation
process has augmented tissue blood flow via mechanisms that are
mediated by nitric oxide production.133 Recent preclinical data
have demonstrated that diagnostic UTMD produces a 40-fold increase in adenosine triphosphate release that is sustained for several
minutes after ultrasound exposure.179 The vasculature that is fed by
the vessels being insonified (downstream vessels) experienced increases in tissue blood flow in this animal model, and increased adenosine triphosphate release was observed for up to 24 hours after
diagnostic UTMD. The therapeutic potential for this has been demonstrated in patients with sickle-cell anemia, in whom intermittent highMI DUS impulses during a commercially available IV UEA infusion
resulted in improved skeletal muscle perfusion.179

VIII. COST-EFFECTIVENESS OF UEAS
In the United States, hospitals are reimbursed for the provision of
inpatient care by the Centers for Medicare and Medicaid Services(and most private commercial payers) under diagnosis-related groups.
Under this system, a particular diagnosis or clinical condition is associated with an essentially flat reimbursement for the hospital stay;therefore, hospitals are incentivized to provide the most efficientcare. With respect to UEAs, cost-effectiveness can be examined in
specific contexts, as outlined below.
Reducing Costs per Patient
Echocardiography is a highly efficient diagnostic test, given relatively
low imaging platform costs (in comparison with radionuclide tracer imaging, CT, CMRI, and cardiac catheterization), low staffing requirements (one sonographer per examination), low supply costs, potential
for portable examinations, excellent reproducibility, and highthroughput. UEA use is reimbursed by Medicare and third-party payers
in the hospital outpatient department setting (C8929, ‘‘TTE rest echo
complete with contrast’’; and C8930, ‘‘stress TTE with contrast and
ECG monitoring’’). As of 2017, these are reimbursed approximately$200 more than the same studies without contrast. In hospitalized patients with technically difficult echocardiographic examinations, the useof UEAs may increase this cost efficiency, even though the agents are
not separately reimbursed. In a study of 632 patients with technicallydifficult echocardiographic examinations, each of whom also underwent a second contrast-enhanced examination,26 UEAs reduced thetechnically difficult study rate from 87% to 10% and resulted in a significant management change (avoidance of downstream diagnostic
testing, an important medication change, or both) in 36% of patients.

268 Porter et al

In the overall cohort, the cost of contrast was $39,184, and the total costof avoided procedures (TEE and nuclear cardiology) was $116,094, fora total savings of $76,910, or $122 per patient. Of note, the impact onpatient management was greater in inpatients than outpatients, and thecost savings in the inpatient arena were likely significantly higher than
was reported for the overall cohort.
Improving Positive Predictive Value
The cost-efficiency of a diagnostic technique is based on initial cost,
the frequency of the diagnostic result obtained, and the accuracy of
the test for the diagnosis and prognosis of the condition. Lack of diagnostic results gives rise to more downstream tests, which increase thecost of the particular strategy. It was clearly shown in the previous section that when UEAs are used for LVO, diagnostic test frequency isdecreased, leading to reduced downstream cost. Improved accuracy
leads to more appropriate referral for coronary angiography, withnegative tests showing minimal rates of hard events and revascularization. It has also been shown that adding perfusion assessment to wallmotion assessment during stress echocardiography further improves
accuracy, for both diagnosis and prognosis of CAD. In a recent study,
perfusion assessment improved the positive predictive value for CAD
detection from 83% to 90% compared with wall motion andimproved outcome assessment.60 In a large randomized study
comparing RTMCE for perfusion and function versus non-MCE
contrast echocardiography for wall motion only, more flow-limiting
CAD was identified by a perfusion technique, which may translate
into improved outcomes.45 Although no formal cost analysis was carried out, on the basis of improved accuracy of diagnosis and prognosis
compared with wall motion, perfusion is likely to be cost saving,although the magnitude of initial cost of LVO stress echocardiography
versus perfusion stress echocardiography is important in this equation. More recent studies in preoperative risk assessment before major
surgery (kidney and liver transplantation) have demonstrated the incremental value of perfusion combined with wall motion imaging
during DSE in predicting adverse cardiovascular outcomes.180,181
Improving the Emergent Evaluation of a Patient
The concept that MP imaging can improve cost-effectiveness in patients presenting to the ED with chest pain was first established using
single-photon emission computed tomographic radionuclide imaging.182 Cost-effectiveness in this setting is based on both the ability
to exclude patients who have cardiac causes of their chest pain andrapid identification of those who are likely to benefit from therapy
for acute coronary syndrome.183 MCE represents a more practical
approach to perfusion imaging in ED patients because it is able tobe performed rapidly at the bedside, it is less expensive than
SPECT, and it provides immediate information to the clinician.
When performed in the ED, MCE for both wall motion and perfusion
has been shown to provide incremental benefit to standard clinicaldata in terms of stratifying patient risk.184 Accordingly, MCE has
been predicted to save approximately $900 per patient in thoseadmitted to the ED, largely because of the prevention of unnecessary
hospital admissions and additional cardiovascular testing.60
In the critical care setting, limited data exist with regard to theimpact of UEAs. In the serial echocardiographic evaluation of LV assist
device therapy, in which image quality is frequently poor, emerging
evidence suggests that UEA use alters patient management in>40% of cases, including adjustments in pump speed and detectionof pump thrombosis.31

Journal of the American Society of Echocardiography
March 2018

Key Points and Recommendations
1. The use of UEAs is recommended in all difficult-to-image hospitalized patients (COR
I, LOE B-NR). Although separate reimbursement for UEAs is not provided in the inpatient setting, overall cost savings are realized because of avoidance of downstream
diagnostic testing, including TEE and nuclear cardiac testing. Additional costeffectiveness studies are warranted, including evaluation of contrast echocardiography on hospital length of stay.
2. When echocardiography laboratories are adequately trained in perfusion imaging,
MCE should be used for both stress echocardiography (COR IIa, LOE B-R) and in
the ED evaluation of patients with chest pain and nondiagnostic ECG to evaluate
both MP and RWM (COR IIa, LOE B-NR).
3. Additional clinical studies are needed to evaluate the impact of UEAs in the criticalcare setting.

IX. SUMMARY OF RECOMMENDATIONS FOR UEA USE FORECHOCARDIOGRAPHY AND ADDITIONAL RESOURCES
Since the 2008 ASE consensus statement,1 there have been significant clinical developments, including additional documentation
regarding the safety and efficacy of UEA use for improving LVO in
several clinical settings. This has been accompanied by the removal
and/or reductions of prior contraindications to use and the provisionof new clinical data to support use in pediatrics as well as nonapproved indications such as MP imaging and therapeutic thrombolysis.
Indeed, the data regarding perfusion imaging is so compelling that
European guidelines have recommended UEAs as a method of evaluating patients with stable chest pain.185 A recent meta-analysis
demonstrated that abnormal perfusion by MCE during exercise, dobutamine, or vasodilator stress imaging has a fivefold greater risk for
cardiac events compared with normal perfusion, with low heterogeneity among trials.186 Table 8 compares the information obtained,
costs, and risks that are part of stress MCE and perfusion stress
SPECT in a hypothetical American Medicare patient.
In the United States, a unique add-on billing code has been established for MP using UEAs (CPT code +0439T), and the Writing
Group recommends that this code be used in laboratories that areexperienced in UEA use, especially during rest studies to evaluate chest
pain or shortness of breath, as well as during stress echocardiography or
viability testing. In those laboratories without adequate experience with
UEAs for the indication of LVO, it is recommended that experience beacquired to provide state-of-the-art contrast echocardiography andcomply with national accreditation standards. Also, ultrasound vendorsof both large and small systems must work in unison to provide frontend presets that will enable users to more readily access the imaging
presets and functionality that are optimized for LVO and perfusion.
Additional educational material in the areas of microbubble physics,
UEA administration protocols and policies, and techniques and tips for
LVO and MP imaging can be found at http://www.asecho.org/contrast.
Further updates are expected as additional clinical studies emerge in theareas of cost-effectiveness of UEA use, perfusion imaging, sonothrombolysis, molecular imaging, and targeted drug and gene delivery. The
Writing Group emphasizes the critical need for vendors to improve their
VLMI imaging protocols and presets on their existing systems, including
their portable systems, as more physicians in cardiology, critical care, andemergency care use UEAs to improve diagnostic capabilities.
ACKNOWLEDGMENTS
We thank Dr. Feng Xie for his assistance with tables, figures, andvideos, and Carol Gould for her administrative assistance with themanuscript.

Journal of the American Society of Echocardiography
Volume 31 Number 3This document was reviewed by members of the 2017–2018 ASE
Guidelines and Standards Committee, ASE Board of Directors, and
ASE Executive Committee. Reviewers included Azin Alizadehal,
MD, FASE, Bonita Anderson, MAPPLSC, DMU, AMS, FASE, ACS,
Alicia Armour, BS, MA, RDCS, FASE, Federico M. Asch, MD,
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SUPPLEMENTARY DATA
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org/10.1016/j.echo.2017.11.013.

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