Echo contrast medium: How the use of contrast echocardiography (ultrasound contrast agents) can improve patient care

Abstract

Conventional echocardiography can sometimes pose a challenge to diagnosis due to sub-optimal images. Ultrasound contrast agents (UCAs) have been shown to drastically enhance imaging quality, particularly depicting the left ventricular endocardial borders. Their use during echocardiography has become a valuable tool in non-invasive diagnostics. UCAs provide higher-quality images that may ultimately reduce the length of hospital stays and improve patient care. The higher cost associated with UCAs in many situations has been an impediment to frequent use. However, when used as an initial diagnostic test, UCA during rest echocardiogram is more cost-effective than the traditional diagnostic approach, which frequently includes multiple tests and imaging studies to make an accurate diagnosis. They can be easily performed across multiple patient settings and provide optimal images that allow clinicians to make sound medical decisions. This consequently allows for better diagnostic accuracies and improvement in patient care.

Key Words: Ultrasound contrast agents; Echocardiography; Myocardial perfusion; Ultrasound; Left ventricle; Optison; Definity; Sonazoid; Lumason

Core Tip: The use of ultrasound contrast agents (UCAs) during resting echocardiography can improve diagnostic accuracy by adequately assessing left ventricular (LV) function. Compared to standard echocardiograms, UCAs, when used, allow physicians to better assess regional wall motion abnormalities and LV ejection fraction. As a result, patients with LV apex disease can be accurately diagnosed without additional imaging. This consequently shortens hospital stays and improves patient outcomes.

INTRODUCTION

Ultrasound contrast agents (UCAs) are microspheres suspensions that consist of an outer albumin or phospholipid shell encompassing an inner high-molecular weight gas[1]. These are intravascular tracers that are similar in size to red blood cells, which allows for opacification of blood in the myocardial vessels and cavities[1,2]. UCAs are strong ultrasound reflectors, thereby producing intense echocardiographic signals that are stronger than standard ultrasound waves[2,3]. As a result, contrast echocardiograms serve as a tool to improve image quality[3,4]. They facilitate interpretability as more than 25% of stress echocardiograms and more than 5% of resting echocardiograms yield suboptimal images[4-6]. UCA during echocardiography is desirable as image improvement may redirect patient management, and its use improves the signal-to-noise ratio in spectral and color Doppler imaging[2,6,7]. When used as part of the initial diagnostic work-up, contrast echocardiography is highly beneficial due to better diagnostic accuracy than standard echocardiography[8]. This is particularly important as UCAs used during echocardiography may shorten hospitalization and improve patient care and mortality[8,9].

TYPES OF CONTRAST AGENTS

Contrast echocardiography has become a valuable tool in non-invasive cardiac imaging[10]. Currently, there are several available contrast agents (Table 1) as listed below.

Table 1 Commercially available ultrasound contrast agents.

Name	Manufacturer	First approved for clinical use	Gas	Shell composition	Countries
Optison	General Electric Healthcare, Buckinghamshire (United Kingdom)	1998	Octafluoropropane	Cross-linked serum albumin	Unites States, Europe
Definity/luminity	Lantheus Medical Imaging Inc, North Billerica (Massachusetts, United States)	2001/2006	Octafluoropropane	Phospholipid	North America, Europe
SonoVue/lumason	Bracco Diagnostics Inc (New Jersey, United States), Bracco Imaging S.p.A (Milan, Italy)	2001/2014	Sulfur hexafluoride	Phospholipid	United States, Europe, China, Brazil
Sonazoid1	General Electric Healthcare, Buckinghamshire (United Kingdom), Daiichi Saniko, (Tokyo, Japan)	2007	Perfluorobutane	Hydrogenated egg yolk phosphatidyl serine (HEPS)	Japan, South Korea, Norway, Taiwan, China
Albunex	Molecular Biosystems Inc., (California, United States)	1993, withdrawn	Air	Sonicated serum albumin	United States, Japan
Imagent/imavist	Schering AG	2002, withdrawn	Perfluorohexane, Nitrogen	Phospholipid	United States
Echovist	Schering AG	1991, withdrawn	Air	Galactose microparticles	United Kingdom, Germany
Levovist	Schering AG	1995, withdrawn	Air	Galactose microparticles, palmitic acid	Europe, Canada, Japan, China

¹Not approved by the Food and Drug Administration for any indication in the United States, but is approved for use in Japan, South Korea, Norway, and China for focal hepatic lesions depiction.

Optison

Optison (perflutren protein-type A microspheres injectable suspension, USP) manufactured by General Electric Healthcare is a non-pyrogenic suspension consisting of microspheres with an Octafluoropropane (perflutren) gas core encapsulated by a 15 nm thick serum albumin shell[11,12]. Its reconstitution is done by mixing, and the concentration of the reconstituted suspension is approximately 5.0-8.0 × 10⁸ microspheres/mL with an average diameter of 3.0-4.5 µm[13,14]. The albumin shell rigidity in Optison is 88.8 MPa with a shear viscosity of 0.177 Ns/m², derived from previous mathematical modeling and experimental measurements[15]. Based on data for Albunex, values for the shell elasticity and dilational viscosity can be estimated as 4 N/m and 3.2 × 10^-8 kg/s, respectively[13-15]. In vitro assessment has indicated that the gas dissolution pressure for speedy destruction of Optison was 0.47 MPa when exposed to 3.5 MHz ultrasound, while a lower threshold was found to facilitate accelerated dissolution[14-16]. These innate features of the albumin shell make Optison an effective UCA for clinical use.

Optison was first introduced to the United States market in 1998[17]. More than 3 million patients have received Optison since it was approved by the Food and Drug Administration (FDA) in 1997[17,18]. It has a well-established safety profile, and it is used to opacify the left ventricle and improve the left ventricular (LV) endocardial border delineation in patients with suboptimal echocardiograms[12-14].

Definity

Definity (United States) is one of the second-generation microbubble contrast agents approved for LV endocardial border detection and LV opacification[19]. It was approved by the FDA in 2001 and the European Medicine Agency under the brand name Luminity in 2006 for patients with technically challenging or suboptimal echocardiograms[20]. Definity injectable suspension is sold as a single-use 2 mL vial containing a clear liquid and Octafluoropropane gas[21]. The liquid solution contains the three phospholipids DPPA (1,2-Dipalmitoyl-sn-glycero-3-phosphate, sodium salt), DPPC (1,2-Dipalmitoyl-sn-glycero-3-phosphocholine), and DPPE-MPEG₅₀₀₀[21,22]. The shell properties for Definity microbubbles have been estimated at low (5-15 MHz) and high (12-29 MHz) ultrasound frequencies[23,24]. At lower frequencies, corresponding values for the shell elasticity and dilatational viscosity have been reported, which are significantly lower compared to those of Optison[24].

In addition to endocardial visualization, Definity is used to measure LV ejection fraction and volumes[22]. It also allows for the diagnoses of apical LV pathologies (i.e., thrombus or apical variant of hypertrophic cardiomyopathy), post-myocardial infarction complications (i.e., ventricular septal defect or LV pseudoaneurysm/rupture), and intracardiac masses, which are drastically enhanced[22-24]. Definity is approved for imaging of the kidney and liver in Australia and Canada[23-25].

SonoVue

SonoVue (sulfur hexafluoride microbubbles) (Italy) or Lumason (sulfur hexafluoride lipid-type A microspheres) (United States) is a UCA supplied as a kit containing a vial of phospholipid lyophilized powder and sulfur hexafluoride headspace, a mini-spike transfer system, and a pre-filled syringe with a 5 mL sodium chloride 0.9% diluent[26,27]. It is administered as an intravenous bolus injection followed by a 5-10 mL saline flush and should be shaken appropriately before administration[28]. The viscoelastic shell parameter values of 0.55 N/m for shell elasticity and 7.2 × 10^-9 kg/s for dilational viscosity have been reported in the literature, which closely resemble the values of Definity[28,29].

SonoVue was approved for use in adult patients with suboptimal echocardiograms to opacify the LV chamber and improve the delineation of the LV endocardial border in China (2004) and Europe (2001)[29,30]. Lumason was subsequently approved in the United States (2014) for adult patients with suboptimal echocardiograms to improve delineation of the LV endocardial border[31]. The FDA approved it for characterizing focal hepatic lesions in adults and pediatric patients in 2016[30]. Lumason has also been recently approved for ultrasonography of the urinary tract for the evaluation of vesicoureteral reflux in pediatric patients in countries including the United States (2016), Europe (2017), and China (2018)[32,33].

Sonazoid

Sonazoid microspheres is a second-generation contrast agent approved in Japan, Norway, South Korea, Taiwan, and China for contrast-enhanced sonography of focal hepatic lesions[34,35]. It is compounded as a lyophilized powder for injection that consists of Perfluorobutane microspheres stabilized by a monomolecular membrane of hydrogenated egg yolk phosphatidyl serine[36]. The viscoelastic shell parameter values of 0.5-0.6 N/m for the shell elasticity and 1.2 × 10^-8-1.6 × 10^-8 kg/s for dilational viscosity have been reported, with the dilational viscosity 2-3 times higher compared to SonoVue and Definity, respectively[36,37].

Sonazoid as a UCA in the liver produces two phases of contrast enhancement: A vascular phase followed by a Kupffer phase (post vascular phase)[38]. The normal liver parenchyma is enhanced during the post-vascular phase, and malignant lesions are visualized as clear contrast defects[38,39]. The pattern of vascular phase and post-vascular phase enhancements are used to better characterize focal hepatic lesions and detect the presence or absence of masses[38-40]. Recently, Sonazoid has been used off-label to detect sentinel lymph nodes in cancer[41].

SAFETY OF CONTRAST AGENTS

UCAs approved for clinical use are often well tolerated, and serious adverse effects are rarely observed[42]. Adverse reactions are minor and commonly include altered taste, sensation of heat, nausea, and headache, which are treated symptomatically[42]. In 2007, the FDA issued a “black box” warning with contraindications to several disease states, including ventricular arrhythmias, decompensated heart failure, acute myocardial infarction, among others, to several contrast agents due to four patient deaths and over 180 serious adverse events associated with UCA use[1,42]. Critics argued that there was no proof in relation to these adverse events and cited other reasons as an explanation. In 2008, the FDA deescalated the contraindications to warnings. Since then, safety studies have been done, particularly with Definity and Optison, which have demonstrated low rates of adverse events[43,44].

BUBBLE TO ULTRASOUND SIGNAL

Contrast agents induced changes in reflection pattern. They increase backscattered signals and appear nonlinear with increasing vibrational patterns when significant acoustic pressures are applied[1,2,44]. Differentiation of signal origin, whether UCA or tissue, is possible as tissue produces harmonic frequencies at a higher mechanical index[45]. With filter systems, several natural frequencies are received, allowing for a certain amount of background signal suppression[44,45]. High-pressure levels disrupt microbubbles and create nonlinear patterns that lead to ultrasound signals[1,43-45].

DISCUSSION

These contrast agents have achieved an established role in LV opacification and identification of the endocardial border[19]. When administered, UCAs can successfully yield LV ejection fraction and volume that correlate well with other imaging techniques, such as magnetic resonance imaging (MRI), in patients for whom the use of unenhanced imaging is technically difficult[19,46]. Additionally, UCAs have the ability to impact and alter disease management[47].

A large prospective cohort study by Kurt et al[48] evaluated the impact of UCAs on patient diagnosis and management. Over 600 patients with technically inadequate echocardiographic studies who received UCAs were enrolled. The quality of studies, estimated ejection fraction, number of LV segments visualized, presence of apical thrombus, and management decisions were compared before and after contrast. Results showed that technically difficult studies decreased from 86% to 9.8% (P < 0.0001), and uninterpretable studies declined from 11% to 0.3%. Before contrast, 11.6 +/- 3.3 of 17 LV segments were visualized, which improved to 16.8 +/-1.1 (P < 0.0001) after contrast. A major impact of UCAs on management was also observed, where additional diagnostic procedures were avoided in 32% of patients, and drug management was altered in 10% of patients. A cost-benefit analysis also showed an average saving of $122 per patient. The study revealed that contrast echocardiography improves endocardial visualization and diagnosis, resource utilization, and patient management. This was evident in both the reduction in the number of additional diagnostic procedures and in the drastic alteration in medical management.

UCAs possess the ability to limit unnecessary diagnostic imaging such as MRI, x-rays, and computed tomography scans to achieve an accurate diagnosis[49]. As a result, they can shorten hospitalization length, ultimately improving patient care and outcomes[49,50]. Conditions such as apical hypertrophic cardiomyopathy and cardiac masses, particularly ventricular thrombi, can be readily identified on contrast echo[51]. An accurate diagnosis saves time and potentially alters treatment decisions, which ultimately benefits the patient. In allowing fewer diagnostic tests to render a medical verdict, contrast echo provides added financial satisfaction to patients[50,52].

CONCLUSION

A compelling case can be made for using UCAs to depict the LV endocardial borders in patients undergoing echocardiography. They significantly improve diagnostic accuracy, reducing the need for additional imaging. Consequently, contrast echocardiography reduces both patient cost and healthcare burden. UCAs can also be used to accurately measure velocities from Doppler signal recordings, which may eliminate the need for cardiac catheterization. An additional case can be made for specialists to train in the use and interpretation of myocardial contrast echocardiography during stress and rest, which may equip the echocardiography laboratory with the ability to diagnose the presence of coronary artery disease in patients with normal regional LV function. Overall, UCAs can be used as a point of care tool to accurately assess myocardial disease, which may shorten hospitalization, reduce resource utilization, and improve patient care.