New contrast media boost image quality
Systemic echo enhancement provided by the agents should increase the diagnostic confidence of clinical users
By: WILLIAM T. SHI, PH.D., FLEMMING FORSBERG, PH.D., JI-BIN LIU, M.D., CHRISTOPHER R. B. MERRITT, M.D., AND BARRY B. GOLDBERG, M.D.

The field of diagnostic ultrasound is again on the cusp of major change. In the last decade, drug companies, ultrasound scanner manufacturers, and academic centers have invested manpower and funding in developing efficacious ultrasound contrast agents and new contrast-specific imaging modalities. Now, by bringing contrast media to the clinic, these efforts appear on the verge of success. As in MRI, CT, and conventional x-ray, the use of contrast media could change the way ultrasound is performed, opening new and unique diagnostic opportunities.

Contrast agents can improve the image quality of sonography either by decreasing the reflectivity of the undesired interfaces or by increasing the backscattered echoes from the desired regions.1 In the former approach, the contrast agents are taken orally, and for the latter effect, the agent is introduced vascularly.

In the upper GI tract, sonographic assessment is limited by the gas-filled bowel, which produces shadowing artifacts. Ingestion of degassed water has been used to improve ultrasound imaging of the GI tract, but with inconsistent results. Alternatively, investigators have studied oral ultrasound contrast agents designed to adsorb and displace stomach and bowel gas. One such agent is SonoRx from Bracco, consisting of simethicone-coated cellulose. This agent recently was approved for clinical use by the FDA. Ingestion in dosages of 200 to 400 mL results in a homogeneous transmission of sound through the contrast-filled stomach.

Vascular enhancing ultrasound agents were first introduced by Gramiak and Shah in 1968, when they injected agitated saline into the ascending aorta and cardiac chambers during echocardiographic examinations.2 Strong echoes were produced within the heart, due to the acoustic mismatch between free air microbubbles in the saline and the surrounding blood. However, microbubbles produced by agitation are both large and unstable, diffusing into solution in less than 10 seconds.

To pass through the lung capillaries and enter into the systemic circulation, microbubbles within a vascular contrast agent should be less than 10 mm in diameter (2 to 5 mm on average for most of the newer agents). Stability and persistence become major issues for such small microbubbles, however. Air bubbles in that size range persist in solution for only a short time; too short for systemic vascular use. So the gas bubbles have to be stabilized for the agent to persist long enough and survive pressure changes in the heart.

Most vascular contrast agents are stabilized against dissolution and coalescence by the presence of additional materials at the gas-liquid interface. In some cases, this material is an elastic solid shell that enhances stability by supporting a strain to counter the effect of surface tension. In other cases, the material is a surfactant, or a combination of two or more surfactants. These promote stability by greatly reducing the surface tension at the interface. Moreover, although air, sulfur hexafluoride, nitrogen, and perfluorochemicals are used as microbubble-filling gases, most newer agents use perfluorochemicals because of their low solubility in blood and high vapor pressure. By substituting different types of perfluorocarbon gases for air, the stability and plasma longevity of the agents have been markedly improved, usually lasting more than five minutes.

Several cardiac and vascular ultrasound contrast agents are commercially available: Albunex and Optison (Molecular Biosystems) in the U.S., and Echovist and Levovist (Schering) in a number of European countries. Other agents undergoing regulatory approval include EchoGen (Sonus Pharmaceuticals), Definity (Du Pont Merck), Imagent (Alliance Pharmaceutical), Sonazoid (Nycomed-Amersham), SonoVue (Bracco Diagnostics), Quantison (Quadrant), Biosphere (Ponit Biomedical), and AI-700 (Acusphere). Albunex and Echovist, used mainly in cardiac evaluations, are effectively one-pass-only agents and have been replaced by the new-generation agents Optison and Levovist. All the vascular contrast agents are intravenously injectable.

CONTRAST TECHNIQUES

Many contrast-specific imaging modalities have been developed in recent years by academic researchers, ultrasound scanner manufacturers, and pharmaceutical companies, but most are either variations, hybrids, or combinations of the following techniques.

- Contrast-enhanced Doppler imaging. Color amplitude imaging (CAI) shows the amplitude of the Doppler signal from moving blood flow, while color Doppler imaging (CDI) depicts the mean frequency shifts of the Doppler signal (i.e., mean flow velocity). CAI is a relatively new ultrasound technique with increased dynamic range and flow sensitivity in comparison to conventional CDI.3 The sensitivity of Doppler ultrasound should be increased markedly in conjunction with the use of vascular contrast agents.

- Contrast harmonic imaging. CHI is a novel technique, opening the possibility of measuring blood perfusion or capillary blood flow-a clinically important task. It utilizes the nonlinear properties of contrast agents by transmitting at the fundamental frequency but receiving at the second harmonic.

A bubble acts as a harmonic oscillator and contrast-enhanced echo signals thus contain significant energy components at higher harmonics, while tissue echoes do not. In other words, the nonlinearity of the contrast produces a "signature" that can be separated from tissue echoes and large vessel blood flow, allowing capillary blood flow (i.e., perfusion) to be calculated. Combined with the pulse inversion technique,4 CHI possesses not only a very high sensitivity to contrast agent but also a high spatial resolution, similar to the spatial resolution of conventional B-mode used in the same transmit-receive frequency band.

- Intermittent imaging. Contrast microbubbles can be destroyed by intense ultrasound and the scattered signal level can increase abruptly for a short time during microbubble destruction, resulting in sudden increase in echogenicity (acoustical "flash").5 Intermittent imaging with high acoustic output utilizes the unique property of contrast microbubbles to improve blood-to-tissue image contrast by imaging intermittently at very low frame rates instead of the conventional 30 frames per second. The frame rate is usually reduced to about one frame per second, or it is synchronized with cardiac cycles so that enough contrast microbubbles can flow into the imaging site where most microbubbles have been destroyed by the previous acoustic pulse. Because bubbles are destroyed by ultrasound, controlling the delay time between frames produces images whose contrast emphasizes regions with rapid blood flow or regions with high or low blood volume.

VASCULAR ULTRASOUND

The sonographic detection of blood flow is limited by factors such as tissue motion (clutter), attenuation properties of the intervening tissue, and slow or low-volume flow. Limitations of ultrasound equipment sensitivity and the operator dependence of Doppler ultrasound are also factors that may impact the result. Vascular ultrasound contrast agents enhance the backscattered Doppler flow signals by up to 25 dB (about a factor of 20) in both color and spectral modes.6

In addition, most agents also improve gray-scale visualization of the flowing blood to such a degree that the tissue echogenicity increases (parenchymal enhancement). Microbubbles within the small vessels of an organ can thus provide a qualitative indication of perfusion.

Contrast should also be useful for evaluating vessels in a variety of organs, including those involved in renal, hepatic, and pancreatic transplants. If an area of ischemia or a stenosis is detected after contrast administration, the use of other more expensive imaging modalities, including CT and MRI, can often be avoided. Transcranial Doppler (TCD) studies suffer from a poor signal-to-noise ratio and so contrast-enhanced TCD is receiving attention. Otis and colleagues reported color and spectral Doppler enhancement in 29 out of 30 patients in a phase II trial with Levovist.7 In 23 cases, there was either a change from precontrast diagnosis or confirmation of a suspected diagnosis.

Intravenous vascular contrast agents will most likely also be used extensively in imaging malignant tumors in the liver, kidney, ovary, pancreas, prostate, and breast.1 Tumor angiogenesis (i.e., neovascularization) can be a marker for angiogenesis, and Doppler signals from small tumor vessels may be detectable after contrast injection. In Figure 1, a breast tumor is shown in three-dimensional CAI mode before and after contrast injection. The enhanced 3-D image clearly depicts the branching intratumoral vasculature (in two planes), as well as the much larger peripheral feeding vessels. This would indicate that 3-D may be better suited than 2-D ultrasound for demonstrating the chaotic vessel tortuosity associated with tumor neovascularity.

Gray-scale enhancement of flow in an organ promises to improve lesion detection, along with the ability to differentiate between normal and abnormal areas, using many of the criteria already routinely used in CT and MRI. Figure 2 is an example of the improved liver lesion detection possible with pulse-inversion CHI. Large tumors and small (< 10 mm) liver masses are better seen after contrast injection, thanks to greater agent uptake in the normal liver parenchyma compared to the lesions. Because it is the most common liver malignancy in the U.S., this should have a large impact on the detection of metastatic liver cancer. When CHI is combined with intermittent imaging, the complete tissue enhancement during the capillary phase can demonstrate perfusion abnormalities. Halpern and colleagues showed that intermittent harmonic imaging is useful to discriminate benign from malignant prostate tissues.8

Contrast kinetics (i.e., the uptake and washout of contrast over time) may become important parameters in helping to differentiate benign from malignant tumors. In an ultrasound contrast study of 34 breast tumors, Kedar and associates found that neovascular morphology (i.e., arterial-venous tumor vessel shunts) as well as contrast washout times were statistically significant (p <0.02) in discriminating between malignant and benign lesions.9 Four cases were reclassified after administration of Levovist-two from benign to malignant, and two vice versa-which increased both sensitivity and specificity to 100%. While such results are clearly limited by the number of cases, they still indicate that vascular ultrasound contrast agents could have a major role in the future diagnosis of breast cancer, and possibly other cancers.

Exciting new clinical possibilities arise from tissue-specific ultrasound contrast agents, which may improve the assessment of certain organs by improving the image contrast resolution through differential uptake. Other concepts being explored include targeted drug delivery via contrast microbubbles. Tissue-specific ultrasound contrast agents are most often injected intravenously into the blood and taken up by specific tissues, such as the reticuloendothelial system,10 or they adhere to specific sites such as venous thrombosis.11

These effects may require several minutes to several hours to reach maximum effectiveness. By enhancing the acoustic differences between normal and abnormal portions of organs, these tissue-specific agents improve the detectability of abnormalities. Sonazoid (Nycomed-Amersham) as well as Levovist and Sonovist (Schering) are such agents. They are taken up by normal Kupffer cells in the liver and spleen, but break down in high-amplitude diagnostic ultrasound fields such as those employed in color Doppler imaging. The bubble rupture produces a transient pressure wave, which results in a characteristic mosaic color pattern from tissues containing the agent (Figure 3). This effect has been termed "induced acoustic emission" (AE).10 Liver tumors that displace the normal Kupffer cells will not display the mosaic color pattern and can therefore be identified easily, as demonstrated in Figure 3. It is important to note that the color patterns of induced acoustic emission do not represent flow signals, but rather the interaction between the agent and the incident ultrasound wave.

ECHOCARDIOLOGY

One of the most important clinical uses of ultrasound contrast is in cardiology, where it will potentially compete with thallium nuclear scans.

The phase III trial of Albunex showed that Albunex was effective in improving left ventricular endocardial definition in 83% of patients and achieving LV chamber opacification in 81% of cases.12 Chamber opacification and improved endocardial border delineation in gray-scale are important clinical objectives, since accurate assessment of the LV volume allows the cardiac output to be calculated more precisely and therefore better determines heart function. Cardiac shunts and valve regurgitations are often evaluated with CDI, which also improves with injections of Albunex, but this agent is pressure-sensitive and does not recirculate. It is effectively a one-pass-only agent, limiting its clinical efficacy.

Newer agents such as Optison, Definity, and Sonazoid have overcome the stability problems of Albunex and can produce myocardial perfusion images in humans. This is clinically significant, since visualization of the myocardial flow permits direct assessment of underperfused or unperfused regions (i.e., areas of ischemia or infarction) in patients with a history of chest pain. Myocardial imaging using ultrasound contrast agents provides an assessment of the coronary arteries and of the coronary blood flow reserve, as well as collateral blood flow that may exist.13

The prolonged duration of contrast effects that is achievable with newer agents-five to 10 minutes is not uncommon-also makes them ideal for use in stress echocardiography. A sequence of four high-amplitude harmonic images of a canine heart were acquired at a frame rate of 58 Hz in flash-echo imaging mode (Figure 4). FEI combines low-amplitude conventional gray-scale imaging for monitoring tissue motion with intermittent harmonic gray-scale imaging for enhancing microbubble echoes.5 Because most microbubbles were destroyed after exposure to the first three frames of ultrasound pulses, "flash" echoes only (from microbubbles perfused into the myocardium) were clearly demonstrated as the difference in myocardial echogenicity between the first and last frames in Figure 4B.

OTHER APPLICATIONS

Any body cavity that can be accessed can, in principle, be injected with vascular contrast. The most successful application in this category is hysterosalpingo-contrast sonography (HyCoSy) for evaluation of fallopian tube patency. Degenhardt and colleagues reported on 103 patients with fertility problems who underwent transvaginal sonography and HyCoSy with Echovist.14 In 58 cases, HyCoSy was compared to established, more invasive techniques such as chromolaparoscopy and 91% agreement was found. HyCoSy is rapidly becoming the screening test of choice to determine tubal patency.

Vesico-ureteral reflux (VUR) is a common problem in children. Reflux sonography, as an alternative to micturating cystography, detects or excludes VUR. Albrecht compared pulse-inversion CHI with Levovist with contrast-enhanced fundamental ultrasound and MCU.1 His study showed that pulse-inversion CHI detected VUR in children at the lowest cost.

Sonographic imaging of the upper abdomen is often hampered by the presence of bowel gas, which commonly causes inadequate abdominal evaluation because of poor visualization of the body and tail of the pancreas. Additional imaging with CT or MRI is often requested by the radiologist to resolve unanswered questions and increase the confidence that a lesion is not being missed. Inconclusive ultrasound examinations often result in additional diagnostic studies that are expensive, time-consuming, inconvenient, or associated with some risk.

Figure 5 demonstrates a case of upper GI examination with uniform echogenicity of contrast-filled stomach and adequate visualization of the pancreas post-administration of the oral contrast agent SonoRx. Clinical studies with this agent have seen improved sonographic visualization of upper abdominal and retroperitoneal structures, generating diagnostic confidence and reducing the need for additional studies such as CT and MRI.

NEW TOOLS

The benefits of contrast enhancement have long been recognized in CT and MRI, and it now appears that ultrasound contrast agents with both Doppler and gray-scale capabilities will soon be available to U.S. physicians. This will likely enhance the diagnostic usefulness of ultrasound. The systemic echo enhancement provided by ultrasound contrast agents should increase diagnostic confidence, especially in technically difficult cases with low image sensitivity. Moreover, contrast-specific imaging modalities, such as harmonic imaging and intermittent imaging, promise to put new tools for tumor diagnosis in the hands of clinicians.

DR. SHI is an assistant professor of radiology, DR. FORSBERG is head of ultrasound research, DR. LIU is an associate professor, and DR. MERRITT is a professor of radiology, all at Thomas Jefferson University, Philadelphia. DR. GOLDBERG is vice chairman of radiology and director of the Jefferson Ultrasound Research and Education Institute.

References for this article are available at diagnosticimaging.com.

References

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