Impact of Ultrasound Enhancing Agents on Clinical Management

STRUCTURED ABSTRACT

Purpose of Review:

Ultrasound enhancing agents (UEAs), microbubbles which are composed of lipid or albumin shells containing high molecular weight gases with nonlinear acoustic properties in the ultrasound field, are important components of the diagnostic armamentarium in echocardiography. This review highlights the substantial value of UEAs in delineating endocardial border definition and influencing downstream decision-making in cardiovascular ultrasound.

Recent Findings:

In this article, we review recent updates to the clinical applications of UEAs, special circumstances regarding use, the impact of use on downstream testing and cost-effectiveness, and recommended approaches for optimizing workflow in the echocardiography laboratory with UEAs.

Summary:

In multiple studies, UEAs have been identified as a useful tool in echocardiography, improving study accuracy and reader confidence, while reducing downstream testing and procedures and resulting in significant changes in clinical management. Despite their proven efficacy and cost-effectiveness, recent studies have suggested utilization remains low, in part due to perceived concerns and workflow issues that impair uptake. With an increasingly broader list of indications for echocardiography, UEAs will continue to play an important role in the diagnosis and management of patients with cardiovascular and non-cardiovascular diseases.

INTRODUCTION

Approximately 10-15% of all ambulatory echocardiograms are estimated to have poor endocardial border definition (1, 2). In this setting ultrasound enhancing agents (UEAs), microbubbles consisting of a lipid or albumin shell containing high molecular weight gases that produce nonlinear acoustic signals and effective tissue contrast in the ultrasound field (1, 2), have been shown to have substantial value in delineating endocardial border definition and influencing downstream clinical decision-making in diverse clinical circumstances. In this article, we will review 1) the clinical applications of UEAs, 2) special circumstances regarding use, 3) the impact of use on downstream testing and cost-effectiveness and 4) recommended approaches for optimizing workflow in the echocardiography laboratory with UEAs.

CLINICAL APPLICATIONS OF ULTRASOUND ENHANCING AGENTS

Numerous studies have supported the use of UEAs in a large variety of clinical circumstances (2-22). First, UEAs have shown value in improving quantification and assessment of left ventricular regional and global function (3-6). Compared to unenhanced imaging, UEAs have been associated with increased left ventricular (LV) volumes both with 2-dimensional and 3-dimensional echocardiography (3) and result in reduced interobserver variability in measurement of left ventricular ejection fraction (LVEF) resulting in improved concordance with similar measurements obtained on cardiac magnetic resonance imaging, the gold-standard for volumetric assessment (3, 5). In assessment of regional wall motion and thickening, use of UEAs has been shown to improve interobserver agreement on regional wall motion abnormalities compared to unenhanced imaging (6) as well as the sensitivity, specificity and reader confidence in stress echocardiogram interpretation of technically difficult studies (TDS) (4). In this circumstance they have also been shown to improve the accuracy and reproducibility of stress test findings (10) and may reduce downstream testing and costs (11).

In addition to Food and Drug Administration (FDA)-approved indications for UEAs for LV opacification in the setting of TDS, UEAs have a number of relevant off-label indications (2). For individuals with intra-cardiac masses, UEAs improve the distinction between avascular and vascular structures (2). They additionally may be helpful to identify the presence of apical hypertrophic cardiomyopathy and determine the presence or absence of an associated apical aneurysm (7), which predisposes to higher cardiovascular risk (23). In individuals with apical LV dysfunction, they are effective for excluding the presence of a mural thrombus (2) and amongst those with suspected LV non-compaction cardiomyopathy, they can be useful to distinguish trabecular recesses (especially using an intermediate mechanical index [i.e. 0.3-0.5]) (24). Amongst patients presenting for electrical cardioversion for whom left atrial or left atrial appendage thrombus must first be excluded, UEAs have been shown to improve confidence in absence of thrombus presence (8) and may result in decreased rates of subsequent embolic events (9).

Additionally, there are a number of off-label indications for use of UEAs for inotropic and vasodilator stress testing (2). In the setting of inotropic stress echocardiography with dobutamine, UEAs improve detection and extent of coronary artery disease vs. visual wall motion analysis alone (12, 13) and improve upon visual wall motion analysis in identifying individuals at risk for myocardial infarction or death (14). In the setting of vasodilator stress echocardiography, UEA-enhanced imaging has been shown to have equivalent specificity but higher sensitivity than single-photon computed tomography (SPECT) for detection of coronary artery disease (15, 16) as well as enhanced prognostic value (5, 17-20), particularly in the setting of pre-existing left bundle branch block or nonischemic wall motion abnormalities (13). Furthermore, as the rate of uptake of UEAs after a high mechanical index flash correlates with myocardial blood flow and the peak intensity with myocardial blood volume, UEAs can be used for quantitative myocardial stress perfusion which has a sensitivity and specificity of > 80% against coronary angiography (21, 22, 25) and offers superior prognostic information to qualitative analysis (20).

SPECIAL CIRCUMSTANCES

While the use of UEAs in patients with known intra-cardiac shunts (or intra-arterial use) is contraindicated due to concerns regarding arterial vascular occlusion, and its use in pregnancy is limited by insufficient data to support safety (2), UEAs are safe and effective in a variety of other clinical scenarios with a fixed rate of anaphylactoid response, a complement activation-related pseudoallergy, that occurs in 1 in 10,000 individuals (26), representing the lowest rate of adverse reactions from any form of contrast media (27). In the setting of coronavirus disease 2019 (COVID-19) infection, UEAs were recommended by the American Society of Echocardiography (ASE) to reduce sonographer exposure risk caused by delay in obtaining adequate diagnostic images (28). Moreover, in this setting, they have also been shown to be safe and effective. In a single-center prospective study of 33 individuals with technically difficult (82%) or uninterpretable (18%) images, admitted to a hospital in New York City, of which 42% were mechanically ventilated and 36% were obese, UEAs resulted in interpretable right ventricular (RV) function in 91% and LV function in 97%, without any adverse events within an hour of use (29). Similarly, in individuals with left ventricular assist devices, UEAs improved image quality in 83% resulting in management changes in 42% (including pump speed changes in 25%, additional inotropic support in 8% and use of anticoagulation in 8%) without a change in device parameters noted (30).

In April 2021, MedWatch, the FDA’s product safety reporting system, upon reviewing cases of COVID-19 vaccine related Type-1 hypersensitivity reactions, issued a safety alert on polyethylene glycol (PEG) containing UEAs (31). PEG is a component of two commercial UEAs (Lumason™/Sonovue™ produced by Bracco Diagnostics and Definity™/Luminity™ produced by Lantheus Medical Imaging), acting to stabilize the agents and reduce opsonization, and is found in numerous household products (31). Over two decades of pharmacovigilance, the report identified eleven cases of anaphylaxis including two deaths, felt related to use of UEAs in those with pre-existing PEG hypersensitivity (31). While case reports of PEG-allergy to UEAs have been reported (32), based on extensive safety data that spanned the time period of pharmacovigilance (26, 33-35), the ASE (31), the European Association of Cardiovascular Imaging (36), and International Contrast Ultrasound Society (37) issued statements recommending avoidance of PEG-containing UEAs in those with a known history of hypersensitivity to PEG or PEG-containing products (including bowel preparations or laxatives) but suggested that no changes in laboratory policies for patient monitoring or treatment algorithms for hypersensitivity reactions were necessary.

IMPACT OF USE ON DOWNSTREAM TESTING AND COST-EFFECTIVENESS

By improving endocardial border resolution and detection of wall motion abnormalities, UEAs have been shown to have significant downstream ramifications for cost-reduction and procedure avoidance in several clinical circumstances. In a single-center study by Kurt et al. (38) enrolling 632 individuals receiving UEAs across inpatient and outpatient wards and intensive care units, use of UEAs resulted in a decrease in uninterpretable studies from 11.7% to 0.3% and a decrease in TDS from 86.7% to 9.8%, with the highest impact observed in the intensive care units (ICUs) where 78.4% of surgical ICU and 96.2% of medical ICU echocardiograms became interpretable (38). This resulted in avoidance of further diagnostics (transesophageal echocardiogram or nuclear imaging) in 32.8% including the majority of patients in the surgical ICU and changed management in 35.6% of surgical ICU studies (procedures avoided or medication changes) (38). Subtracting the cost of avoided procedures or diagnostics from the cost of UEAs, the net savings were $122 per patient (in 2008 dollars) or $189 spent to avoid one diagnostic test (38).

More recently, in a study of 9,115 heart failure admissions over 4 years (39*), use of UEAs on the baseline echocardiogram, regardless of image quality, resulted in a reduction in unjustified repeat echocardiograms from 1.3% to 0.9% (odds ratio 0.18, 95% confidence interval 0.12-0.29, p < 0.001) (39*). Perhaps more remarkably, use of UEAs in the first echocardiogram was associated with a reduction in length of stay by an average of half a day and a 20% lower odds for prolonged (> days) length of stay (39*).

This cost-effectiveness extends to myocardial perfusion imaging as well. In a study of 1,116 individuals presenting to the Emergency Department (ED) with chest pain for greater than 30 minutes (40), a risk model containing information on electrocardiographic changes, regional wall motion, and abnormal myocardial perfusion using UEAs, accurately stratified an individual’s probability of subsequent cardiac events ranging from 0.4% to 55.3%, suggesting its use as a screening tool (40). In a separate study (41) of 1,194 patients with chest pain presenting to the ED from 2000-2003, a UEA-driven myocardial perfusion guided approach would have resulted in preventing 207 admissions for chest pain and decreased observation stay length for 316 others with normal perfusion, with a net savings of $900 per patient (or $861,300 total). In this study the cost of the myocardial perfusion imaging with UEAs would need to exceed $1,151 before the costs of usual care would be exceeded.

Moreover, empowerment of sonographers to administer UEAs, supported by both the ASE (7) and Society of Diagnostic Medical Sonography (42) as within sonographers’ scope of practice, has been shown to improve UEA utilization and cost savings (43). In a study (43) of sonographer driven UEA administration after 3 months of a feasibility phase in which UEAs were made physically available in the ICUs and wards and sonographers trained in venipuncture, the time required to make the decision to use UEAs was reduced by a mean of 0.7 minutes and the time required to administer UEAs reduced by 3.2 minutes. In this study if 10 minutes or more was saved for a particular study, cost savings linearly increased at a rate of $3.28 for every minute saved.

RECOMMENDED APPROACHES FOR OPTIMIZING WORKFLOW

While UEAs have significant value, their use remains relatively uncommon. In a study (44) of 97,649 patients over 18 years at a single academic medical center (the IN-USE study), UEAs were used in 2.6% of echocardiograms, despite TDS in 16.6%. While the use of UEAs increased at a mean rate of 0.3% per year, the rate of TDS increased faster, by a mean rate of 0.4% per year, as a result of increasing rates of obesity and application of echocardiography as a diagnostic tool in a broader population. Factors related to improving workflow include starting examinations with apical views which are optimal for assessment of image quality, empowering sonographers to administer UEAs and place intravenous (IV) catheters, presence of a standing order for UEA administration and a decision aide to guide use. While the role of UEAs should be considered in all inpatients based on the presence of IVs, the higher rate of TDS (44), and the need for accurate decision-making in this setting, decision aides may be helpful in determining whether outpatients require UEAs. In particular, in the IN-USE study, 3 variables (weight, age and heart rate), available prior to image acquisition predicted the composite outcome of UEA use or TDS (i.e. potential need for UEAs) with a C-statistic of 0.74 in internal validation. As such, this score could guide IV placement with the decision to administer UEAs made based on assessment of image quality. In 2022 this score was externally validated in a cohort of 12,086 individuals undergoing echocardiography at a high UEA utilizing (22.6% of echocardiograms) academic medical center (45**). Despite testing this score to predict UEA use alone (rather than the composite of UEA use or TDS), the score performed similarly to other clinically-used algorithms, such as the CHA₂DS₂-VASC score, with a C-statistic of 0.63. The IN-USE algorithm is undergoing prospective testing to determine if it improves uptake of UEAs and reader confidence, and point-of-care calculators are in development.

In the setting of stress echocardiography, an 11-point decision aide has been developed to predict the likelihood of subsequent UEA use (46). This decision aide which leverages information on age, sex, smoking history, cardiac risk factors, body mass index, prior coronary artery disease, an abnormal electrocardiogram or use of dobutamine for inotropic stress was shown to have a graded relationship with UEA use in 15,232 patients undergoing stress echocardiography at Mayo Clinic. A score ≥ 5 had a sensitivity and specificity for UEA use of 66% and 64%, respectively.

CONCLUSIONS

In multiple studies, UEAs have been shown to be a useful tool in echocardiography, improving study accuracy and reader confidence, while reducing downstream procedures and supporting important changes in clinical management. Despite their proven efficacy and costs-effectiveness, UEA utilization remains low, hampered by perceived barriers and clinical workflow issues. Preparing for use, enabling sonographers to place IVs and administer UEAs and enacting decision aides to guide use may result in improved uptake and utilization and are best implemented under the guidance of a physician/staff advocate who is able to identify local needs and treatment gaps. As the frequency of and indications for echocardiography expand, UEAs will remain an increasingly important tool for optimizing clinical decision-making and promoting value-based care for patients.

KEY POINTS.

1. Ultrasound enhancing agents (UEAs) have a number of demonstrated and expanding uses in echocardiography, with data suggesting use is associated with lower healthcare costs to improved clinical decision-making.

2. While utilization of UEAs has been low due to perceived barriers, UEAs may promote more efficient clinical workflow and decreased downstream testing and utilization.

3. Use of decision aides to guide UEA utilization may improve appropriate use and help promote value-based care for patients.