On completion of this chapter, you should be able to:
List the current limitations of ultrasound imaging that may be overcome by the use of ultrasound contrast agents
Describe the properties that an ultrasound contrast agent must have to be clinically accepted
Describe the difference between tissue-specific ultrasound contrast agents and vascular agents
Describe how contrast harmonic imaging improves the clinical capabilities of ultrasound contrast agents
Describe the hepatic applications of contrast agents
Since the 1980s, a significant amount of research has been conducted toward the development of ultrasound contrast agents (UCAs) . Most of the work has centered on developing agents that can be administered intravenously to evaluate blood vessels, blood flow, tumors, and solid organs.
The clinical utilization of contrast-enhanced sonography (CES) has been shown to reduce or eliminate some of the current limitations of ultrasound (US) imaging and Doppler blood flow detection. These include limitations of spatial and contrast resolution on gray-scale US and the detection of low-velocity blood flow and flow in very small vessels using Doppler flow detection modes, including color flow imaging and pulsed-wave Doppler with spectral analysis. Advances in US equipment technology following the development of UCAs have resulted in contrast-specific imaging modes, including gray-scale US methods that allow detection and display of blood flow without the limitations of Doppler US. The use of CES is growing around the world and there are published clinical guidelines describe the most appropriate use of CES for a variety of abdominal, retroperitoneal, and other applications. Ultrasound contrast agents are increasingly being used to improve the sensitivity and specificity of US diagnoses and are expanding sonography’s already broad range of clinical applications.
Types 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 US equipment sensitivity and the operator dependence of Doppler US are also factors that may affect the results of a vascular examination. Vascular or blood-pool UCAs enhance Doppler (color and spectral) flow signals by adding more and better acoustic scatterers to the bloodstream ( Figures 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) ( Figure 17-3 ). In addition to enhancing Doppler signals, vascular ultrasound contrast agents also improve gray-scale US visualization of flowing blood and demonstrate changes to the gray-scale echogenicity of tissues with the use of contrast-specific imaging software such as contrast harmonic imaging (CHI).
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 unstable, which makes them unsuitable for sonographic evaluations of the left side of the 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 ).
|Agent Name, Manufacturer||Approved Indications|
|Optison, GE Healthcare, Princeton, NJ||LVO/EBD|
|Definity, Lantheus Medical Imaging, N. Billerica, MA||LVO/EBD|
|Imagent, IMCOR Pharmaceuticals, Inc., San Diego, CA (Imagent is not currently being marketed)||LVO/EBD|
|Lumason Bracco International, Milan, Italy||LVO/EBD and characterization of focal hepatic tumors in adult and pediatric patients.|
|Agent Name, Manufacturer||Countries||Approved Indications|
|Definity, Lantheus Medical Imaging, London, U.K. |
(Marketed as Luminity in some countries)
|Canada, Mexico, Israel, New Zealand, India, Australia |
† European Union, Korea, Singapore, United Arab Emirates
|LVO/EBD, liver, kidney|
|Optison, GE Healthcare, Chalfont St. Giles, U.K.||European Union||LVO/EBD|
|Sonazoid, Daiichi Pharmaceutical Co., LTD, Tokyo, Japan |
(Manufactured and distributed in partnership with GE Healthcare)
|Japan||Focal liver lesions |
Focal breast lesions
|SonoVue, Bracco International, Milan, Italy||European Union, Norway, Switzerland, China, Singapore, Hong Kong, S. Korea, Iceland, India |
|LVO/EBD, breast, liver, portal vein, extracranial carotid, peripheral arteries (macrovascular and microvascular)|
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 pool. , In 1998, Optison (FSO 69) was approved by the U.S. Food and Drug Administration (FDA) for cardiac applications in the United States. 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 gray-scale CHI and Doppler modes for echocardiography, as well as systemic vascular, tumor characterization, and abdominal applications. , , ,
SonoVue (BR-1) is an aqueous suspension of phospholipid-stabilized sulfur hexafluoride (SF-6) microbubbles having 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 US’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 non-cardiac indication. It is FDA approved for characterization of focal liver lesion in adult and 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. Some tissue-specific UCAs also enhance the sonographic detection of blood flow and are therefore potentially multipurpose. Because tissue-specific UCAs 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. 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 ( Figure 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 that follows) ( Figure 17-5 ). , Improvements in contrast-specific US technologies have obviated the use of Doppler modes with UCAs for the majority of applications.
It is important to remember that the AE effects are independent of contrast motion. In other words, the AE effect can result from oscillation and eventual rupture of stationary contrast microbubbles, and agents that demonstrate the AE phenomenon also can be utilized for nonvascular applications where there is little or no movement of the microbubbles.
Currently, tissue-specific agents that are taken up by the RES appear to be most useful in the assessment of patients with suspected liver abnormalities, including the ability to both detect and characterize liver tumors using CES. Other target- or tissue-specific agents are being developed to enhance the detection of thrombus and tumors.
Ultrasound equipment modifications
Microbubble-based UCAs enhance the detection of blood flow when used with conventional ultrasound imaging techniques, including gray-scale US, and Doppler techniques (i.e., color flow imaging and pulsed-wave Doppler with spectral analysis). However, research and experience have led to a better understanding of the complex interactions between acoustic energy (i.e., the US beam) and UCA microbubbles, which in turn has led to contrast-specific US imaging modes that greatly improve the clinical utility of CES.
Harmonic imaging (HI) uses the same broadband transducers used for conventional US, but in HI mode the US system is configured to receive only echoes at the second harmonic frequency, which is twice the transmit frequency (e.g., 7.0 MHz for a 3.5-MHz transducer). , When using a microbubble-based UCA, the microbubbles oscillate (i.e., they get larger and smaller) when subjected to the acoustic energy present in the US field. The reflected echoes from the oscillating microbubbles contain energy components at the fundamental frequency and at the higher and lower harmonics (i.e., subharmonics). Contrast harmonic imaging (CHI) allows detection of contrast-enhancement of blood flow and organs with B-mode US. The use of CHI for CES avoids many of the limitations and artifacts encountered when using Doppler US techniques and UCAs, such as angle dependence and “color blooming” artifacts. In CHI mode the echoes from the oscillating microbubbles have a higher signal-to-noise ratio than would be provided by using conventional US, so that regions with microbubbles (e.g., blood vessels and organ parenchyma) are more easily appreciated visually. Advanced CHI technology (e.g., wideband HI, phase-inversion HI, and pulse-inversion HI) employ image processing algorithms to subtract echoes arising from body tissues while echoes arising from contrast microbubbles are preferentially displayed. Thus CHI provides a way to better differentiate areas with and without contrast and has the potential to demonstrate real-time B-mode blood-pool imaging (i.e., “perfusion imaging”). The benefits of using CHI for CES (e.g., higher frame rates, improved contrast resolution, reduced artifacts) are so great that conventional (non-HI) color flow imaging is neither necessary nor advised.
When using microbubble-based UCAs, the energy present within the acoustic field can have a detrimental effect on the contrast microbubbles. A significant number of the microbubbles can be destroyed by the acoustic pressure even though the actual pressure contained within the US field is relatively low. Once the microbubble is destroyed, contrast enhancement is no longer provided, which reduces the clinical utility and duration of contrast enhancement. Several approaches have been used to minimize this problem. One relatively easy technique is to use a low acoustic output power as defined by the mechanical index (MI) . However, reducing the MI also limits tissue penetration, so this is not always an adequate solution. Furthermore, the MI may be an imprecise predictor of the effect of acoustic energy on contrast microbubbles. ,
Equipment manufacturers have incorporated intermittent imaging (also referred to as interval delay imaging ) capabilities on their systems to provide an additional option to the user seeking to reduce microbubble destruction during contrast-enhanced examinations. , , , In this mode the system is gated to only transmit and receive data at predetermined intervals. The gating may be triggered on a specific portion of the electrocardiogram (e.g., the r-wave) or a time interval such as once or twice per second. Intermittent imaging reduces the exposure of contrast microbubbles to the acoustic energy and allows additional microbubbles to enter the field between signal transmissions. The additional microbubbles then contribute to an even greater increase in reflectivity of the contrast-containing blood or tissue than would be possible by continuous real-time imaging. A disadvantage to intermittent imaging is its lack of a real-time display of data, but advances in instrumentation such as “flash echocardiography” address this weakness. Intermittent imaging is commonly combined with CHI to further improve the clinical utility of CES.
Moriyasu and colleagues used intermittent imaging for CES of hepatic tumors. This study showed that the signal intensity is dependent on an interscan delay time during which the acoustic power is lowered under the threshold for passive cavitation of the microbubbles. A study by Sirlin and colleagues demonstrated that intermittent imaging improved image contrast resolution and a 1-frame-per-second rate provided greater contrast resolution than that provided by continuous real-time imaging.
Other contrast-specific technologies include advanced three-dimensional (3D) and four-dimensional (4D) imaging ( Figures 17-6 and 17-7 ). Furthermore, a number of contrast-specific measurements and calculations can be performed, including onboard video densitometry, calculation of the integrated backscatter from contrast, measurement of the transit time of contrast-containing blood through normal and diseased tissue, estimations of blood volume, and assessment of tissue perfusion differences in solid organs. , , Systems have been developed that allow onboard calculation of the unique data provided by the use of UCAs ( Figure 17-8 ).
There are limitations to the sonographic evaluation of hepatic lesions and other hepatic abnormalities. Although US is usually sensitive for the detection of medium to large hepatic lesions, it is limited in its ability to detect small (less than 10 mm), isoechoic, or peripherally located lesions, particularly in obese patients or patients with diffuse liver disease. Furthermore, sonography is not as effective as computed tomography (CT) or magnetic resonance imaging (MRI) for characterization of hepatic tumors.
Hepatic US blood flow studies are limited by low-velocity blood flow (e.g., in cases of portal hypertension) or for the detection of flow in the intrahepatic artery branches. Ultrasound contrast agents have shown the potential to improve the accuracy of hepatic sonography, including enhanced detection and characterization of hepatic masses and improved detection of intrahepatic and extrahepatic blood flow.
Hepatic blood flow.
Vascular UCAs have been shown to improve the assessment of hepatic blood flow in normal subjects, as well as in patients with liver disease and portal hypertension (PHT). , , , ,
Most sonographic examinations for PHT include qualitative assessment of blood flow with color flow imaging to identify the presence and direction of flow in the splenic and superior mesenteric veins, as well as the main portal vein and the intrahepatic portal and hepatic veins. When scanning patients with PHT, slow-moving portal flow can be difficult to detect using conventional Doppler techniques. Studies have found that the increased reflectivity of contrast-containing blood allows the detection of abnormal blood flow in the portal and hepatic veins, as well as in portal-systemic collaterals. , ,
Contrast-enhanced sonography has also been used effectively in the assessment of flow through transjugular intrahepatic portosystemic shunts (TIPS). ,
Uggowitzer and colleagues found that Levovist provided Doppler signal enhancement lasting from 30 seconds to 7 minutes, and Levovist-enhanced scans improved the diagnosis of stent stenosis compared with conventional US examinations.
Published reports have described CES-detectable alterations in blood flow transit time through the livers of patients with diffuse hepatic disease compared with normal controls. , , In cases of cirrhosis there is often reduced portal venous flow and a compensatory increase in hepatic artery flow. Zhou and colleagues examined blood flow in the hepatic arteries and hepatic veins of 52 patients with metastases and 23 normal control subjects after bolus injections of SonoVue. The parameters that were evaluated included contrast arrival time, time to peak enhancement, and peak intensity values in the vessels. Additionally, the difference between the arrival times in the hepatic artery and the hepatic veins was calculated. The arrival times and transit times in the patient group were significantly shorter than those of the control group, and the peak intensity values in the patient group were significantly higher than those of the control group. The results of this study suggest that CES assessment of changes in the hemodynamic parameters of the hepatic artery and vein can be used to improve diagnosis of liver metastases possibly before sonographic detection of focal lesions.
Many patients who have hepatic tumors first identified sonographically eventually require a CT or MRI examination to better determine the extent of disease and to more accurately characterize the lesions. Using CES, it is possible to distinguish the various phases of blood flow to and within the liver. In normal situations after IV administration of a UCA, contrast-enhanced flow in the hepatic artery is identified first (arterial phase), followed by enhanced portal venous flow (portal venous phase). Detection of flow in the hepatic capillaries is identified later (late phase) as a parenchymal blush ( Figure 17-9 ). If an RES-specific agent is used, identification of the delayed enhancement phase representing the enhancement from the stationary microbubbles that have been phagocytosed by the RES is possible.