Ultrasound contrast medium

exogenous substance that alter the echo amplitude in ultrasonography or Doppler ultrasound applications. The altered echo amplitude may be due to changes in the absorption (see absorption, ultrasonic), reflection, and/or refraction of the ultrasound. Many substances may act as contrast media, e.g. orally ingested fluids may expel gas from the stomach and create an acoustic window to the pancreas. Echo-free fluids, e.g. water or saline, may distend body cavities to improve visualization of the luminal walls. Ultrasound contrast media for intravenous injection have been developed along various lines, but aqueous solutions, particle suspensions or emulsions have not proved sufficiently efficient and safe. Today, all commercial ultrasound contrast media for human applications are encapsulated microbubbles. Microbubbles are less than 10 µm in diameter, and contrary to most X-ray and MR contrast media which are rapidly distributed to the extravascular, extracellular space, most microbubbles are confined to the vascular space. Microbubbles may produce up to 25 dB (more than 300-fold) increase in echo strength. The main mechanisms for signal enhancement are backscattering, bubble resonance and bubble rupture. These mechanisms are highly dependent on the acoustic power of the transmitted ultrasound, which is reflected by the mechanical index (MI).

Backscattering
Ultrasound is reflected whenever there is a change in acoustic impedance. The larger the change, the more ultrasound is reflected. Gas bubbles have a tremendous difference in acoustic impedance as compared to surrounding fluid due to the large differences in density, elasticity and compressibility. At low acoustic power (MI < 0.1), gas microbubbles may be regarded as point scatterers, and the mechanism of ultrasound reflection is that of Rayleigh Tyndall scattering. The scattering strength of a point scatterer is proportional to the sixth power of the particle radius and to the fourth power of the ultrasound frequency; the echogenicity of such contrast media is therefore highly dependent upon particle size and transmit frequency (see also scattering cross-section). The backscattered intensity of a group of point scatterers is furthermore directly proportional to the total number of scatterers in the insonified volume; the concentration of the contrast medium is therefore also of importance.

Bubble resonance and harmonics
At intermediate acoustic power (0.1 < MI < 0.5) gas microbubbles may show strong oscillatory motion provided the frequency of the incident ultrasound is close to the resonant (fundamental) frequency of the microbubbles. This resonant frequency is approximately inversely proportional to the bubble radius as expressed by the formula:

See formula 1 on the right

where f_o is the resonant frequency, r is the bubble radius, g is the adiabatic ideal gas constant at ambient fluid pressure P_o and ambient fluid density ro. Bubbles larger than 10 µm will have resonance frequencies below 1 MHz, while smaller bubbles, on the order of 5 µm or less, will have resonance frequencies in the frequency range used in medical ultrasound imaging, i.e., 110 MHz. Ultrasound contrast media have microbubbles with a large size distribution, and resonance therefore occurs at a frequency range, not at a single frequency. Bubble resonance increases the average size of the bubbles over time, and since the scattering cross-section increases to the sixth power with bubble size, resonance may vastly increase the echo strength (Fig. 1). The acoustic properties of microbubbles are very different below and above the resonance frequency (Fig. 1). The efficiency of microbubbles as scatterers may be expressed as the ratio of scattering cross-section to physical cross-section. Below the resonance frequency this ratio increases with the ultrasound frequency to the fourth power, and above the resonance frequency the ratio is constant with frequency and equals 4pr2 (four times the physical cross-section).
At increasing acoustic power (in the intermediate range), the microbubbles start to oscillate in a non-linear fashion. The bubbles are more easily expanded than compressed, and this non-linear behaviour generates harmonics, which are exploited in non-linear imaging.

Bubble rupture
At high acoustic power (MI > 0.5), ultrasound at the microbubble resonance frequency will cause the bubbles to rupture. The result is a transient high-amplitude, broadband signal containing all frequencies, not only the harmonics. It will create a transient, strong signal in B-mode, or a short-lasting multicoloured, mosaic-like effect in colour Doppler sonography. Several terms for the strong, transient signal have been proposed: induced or stimulated acoustic emission, loss of correlation imaging and sono-scintigraphy.

Gas microbubble contrast media
Gas bubbles have a tremendous difference in acoustic impedance as compared to surrounding fluid due to the large differences in density, elasticity and compessibility. Free gas bubbles represent the simplest form of ultrasound contrast media. The bubbles may pre-exist in the liquid, or they may be created via cavitation during injection. Intravascular injection of physiological saline has been used as a contrast medium in echocardiography since the late sixties, but the utility of free gas bubbles is highly limited due to their low stability. These bubbles are also too large to pass the pulmonary vasculature. For gas bubbles to be used as transpulmonic contrast media, i.e., to be effective in the systemic circulation after intravenous injection, the gas bubbles should be stable and smaller than 5 µm. Bubbles larger than 10 µm may transiently obstruct the capillaries and act as gas emboli. Several stabilizing coatings have been developed to produce encapsulated gas microbubble contrast media (Table 1).

The coatings include albumin, gelatin, galactose microspheres, polyglutaminic acid, lipophilic monolayer surfactants, and lipid bilayers (liposomes). Several "generations" of gas microbubble contrast media have evolved; the "1st generation" products do not pass the pulmonary vascular bed, and are therefore limited to the venous system and the right heart cavities after intravenous injection. The "2nd generation" contrast media are both sufficiently small and stable to pass into the systemic circulation, and these contrast media enhance the Doppler signal in various arteries after intravenous injection (Fig. 1). They are short-lived, however, the effect is over in a few minutes. The "3rd generation" gas microbubble contrast media are even more echogenic and stable, and are able to enhance the echogenicity of parenchyma on B-mode images. They may thus show perfusion, even in such a difficult region as the myocardium. The various gas microbubble contrast media are generally safe with low toxicity in humans.
 
Particle suspensions or emulsions

Several types of particles have been reported as ultrasound contrast media, such as collagen microspheres and iodipamide ethyl ester, which are solids, and perfluorochemicals which are inert, dense liquids. Perfluorocarbons lead to a large tissue impedance mismatch due to their high density and compressibility. Perfluorooctylbromide (PFOB) is a suspension of brominated fluorocarbons in lecithin with particle sizes 0.5 µm or less which has been studied widely in animals. After intravenous injection, it can be detected in the intravascular space for several hours. Due to the small particle size, the contrast medium passes all capillary beds and will therefore enhance perfused tissue. Perfluorochemicals are eliminated by the body either by phagocytosis of the reticuloendothelial system or by evaporation in the lungs. Due to the selective phagocytosis, liver and spleen are enhanced by PFOB for several hours. Particle suspensions are generally less effective than gas bubbles, and much larger doses are needed for enhancement. Perfluorocarbons may furthermore be less safe than the gas bubbles; a relatively high percentage of mild allergic reactions have been shown in humans. This may restrict their future clinical use.

ultrasound contrast medium, table 1
Classification of gas microbubble contrast media

The gas inside the shell may be either air or various perfluorocarbons, which are liquids at room temperature but gas at body temperature (Table 1). The large molecules of perfluorocarbons have slow diffusion and solubility which increase the enhancement time of the contrast medium as compared to air. Several "generations" of gas microbubble contrast media have evolved (Table 1); the "1st generation" products do not pass the pulmonary vascular bed, and are therefore limited to the venous system and the right heart cavities after intravenous injection. The "2nd generation" contrast media are both sufficiently small and stable to pass into the systemic circulation, and these contrast media enhance the Doppler signal in various arteries after intravenous injection (Fig. 2). They are short-lived, however, the effect is over in a few minutes. The "3rd generation" gas microbubble contrast media are even more echogenic and stable, and are able to enhance the echogenicity of parenchyma on B-mode images (Fig.3). They may thus show perfusion, even in such a difficult region as the myocardium. Finally, some microbubble contrast media have a specific hepatosplenic parenchymal phase. They accumulate in normal hepatic tissue; some are phagocytosed by Kupffer cells in the reticuloendothelial system and others may stay in the sinusoids. The hepatic parenchymal phase, which may last from less than an hour to several days, depending on the specific contrast medium used, may be imaged by bubble-specific modes such as stimulated acoustic emission (colour Doppler using high MI) or pulse inversion imaging. The various gas microbubble contrast media are generally safe with low toxicity in humans.

HJS

HJS