Contrast echocardiography refers to diagnostic ultrasound of the heart that is performed in conjunction with any acoustically active particle, including agitated saline. This mini-review will focus primarily on procedures performed with the administration of stable, commercially produced ultrasound contrast that can transit to the systemic circulation after intravenous injection with the overall goal of producing opacification of the blood pool and the microcirculation. Over the past decade, there has been a year-by-year increase in the performance of contrast echocardiography. This pattern is attributable to increased recognition outside of major academic centers that diagnostic performance of echocardiography is improved by adoption of policies for using contrast in selected patients, and that contrast material is both safe and without significant financial penalty. Yet penetration of the technology is still low, at around 7% of transthoracic studies, which reflects a need for better understanding of technical components, clinical applications, and workflow issues. Those are the focus of this review.

Ultrasound Contrast Agents

The rationale for using microbubbles as ultrasound contrast agents is based on their ability to undergo volumetric oscillation, termed stable cavitation, in the pressure fluctuations in an ultrasound field. Producing opacification with an intravenous route of injection relies on microbubbles remaining intact and acoustically active after their transit from the venous to systemic circulation. This property has been achieved through specific compositional designs that stabilize and control the size of microbubbles.^1,2 Compositional details for the agents approved for contrast echocardiography by the US Food and Drug Administration (FDA) and other regulatory bodies outside of the United States for opacification of the heart chambers are presented in Figure 1. The use of inert gases (perfluorocarbons and sulfur hexafluoride) with lower solubility and diffusivity than air markedly increases their lifespan after injection. Stability is further enhanced by encapsulation of microbubbles with lipid or protein shells, which acts as a barrier to reduce outward diffusion of the gas and reduces microbubble surface tension. These modifications are also important factors for the manufacture of stable microbubbles that are small enough to pass unimpeded through the pulmonary or systemic microcirculations (<6 mcm) and, in some cases, have long shelf life.

Figure 1

With regard to workflow, some of the agents require reconstitution of a lyophilized product, and others require devices to activate the agent through physical agitation. Most agents are stable and can be used for several hours after reconstitution or activation. Contrast agents can be administered intravenously by one of two approaches. Repeated bolus injection has the advantages of ease of use. However, far-field attenuation from excessive blood pool concentration often occurs early after injection, and blood pool concentration is not stable over time, which is a requirement for off-label perfusion imaging. Continuous venous infusion with a small pump is an approach that requires slightly more set-up time, but it results in a more reproducible and constant concentration of microbubbles in the blood pool and allows uninterrupted imaging.

Because microbubbles are sufficiently small for trans-capillary transit and have been composed with inert gases and shell materials that are biocompatible, they are generally considered to be among the safest of all imaging contrast agents. However, these particles are recognized as foreign by blood proteins such as serum complement.³ Accordingly, serious cardiopulmonary reaction due to non-Ig E-related pseudoanaphylaxis occurs in approximately 1 in every 10 thousand patients receiving lipid-shelled ultrasound contrast agents.⁴ The only major contraindication to the use of ultrasound contrast agents that are FDA-approved is previous hypersensitivity. Other contraindications for some but not all agents include right-to-left shunts and allergy to blood products. Contrast is both safe and effective in patients who have left ventricular (LV) assist and extracorporeal membrane oxygenation devices.

Clinical Use of Contrast Echocardiography

Despite continued improvements in non-contrast echocardiography, that image quality is still suboptimal for assessing regional and segmental wall motion in up to 20% of patients. Overcoming "technically difficult" studies is of importance based the increasing use of echocardiography to guide urgent treatment decisions in critically ill patients or for making guideline-based treatment decisions such as in device therapy (implantable cardioverter-defibrillator or bi-ventricular pacemaker), timing of valve surgery, or monitoring cardiotoxic drug effects.

The use of contrast for LV opacification (LVO) provides a valuable option for improving endocardial border resolution in these patients (Videos 1A-B). By more clearly defining the endocardial border, LVO improves accuracy and reproducibility in the assessment of LV volumes and LV ejection fraction, particularly in those with lower quality non-contrast images.^5-7 Contrast has also been shown to reduce overall costs of echocardiography in select populations by avoiding the need for other, more expensive methods for assessing LV function (Figure 2).⁷

Videos 1A-B

Figure 2

The ability to accurately evaluate contractile response in every segment and to have a high level of reader confidence are critical issues in stress echocardiography and when resting echocardiography is used to evaluate for ischemia in a patient with resting chest pain. Accordingly, LVO plays an important role in stress echocardiography where microbubble contrast can increase the number of interpretable myocardial segments at rest and during stress and reduce the percentage of studies that are technically limited in quality.^8,9 Contrast echocardiography has also been used in several specific clinical scenarios in which delineation of intracavitary anatomy is important.² Examples include evaluating for thrombus, ventricular pseudoaneurysm, non-compaction, apical hypertrophic cardiomyopathy, and eosinophilic cardiomyopathy (Videos 2A-B). Myocardial contrast echocardiography refers to the detection of contrast material present within the myocardial microcirculation. Quantitative myocardial contrast echocardiography, which relies on kinetic modeling of contrast in the microcirculation, has been used for a variety of applications in ischemic and non-ischemic heart disease. This topic has been reviewed elsewhere and is not included in this brief review.^1,10

Videos 2A-B

The positive impact that contrast has been shown to have on diagnostic accuracy, cost, reproducibility, and reader confidence in a wide variety of situations has led to practice guidelines from the American Society of Echocardiography regarding its use.² However, specific recommendations for selecting patients in whom contrast should be used have been based simply on the inability to visualize a certain number of myocardial segments. In clinical practice, it is often important to consider the clinical circumstance when deciding on the impact of contrast. For example, contrast may have little role when the primary aim is to evaluate for the presence of a pericardial effusion. On the other hand, issues of reliability, reproducibility, accuracy, and confidence can justify the use of contrast in situations when image quality is adequate but marginal, such as the need to detect a regional wall motion abnormality or exclude an apical thrombus.

Laboratory Workflow

The American Society of Echocardiography guidelines on contrast echocardiography provide a detailed description of policies that must be implemented regarding contrast use and the roles of different healthcare providers in this process.² There are several important features. An echocardiography laboratory must possess imaging systems with the specific ultrasound detection algorithms that have been developed for enhancing contrast signal based on their ability to generate non-linear signals.¹ Personnel must be trained on how to optimize systems for contrast use because interactions between microbubbles and ultrasound are complex. It is also important that quality assurance policies are in place to ensure safety, quality, and efficiency. Ideally, the decision to use contrast should reside with the individual who is acquiring images, most commonly the sonographers, which is a policy that is achievable only in an environment where there is active feedback between sonographers and interpreting physicians. Institutional policies vary regarding the need for written consent and who is allowed to administer contrast. However, efficiency of implantation is optimal when written consent is not required and contrast is considered to be inherent in the practice of echocardiography.

Summary

Contrast echocardiography is now considered an essential component for a modern echocardiography laboratory based on its ability to provide unique information that enhances diagnostic performance and reader confidence. The implementation of contrast requires knowledge of contrast-specific imaging protocols, a process for identifying patients who are likely to benefit from contrast, and sound laboratory policies that ensure quality, efficiency, and safety.

References

1. Kaufmann BA, Wei K, Lindner JR. Contrast echocardiography. Curr Probl Cardiol 2007;32:51-96.
2. Mulvagh SL, Rakowski H, Vannan MA, et al. American Society of Echocardiography Consensus Statement on the Clinical Applications of Ultrasonic Contrast Agents in Echocardiography. J Am Soc Echocardiogr 2008;21:1179-201.
3. Fisher NG, Christiansen JP, Klibanov A, Taylor RP, Kaul S, Lindner JR. Influence of microbubble surface charge on capillary transit and myocardial contrast enhancement. J Am Coll Cardiol 2002;40:811-9.
4. Wei K, Mulvagh SL, Carson L, et al. The safety of deFinity and Optison for ultrasound image enhancement: a retrospective analysis of 78,383 administered contrast doses. J Am Soc Echocardiogr 2008;21:1202-6.
5. Hoffmann R, von Bardeleben S, ten Cate F, et al. Assessment of systolic left ventricular function: a multi-centre comparison of cineventriculography, cardiac magnetic resonance imaging, unenhanced and contrast-enhanced echocardiography. Eur Heart J 2005;26:607-16.
6. Thomson HL, Basmadjian AJ, Rainbird AJ, et al. Contrast echocardiography improves the accuracy and reproducibility of left ventricular remodeling measurements: a prospective, randomly assigned, blinded study. J Am Coll Cardiol 2001;38:867-75.
7. Kurt M, Shaikh KA, Peterson L, et al. Impact of contrast echocardiography on evaluation of ventricular function and clinical management in a large prospective cohort. J Am Coll Cardiol 2009;53:802-10.
8. Crouse LJ, Cheirif J, Hanly DE, et al. Opacification and border delineation improvement in patients with suboptimal endocardial border definition in routine echocardiography: results of the Phase III Albunex Multicenter Trial. J Am Coll Cardiol 1993;22:1494-500.
9. Rainbird AJ, Mulvagh SL, Oh JK, et al. Contrast dobutamine stress echocardiography: clinical practice assessment in 300 consecutive patients. J Am Soc Echocardiogr 2001;14:378-85.
10. Bhatia VK, Senior R. Contrast echocardiography: evidence for clinical use. J Am Soc Echocardiogr 2008;21:409-16.

Keywords: Diagnostic Imaging, Sulfur Hexafluoride, Echocardiography, Stress, Injections, Intravenous, Pericardial Effusion, Echocardiography, Ultrasonography, Cardiomyopathy, Hypertrophic, Cardiomyopathies, Thrombosis, Algorithms, Chest Pain, Lipids

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