Contrast echocardiography refers not to one technique but rather to an array of structural and functional assessments made using stable ultrasound microbubble contrast agents designed to cross the pulmonary microvasculature after intravenous injection. In 1994, the first commercially-produced transpulmonary contrast agent was approved by the U.S. Food and Drug Administration (FDA) for left ventricular (LV) cavity opacification. Since then, the FDA has approved several second generation contrast agents that have enhanced in vivo stability by virtue of their high molecular weight inert gases, which are encapsulated with either lipid (Definity, Lumason) or albumin (Optison) shells.

It is difficult to identify any other major advance in echocardiographic imaging that has had as much vacillation in opinion and adoption as contrast echocardiography. The fluctuation of enthusiasm for using contrast in routine clinical echocardiography practice can be attributed to several influences that have varied over time, including: 1) market forces such as product availability and reimbursement, 2) the voice of key opinion leaders in cardiovascular imaging, 3) reaction to safety concerns, and 4) policies of institutional and state oversight authorities that can either promote or hinder the smooth incorporation of contrast echocardiography into the workflow of a busy echocardiography laboratory. Although contrast is administered in only a small fraction of studies, it is still somewhat reassuring that over the last half decade there has been rapid growth evidenced by a greater than four-fold increase between 2008 and 2013 in the percentage of echocardiographic studies performed in the U.S. where commercially-produced contrast agents were administered.¹

There are several reasons for the recent steady increase in contrast echocardiography. On an optimistic note, medical educational programs have resulted in greater recognition that contrast is vital when using echocardiography as a frontline tool for rapid decision making or for accurate evaluation of ventricular function. For example, echocardiographic evaluation of wall motion is increasingly being employed to evaluate patients in the emergency department setting since its negative predictive value for excluding acute coronary syndrome in those with active or recent chest pain is very high.² This approach, however, requires not only the visualization of every single ventricular segment but also a very high level of interpreter confidence. Echocardiography is increasingly used to evaluate causes of hemodynamic instability in critically ill patients who are more likely to have difficult acoustic windows because of positive pressure ventilation, inability to position, or surgical dressings. Evaluation of the LV apex by echocardiography continues to be difficult in some patients due to near-field clutter artifact, low-amplitude harmonic signals, and a tendency for foreshortening. Apical evaluation with contrast has been shown to aid not only in the evaluation of wall motion, but also for identification of thrombus, apical hypertrophy, noncompaction cardiomyopathy, eosinophilic cardiomyopathy, and apical entrapment from apical or mid-cavity outflow obstruction. Lastly, endocardial definition with contrast aids in the measurement of LV volumes. Accordingly, it is increasingly used in situations in which it is necessary to quantify left ventricular function with accuracy and precision, such as in patients being considered for certain device therapy (implantable cardioverter-defibrillator [ICD] therapy, cardiac resynchronization therapy [CRT]) or for following patients being treated with cardiotoxic chemotherapy regimens.

In the past, the perception, or perhaps more accurately the misperception, of the safety of microbubble contrast agents has been a major obstacle in the willingness of clinicians to use what is otherwise thought to be a valuable diagnostic asset. In October 2007, the U.S. FDA mandated a "black box" prescribing warning based on a handful of adverse outcomes identified by post-marketing surveillance in patients receiving ultrasound contrast agents. Most of these adverse outcomes could not be directly attributed to the use of contrast, particularly since echocardiography (with or without contrast) is often used to assess cardiovascular status in critically ill patients with acute hemodynamic instability. The FDA's actions led to a series of safety studies in different patient populations that have given greater confidence in contrast agent safety. These studies demonstrated that ultrasound contrast agents have a very low (approximately 0.01%) incidence of severe allergic reaction, and do not increase mortality.^3,4 The better understanding of safety and of the clinical impact of contrast in echocardiography led the FDA to retract the contraindications and to ease the warnings and administration restrictions. More importantly, the recognition that ultrasound contrast agents are among the safest of all imaging agents has gradually eased clinician angst.

With regards to market forces, the uptick of contrast use coincided with the establishment of Medicare "C-codes" for reimbursement for the use of microbubble contrast agents in hospital outpatient rest and stress echocardiography. The average amount of extra reimbursement for a contrast versus non-contrast rest echocardiogram exceeds the cost of the contrast agent in order to compensate for additional time, supplies, or infrastructure needed to perform these types of studies. The American Society of Echocardiography efforts, primarily educational programs, have been key for not only informing clinicians on the beneficial clinical impact of contrast, but also on on guiding lab directors on coding/reimbursement. Most importantly, these programs have also focused on key lab policies needed to address key questions that hinder contrast adoption (e.g., is consent needed, who makes the decision for giving contrast, is there ready access to contrast, who is allowed to place an IV?). Often, it is the practical issues rather than any safety or efficacy concerns that present the greatest challenge to implementation.

In summary, the use of contrast in echocardiography is once again on the rise. Yet the number of echocardiographic studies in which contrast is used for LV opacification is still quite small (just over 3%). Clinicians will only understand the potential impact this technology has in terms of diagnostic accuracy, cost-efficiency, and patient safety through concerted educational efforts. Perhaps more importantly, a more uniform set of guidelines and regulations are needed for echocardiography labs to be able to implement policies that will allow this technology to permeate.

References

1. Arlington Medical Resources. Vital Clinical Insights From Experts for Experts (AMR website). Available at: http://www.amr-data.com/. Accessed on 3/6/2015.
2. Rinkevich D, Kaul S, Wang XQ, et al. Regional left ventricular perfusion and function in patients presenting to the emergency department with chest pain and no ST-segment elevation. Eur Heart J 2005;26:1606-11.
3. Main ML, Ryan AC, Davis TE, Albano MP, Kusnetzky LL, Hibberd M. Acute mortality in hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (multicenter registry results in 4,300,966 consecutive patients). Am J Cardiol 2008;102:1742-46.
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.

Keywords: Acute Coronary Syndrome, Albumins, Artifacts, Bandages, Cardiac Resynchronization Therapy, Cardiomyopathies, Contrast Media, Critical Illness, Decision Making, Defibrillators, Implantable, Echocardiography, Echocardiography, Stress, Emergency Service, Hospital, Fluorocarbons, Heart Ventricles, Hemodynamics, Humans, Hypersensitivity, Hypertrophy, Incidence, Injections, Intravenous, Lipids, Marketing, Medicare, Microbubbles, Microvessels, Molecular Weight, Noble Gases, Outpatients, Patient Safety, Positive-Pressure Respiration, Thrombosis, United States, United States Food and Drug Administration, Ventricular Function, Left, Virtues, Workflow, Cardiotoxicity

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