Ultrasound contrast agents: basic principles

Ultrasonography lacked substances to be administered to patients to improve or increase the diagnostic yield, which is peculiar considering that contrast agents have long been used with all the other imaging techniques. Fortunately some contrast agents, most of them consisting in gas microbubbles, have been recently introduced for ultrasound imaging too: this review will focus on their history, behavior, current applications and future developments. Echocontrast agent research is in progress and many new agents are expected to be marketed this and next year, to be added to Levovist by Schering AG (Berlin, Germany), to enhance the ultrasound signal safely and effectively. No definitive conclusions can be drawn yet on the actual merits of each contrast agent, but all of them seem to be both effective and safe, meaning that their future success will depend on the relative cost-effectiveness and peculiarities.

The microbubbles act as echo-enhancers by basically the same mechanism as that determining echo-scattering in all the other cases of diagnostic ultrasound, namely that the backscattering echo intensity is proportional to the change in acoustic impedance between the blood and the gas making the bubbles. The different acoustic impedance at this interface is very high and in fact all of the incident sound is reflected, even though not all of it will of course go back to the transducer. But the acoustic wave reflection, though nearly complete, would not be sufficient to determine a strong US enhancement because the microbubbles are very small and are sparse in the circulation. Moreover, reflectivity is proportional to the fourth power of a particle diameter but also directly proportional to the concentration of the particles themselves.

As we said above, the microbubbles reached by an ultrasound signal resonate with a specific frequency depending on microbubble diameter. However, the main resonance frequency is not the only resonance frequency of the bubble itself and multiple frequencies of the fundamental one are emitted, just like in a musical instrument. These harmonic frequencies have decreasing intensity, but the second frequency, known as the second harmonic, is still strong enough to be used for diagnostic purposes. The theoretical advantage of the harmonic over the fundamental frequency is that only contrast agent microbubbles resonate with harmonic frequencies, while adjacent tissues do not resonate, or else their harmonic resonation is very little. Thus, using a unit especially set to produce ultrasounds at a given frequency (3.5 MHz) and receive an ultrasound signal twice as powerful (7 MHz) it will be possible to show the contrast agent only, without any artifact from the surrounding anatomical structures, with a markedly improved signal-to-noise ratio. A similar effect to digital subtraction in angiography can thus be obtained, even though through a totally different process. Moreover, second harmonic imaging permits to show extremely small vessels (down to 40 microm) with very slow flow, which would be missed with a conventional method. B-mode imaging can also depict the microbubbles in the myocardium suppressing nearly all the artifacts from cardiac muscle motion. Recently a peculiar behavior of microbubbles has been observed which may permit contrast agent detection even in capillaries. This method is variously known as sonoscintigraphy, loss of correlation, stimulated acoustic emission and transient scattering. The contrast agent microbubbles reached by an ultrasound beam powerful enough explode producing a strong and very short backscatter echo which is read by the unit as a Doppler signal and results in a color pixel where the individual microbubble exploded.

The microbubble contrast agents developed and introduced as safe and effective echo-enhancers in present-day clinical practice will open up new oppurtunities