Abdominal Applications of Ultrasound Contrast Agents

Vascular Ultrasound Contrast Agents

Sonographic detection of blood flow is limited by factors including the depth and size of a vessel, the attenuation properties of intervening tissue, or low-velocity flow. Limitations of ultrasound equipment sensitivity and the operator dependence of Doppler ultrasound are also factors that may affect the results of a vascular examination. UCA are gas microbubbles encapsulated by an outer shell for stability. When injected intravenously, the agents are small enough (<8 μm) to pass through the pulmonary capillary beds but large enough to remain trapped within the vasculature. Vascular or blood-pooling UCAs can enhance Doppler (color and spectral) flow signals by adding more and better acoustic scatterers to the bloodstream ( Figs. 17.1 and 17.2 ). The use of these UCAs improves the color flow imaging detection of blood flow from vessels that are often difficult to assess without their use, such as the renal arteries, intracranial vessels, and small capillaries within organs (i.e., tissue perfusion) ( Fig. 17.3 ). However, contrast-specific imaging modes, which utilize the nonlinear scattering properties of UCAs, provide substantial improvements in contrast-to-tissue signal and improved detection of smaller vessels relative to contrast-enhanced Doppler. These modes are the preferred approach for CEUS imaging and are now available on most mid- to high-end commercial ultrasound scanners.

The concept of a UCA was first introduced by Gramiak and Shah in 1968, who, in their initial work, injected agitated saline directly into the ascending aorta and cardiac chambers during echocardiographic examinations. The microbubbles formed by agitation resulted in strong reflections arising from within the normally echo-free lumen of the aorta and chambers of the heart. Eventually, other solutions were discovered that could produce similar effects. However, microbubbles produced by simple agitation are nonuniform in size, relatively large, and quickly diffuse, which makes them unsuitable for sonographic evaluations of the left heart and systemic circulation because the microbubbles do not persist through passage of the pulmonary and cardiac circulations. Furthermore, to provide contrast enhancement, agitated saline required direct injection into the vessel under evaluation (e.g., the aorta), and a more clinically practicable administration method, such as intravenous (IV) injection, was desired.

For a UCA to be clinically useful, it should be nontoxic, have microbubbles or microparticles that are small enough to traverse the pulmonary capillary beds (i.e., less than 8 microns in size), and be stable enough to provide multiple recirculations. Furthermore, the contrast agent should be administered via IV injection and provide enhancement of ultrasound signals. A number of agents possess these desirable traits, and presently several microbubble-based UCAs are commercially available worldwide ( Tables 17.1 and 17.2 ). Specific UCA properties and their instructions for reconstitution and administration are provided in the product package insert.

The specific type of gas contained within a UCA microbubble and its shell composition influence the microbubble’s acoustic behavior (e.g., reflectivity and elasticity), method of metabolism, and stability within the blood. In 1998, Optison (FSO 69; GE Healthcare) was approved by the United States Food and Drug Administration (FDA) for cardiac applications. The microbubbles of Optison are composed of a shell of 5% sonicated human serum albumen that contains a high-molecular-weight gas (perfluoropropane), which extends the stability and plasma longevity of the agent. Optison has shown potential for use with nonlinear harmonic imaging and Doppler modes for echocardiography, as well as systemic vascular, tumor characterization, and abdominal applications.

Similarly, Definity (Lantheus Medical Imaging; marketed as Luminity in some countries) is composed of octafluoropropane microbubble encapsulated in an outer lipid shell. The agent was cleared by the US Food and Drug Administration in 2001 and is indicated for patients with suboptimal echocardiograms to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border. Definity is approved for numerous other applications worldwide and can be used off-label for improved visualization of the vasculature in a variety of clinical applications.

SonoVue (Bracco Diagnostics; marketed as Lumason within the United States) is an aqueous suspension of phospholipid-stabilized sulfur hexafluoride microbubbles which have a low solubility in blood. SonoVue enhances the echogenicity of blood and provides opacification of the cardiac chambers resulting in improved left ventricular endocardial border definition. In clinical trials, it has been shown to increase ultrasound’s accuracy in detection or exclusion of abnormalities in intracranial, extracranial carotid, and peripheral arteries. SonoVue also increases the quality of Doppler flow signals and the duration of clinically useful signal enhancement in portal vein assessments. SonoVue improves the detection of liver and breast lesion vascularity resulting in more specific lesion characterization. SonoVue has been approved for use in Europe for echocardiography and macrovascular applications. In the United States, SonoVue is marketed as Lumason, and it received FDA approval for echocardiography applications in 2014. Lumason has also been studied for liver lesion characterization, and in April 2016, it became the first UCA to gain FDA approval for a radiologic application with the indication for the characterization of focal liver lesions in both adult and pediatric patients. It is also FDA approved for ultrasonography of the urinary tract for the evaluation of suspected or known vesicoureteral reflux in pediatric patients.

Tissue-Specific Ultrasound Contrast Agents

The kinetics of UCA microbubbles following IV injection is complex, and each agent has its own unique characteristics. In general, after IV administration, blood-pool UCAs are contained exclusively in the body’s vascular spaces. Once a vascular agent’s microbubbles are ruptured or otherwise destroyed, the microbubble shell products are metabolized or eliminated by the body, and the gas is exhaled.

Tissue-specific ultrasound contrast agents differ from vascular agents in that the microbubbles of these agents are removed from the blood pool and taken up by, or have an affinity toward, specific tissues, for example, the reticuloendothelial system (RES) in the liver and spleen, or thrombi in blood vessels. Over time the presence of contrast microbubbles within or attached to the target tissue changes its sonographic appearance. By changing the signal impedance (or other acoustic characteristics) of normal and abnormal tissues, these agents improve the detectability of abnormalities and permit more specific sonographic diagnoses. Tissue-specific UCAs are typically administered by IV injection. Most tissue-specific UCAs also enhance the sonographic detection of blood flow and are therefore potentially multipurpose. Because tissue-specific UCAs passively target specific types of tissues and their behavior is predictable, they can be considered in the category of molecular imaging agents .

Sonazoid is a tissue-specific UCA that contains microbubbles of perfluorobutane gas in a stable lipid shell. Sonazoid is currently approved for use in Japan, China, Korea, Taiwan, and Norway. After being injected intravenously, Sonazoid behaves as a vascular agent (i.e., enhances the detection of flowing blood) and, over time, the microbubbles are phagocytosed by the RES (macrophage Kupffer cells) of the liver and spleen. The intact microbubbles may remain stationary in the tissue for several hours. When insonated after uptake, the stationary contrast microbubbles increase the reflectivity of the contrast-containing tissue. If an appropriate level of acoustic energy is applied to the tissue, the microbubbles first oscillate (emitting harmonic signals that can be detected with gray-scale CHI) and then rupture. The rupture of the microbubbles results in random Doppler shifts appearing as a transient mosaic of colors on a color Doppler display ( Fig. 17.4 ). This effect has been termed induced acoustic emission (IAE), stimulated acoustic emission (SAE), or simply acoustic emission (AE) . By exploiting the color Doppler–depicted AE phenomenon, masses that have destroyed or replaced the normal Kupffer cells will be displayed as color-free areas and thus become more sonographically conspicuous. These same AE effects can also be demonstrated using gray-scale CHI (see the CHI discussion below) ( Fig. 17.5 ). Improvements in contrast-specific ultrasound imaging technologies have obviated the use of Doppler modes with UCAs for the majority of applications.