Albrecht Bauer

Stimulated acoustic emission to image a late liver and spleen-specific phase of Levovist® in normal volunteers and patients with and without liver disease

Quantitative studies were performed to investigate liver- specific uptake of the microbubble Levovist, using stimulated acoustic emission (SAE), which can detect microbubbles even when stationary or slow-moving. These comprised studies of biodistribution comparing the liver and kidney in five normal volunteers, reproducibility in 34 patients, comparison between cirrhotics and controls (n = 9 each) and maximal depth of effect at different frequencies (180 measurements in 31 patients). Stimulated acoustic emission lasted beyond 30 min, with strongly liver-specific properties in each volunteer and was highly reproducible. No difference in the amount of SAE in the superficial liver was seen between cirrhotic and normal livers, but attenuation was higher in cirrhotics. This demonstrates a frequency-dependent effect on liver SAE penetration. We conclude that the liver uptake of Levovist lasts over 30 min, is reproducible, occurs even where diffuse liver disease is present and can be used to assess tissue attenuation in a novel fashion.

Wideband harmonic imaging: A novel contrast ultrasound imaging technique

Abstract. A novel ultrasonic imaging method, wideband harmonic imaging, for nonlinear imaging of microbubble contrast agents is evaluated. In wideband harmonic mode, two pulses of alternate phase are send out. The image is then processed from the sum of both pulses, resulting in an image of nonlinear scatterers such as microbubbles. A prototype ultrasound system, Siemens Elegra, was evaluated with in vitro investigations and animal trials, using conventional, harmonic and wideband harmonic settings with the galactose based ultrasound contrast agent Levovist. Wideband harmonic imaging offers superior sensitivity for ultrasound contrast agents compared to conventional imaging and harmonic imaging. At low transmit power settings (MI 0.1–0.5) the nonlinear response is already sufficient to generate a image of the blood pool distribution of Levovist in the rabbit kidney including the microvasculature, with clear delineation of vessels and perfused parenchyma. At high transmit amplitudes, nonlinear tissue response reduced the apparent image contrast between contrast agent and tissue. The results suggest that wideband harmonic imaging is currently the most sensitive contrast imaging technique, maintaining highest spatial resolution. This may add to image quality and offer new clinical potential for the use of ultrasound contrast agents such as Levovist.

Acoustically stimulated microbubbles in diagnostic ultrasound: properties and implications for diagnostic use

Ultrasound echo enhancement depends upon the enhancement of backscatter so that the intensity of the signal reflected back to the transducer is increased. However, the interaction between the incident ultrasound wave and the reflecting microbubbles is complex and dynamic. The incident ultrasound can drive the microbubbles into oscillation and, depending on the size of the microbubbles and the properties of their shells, that oscillation can become resonant. When some microbubble echo enhancers such as SHU 563A are exposed to high amplitude ultrasound this non-linear oscillation gives rise to a phenomenon called stimulated acoustic emission [1]. As the microbubbles oscillate they emit signals containing the second harmonic of the fundamental frequency to which they were exposed. With further increased transmit amplitude the microbubbles respond with high intensity broad-band signals and subsequent collapse. The signals originating from microbubbles due to stimulated acoustic emission can be used for specific detection of the ultrasound contrast agent with different techniques. This review will cover some of the basic principles involved and outline the diagnostic potential of stimulated acoustic emission and its use for microvascular imaging.

Liver-specific imaging with SHU 563A: Diagnostic potential of a new class of ultrasound contrast media

Abstract. The purpose of this study was to evaluate the imaging properties and diagnostic potential of the novel polymeric ultrasound contrast agent SHU 563 A. After i. v. injection, the agent circulates in the blood pool for about 10 min and is then subsequently sequestered by the RES cells predominantly in the liver. The acoustic emission capabilities enable a very sensitive detection during the blood pool phase and after uptake in the RES cells, contributing to differential diagnosis as well as detection of liver lesions. During a multicenter study, 28 patients with liver lesions were examined. In all patients the results were compared to baseline ultrasound and Contrast enhanced Spiral CT. With respect to lesion size and location, very good agreement between SHU 563 A ultrasound and Spiral CT was achieved. Additional lesions could be shown in the RES phase by SHU 563 A enhanced ultrasound. 26 further patients were examined in other indications. The results in all 54 patients indicate good safety and tolerance of SHU 563 without limitations for diagnostic use. SHU 563 A enhanced ultrasound adds significantly to the detection and delineation of focal liver lesions by improving conspicuity due to RES based contrast after uptake.

Microvascular imaging — results from a phase I study of the novel polymeric ultrasound contrast agent SHU 563A

Ultrasound diagnosis uses B-mode images to provide anatomical information and Doppler analysis to measure the velocity of blood flow. In the capillaries, however, the velocity of blood flow (0.03–0.3 cm/s) is comparable to the speed of motion of the surrounding tissue, so capillary flow cannot be imaged by conventional Doppler techniques. Another limiting factor is the extreme spatial complexity of the capillary network. A new ultrasound contrast enhancer, SHU 563A, with non-linear acoustic properties, could overcome these limitations [1]. When the new agent is exposed to high power ultrasound it produces a characteristic sound which, on a color Doppler display, appears as pseudo-Doppler shifts. Color Doppler flow mapping depends upon the correlation between successive pulses which is infringed by the non-linear response of SHU 563A. The image based on pseudo-Doppler shifts shows the location of the contrast enhancer and gives a map of microparticle distribution. This new procedure may be described as ‘LOC’ imaging (loss of correlation representing contrast agent localization). The image provided by a conventional color Doppler ultrasound scanner after injection of SHU 563A contains no information on fluid flow velocities. Instead it provides a color map of the distribution of the contrast agent. It gives a direct image of the microvascular compartment that contains anatomical and functional information on microvascular perfusion.

Stimulated acoustic emission imaging (“Sono-scintigraphy”) with the ultrasound contrast agent Levovist: A reproducible Doppler ultrasound effect with potential clinical utility

Levovist (Schering AG, Berlin, Germany) is a microbubble agent which improves Doppler ultrasound examinations by increasing the intensity of the Doppler signal. It is licensed for the improvement of suboptimal Doppler examinations in several countries, including the UK. Levovist is constituted from galactose microaggregates and water, with a small admixture of palmitic acid (0.1%). When made up, multiple small stabilized air microbubbles are produced with a mean diameter of 2-3 mm. Extensive clinical trials with Levovist have demonstrated excellent tolerance and a very good safety profile (1). This increase in backscatter is generally regarded as the major clinically important mechanism of most microbubble agents, but there is increasing evidence that ultrasound at diagnostic energies can also disrupt microbubbles to produce transient intense Doppler signals. In color Doppler ultrasound mode, these are displayed as strong random-velocity Doppler shifts, producing a mosaiclike display. A novel microbubble agent, SHU563A (Schering AG), is known to be particularly effective at producing

Ultrasonic Imaging of Organ Perfusion with SH U 563A

Ultrasound (US) diagnosis uses B-mode images to provide anatomic information and uses Doppler analysis to measure the velocity of blood flow. It has recently been discovered that the active acoustic response of US contrast agents, acoustic emission, allows detection of some contrast agents in the microvascular compartment and even as stationary contrast with color Doppler imaging (1–3). The underlying phenomenon is the complex interaction between the incident ultrasound wave and microbubbles. The incident ultrasound can drive the microbubbles into oscillation, and depending on the size of the microbubbles and the properties of their shells, that oscillation can become resonant. As the microbubbles undergo nonlinear oscillation, they emit signals containing harmonic components of the fundamental frequency as well as broadband signal components. In principle, the microbubbles act as an active sound source within the US field (4). The signals originating from microbubbles due to stimulated acoustic emission can be used for specific detection of the US contrast agent with different techniques: conventional color Doppler imaging; and more complex pulse sequences, such as wideband harmonic imaging (5,6), in new high-end US equipment. With color Doppler imaging, the induced acoustic emissions are detected as signals with a random value, resulting in a peculiar mosaic pattern varying with time. The underlying mechanism is that color Doppler flow mapping depends on the correlation between successive pulses. This is infringed by the nonlinear response of SH U 563A (Schering, Berlin, Germany) resulting in a loss of correlation of the pulses during the destruction of the microbubble. Because this technique is not using color Doppler imaging in its original fashion, it may also be described as “loss of correlation” (LOC) imaging, to distinguish this technique from vascular color Doppler imaging. Although the same technique, color Doppler imaging, is used, the image content is changed from a flow image based on correlation to a map of the contrast distribution based on LOC and destruction of the microbubbles during the scanning process (1). The contrast agent distribution, the localization map, is generated by the presence of the random color spots, with varying color in the image and between subsequent images. The information on tissue perfusion during the vascular phase and the distribution of active reticuloendothelial system (RES) cells after uptake is provided by this map. It gives a direct image of the microvascular compartment and the RES compartment, independent of flow velocity. SH U 563A is a novel polymeric US contrast agent, optimized for this nonlinear acoustic response. Due to the durability of the polymer shell, no degradation is observed during the capillary passage in the vascular phase, allowing a complete delineation of the microvascular compartment. Therefore, SH U 563A may be considered as an ideal perfusion tracer, demonstrating, in theory, the blood volume distribution. Acad Radiol 2002; 9(suppl 1):S46–S51