Clinical Applications of Ultrasonic Enhancing Agents in Echocardiography

Publication Date: March 1, 2018

Key Points


Current FDA Labeling of UEA Use

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 practice guidelines. (, )
The approved indications for use of ultrasound enhancing agents are governed by each country and societal endorsement of this document does not imply otherwise.

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 composi- tion (diffusivity and solubility), pharmacokinetics, and shell properties.
  4. Three UEAs (Optison, Definity, and Lumason) are approved for use by the FDA for the indication 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 evaluation for vesicoureteral reflux.


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 and quantification of LV ejection fraction (LVEF). (, )
2. VLMI multipulse imaging techniques can also be useful for detecting MP (Videos 2–4; available at using brief high-MI flash impulses to clear myocardial contrast and subsequently analyzing myocardial replenishment kinetics and plateau intensity.
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.
impulses (MI > 0.5) to clear myocardial contrast and enhance endocardial border delineation with these pulse sequence schemes.


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 for the assessment of LV function (LVEF and RWM assessment) and/or in settings in which the study indication requires accurate analysis of RWM.
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 delineation for volume and ejection fraction measurements.
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.
4. LV volumes obtained by enhanced echocardiography are typically larger than those measured without UEAs, and therefore 2015 ASE chamber quantification guidelines should be applied with caution when determining normal ranges. Although the normal range for LVEF does not appear to be different, new reference ranges for end-diastolic and end-systolic LV volumes when using UEAs should be established.
5. As per section III of the 2014 ASE guidelines for sonographers, 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.

Use of UEAs in Detecting LV Cavity Abnormalities and Intracardiac Masses

1. Ultrasound enhancement should be used in patients in whom LV thrombus cannot be ruled in or out with noncontrast echocardiography.
2. Ultrasound enhancement should be considered in patients inwhomstructural abnormalities of the left ventricle (noncompaction cardiomyopathy, apical hypertrophy and aneurysms) cannot be adequately assessed with noncontrast echocardiography.
3. Ultrasound enhancement should be used for ruling in or out an LV pseudoaneurysm.
4. Ultrasound enhancement with VLMI imaging should be used in the differential diagnosis of cardiac masses by assessing the vascularity of the mass.
5. Ultrasound enhancement should be considered during TEE whenever the atrial appendage has significant spontaneous contrast or cannot be adequately visualized with unenhanced imaging.

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.
2. impulses (five to 15 frames at an MI of 0.8–1.0) to achieve homogeneous LVO and analysis of RWM. (, )
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.
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 myocardial ischemia 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 demand stress using real-time high-MI flash replenishment technique for simultaneous perfusion and wall motion assessment.
6. Perfusion analysis combined with RWManalysis using RTMCE should be considered during DSE to maximize the sensitivity and accuracy of the study for the detection of CAD and prediction of clinical outcome.
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 detection of CAD.
8. Adenosine and regadenoson stress should be performed with RTMCE to analyze both RWM and MP to maximize test sensitivity and specificity.
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 micro- bubble 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 under resting conditions and within 2 sec in a constant imaging plane during any form of stress imaging
11. Quantitative MCE appears to have additional value over visual analysis in detecting myocardial blood flow abnormalities due to significant CAD but requires dedicated software 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.

UEA Use in Vascular Applications

1. Although the use of UEAs is off label for this purpose, there are numerous recent and developing vascular applications.
2. UEAs are recommended with low-MI ultrasound imaging of endovascular grafts to detect and classify any suspected endoleak.
3. Contrast ultrasound with VLMI imaging has the capability of assessing carotid artery stenosis severity and presence of plaque vascularity. Prospective studies are needed to determine the predictive value of these imaging techniques.
4. Contrast ultrasound has been used to assess limb skeletal muscle blood flow reserve in patients with diabetes and chronic PAD. Further studies are needed to determine the predictive value of this technique compared with ankle-brachial indices and CT of the peripheral vasculature.

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.
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.
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.
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 and interpretation of MP echocardiography.

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 ventricular wall motion analysis is not feasible with standard tissue harmonic imaging. VLMI imaging techniques should be used to optimally enhance images.
2. The use of UEAs is safe in pediatric and adult patients with patent foramen ovale and small right-to-left shunts. Further safety studies are needed in children and adults with large right-to-left shunts.

Safety of UEAs

1. Abundant literature 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.
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.
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.


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 interpretation of additional rest and stress perfusion studies.
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.


1. The use of UEAs is recommended in all difficult-to-image hospitalized patients.

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
and in the ED evaluation of patients with chest pain and nondiagnostic ECG to evaluate both MP and RWM.
3. Additional clinical studies are needed to evaluate the impact of UEAs in the critical care setting.

Recommendation Grading


  • 2D: 2-dimensional
  • 3D: 3-dimensional
  • ASE: American Society Of Echocardiography
  • CAD: Coronary Artery Disease
  • CHD: Congenital Heart Disease
  • CMRI: Cardiac Magnetic Resonance Imaging
  • COR: Class Of Recommendation
  • CPT: Current Procedural Terminology
  • CT: Computed Tomography
  • DSE: Dobutamine Stress Echocardiography
  • DUS: Diagnostic Ultrasound
  • ECG: Electrocardiography
  • ED: Emergency Department
  • FDA: 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 Computerized Tomography
  • STEMI: ST-elevation Myocardial Infarction
  • TEE: Transesophageal Echocardiography
  • TTE: Transthoracic Echocardiography
  • UEA: Ultrasound Enhancing Agent
  • UTMD: Ultrasound-targeted Microbubble Destruction
  • VLMI: Very Low Mechanical Index




Clinical Applications of Ultrasonic Enhancing Agents in Echocardiography

Authoring Organization

Publication Month/Year

March 1, 2018

Document Type


External Publication Status


Country of Publication


Inclusion Criteria

Female, Male, Adolescent, Adult, Child, Infant, Older adult

Health Care Settings

Ambulatory, Emergency care, Hospital, Outpatient

Intended Users

Radiology technologist, nurse, nurse practitioner, physician, physician assistant


Assessment and screening, Prevention

Diseases/Conditions (MeSH)

D004452 - Echocardiography, D014463 - Ultrasonography


echocardiography, ultrasound, Ultrasonic Enhancing Agents

Source Citation

Porter, T. R., Mulvagh, S. L., Abdelmoneim, S. S., Becher, H., Belcik, J. T., Bierig, M., … Villanueva, F. (2018). Clinical Applications of Ultrasonic Enhancing Agents in Echocardiography: 2018 American Society of Echocardiography Guidelines Update. Journal of the American Society of Echocardiography, 31(3), 241–274. doi:10.1016/j.echo.2017.11.013

Supplemental Methodology Resources

Methodology Supplement, Data Supplement, Data Supplement