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Microbubble harmonics are produced in a different way. Microbubbles are gas bodies ranging from 1 to 7 microns in diameter, enclosed by some sort of membrane. A large number are licensed or being developed but, for radiology, the two most important are Levovist (Schering) and SonoVue (Bracco). Levovist is an air containing microbubble made in the clinic by shaking galactose micro particles with water. The galactose microparticles contain micro defects, which constrain the attached air microbubbles to the requisite size. They are stabilised by a monomolecular layer of a surfactant, palmitic acid. In essence therefore they are minute soap bubbles! SonoVue uses a high-density gas (sulphur hexafluoride), which improves the longevity of the microbubbles on account of its high molecular weight, which slows diffusion. Its membrane is a phospholipid which is similar to cell membranes.
The essence of their function as contrast agents is that they behave quite differently from solid or watery tissues in that they can be compressed and expanded much more readily. Thus they change their diameter by two to tenfold, depending of the power of the incident ultrasound and, like all reactive processes, they have a natural resonant frequency at which they respond most actively. It happens that the resonant frequency for 1-7 micron microbubbles lies in the 2-10 MHz range that is used for diagnostic imaging. This fortunate coincidence explains the remarkable reflectivity of microbubbles which are many fold more echogenic than comparable tissue elements such as red blood cells.
However, microbubbles like any gas particle, resist compression more than they respond to expansion so that they may respond asymmetrically to the symmetrical transmitted ultrasound waves. This asymmetry make take the form either of a change in the bubbles shape where by they become geometrically distorted or, and this is perhaps more usual, as an asymmetry in the temporal response, i.e. they expand more quickly than they compress. In either case the result is that the returning wave contains frequencies different than those of the insonant wave and if these can be extracted, images favouring the contribution of the microbubbles can be created.
As is usual in medicine, the first of these microbubble-specific modes to be discovered was encountered by chance. Simply using conventional colour Doppler produced striking images depicting the localisation (but not the velocity) of microbubbles, an effect that came to be known as stimulated acoustic emission (SAE). It arises simply from the fact that colour Doppler uses a train of pulses, the echoes from which are then compared to search for discrepancies between consecutive signals. Any changes are recorded as movement, the familiar colour Doppler image. However, if a microbubble lies along the acoustic line and is in some way altered by the ultrasound pulse, then a major change is seen in the returning echoes and this is registered as a sharp Doppler shift. In fact, most of the signals turn out to be caused by microbubbles that are so violently excited by the ultrasound beam that they are destroyed; pulse 1 sees a strong signal while pulse 2 (or 3) sees a void at that location. This loss of correlation produces signals that are similar to aliasing.
This method works best for microbubbles that are fragile, especially those that are air containing, such as Levovist. It produces striking colour-mosaic images that reflect the distribution of the microbubbles (not their flow velocity) and thus can depict the microvasculature as well as the large vessels in a tissue. Although it works well in any phase of the microbubbles’ pharmacokinetics, clinically it is most useful in the liver- and spleen-specific phases of trophic agents such as Levovist. A scan four or five minutes after administration using a sweep-and-cine review technique at high Mechanic Index (MI) depicts the distribution of the microbubbles as a colour mosaic. Lesions that do not take up microbubbles, notably malignancies but also, obviously cysts and abscesses, are revealed as clear colour defects. SAE has been the subject of individual and multi-centre trials and consistently showed higher contrast between the surrounding liver and lesions that do not contain liver tissue, especially metastases and to some extent also HCCs. Lesions composed of normal liver tissue such as FNH and focal fatty change as well as regenerating nodules, blend with the surrounding liver because the take up the same amount of contrast. Haemangiomas are a special case: some show as clear cut defects in this late (Kupffer) phase. Others however, retain enough contrast to appear similar to normal liver, though usually they are slightly less intense.
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