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For ultrasonography (US), contrast agents were first introduced in 1996 and have since been used mainly for echocardiography, vascular US, Doppler US, and abdominal US in Europe and Asia.
Although contrast-enhanced US (CEUS) has several advantages over the contrast-enhanced computed tomography (CECT) or contrast-enhanced magnetic resonance imaging (CEMR), such as no radiation, no harmful effects to the kidney or thyroid, easy accessibility, and comparable comfort during use with patients. 
Contrast enhancement was caused by the compressible gas core of saline bubbles, enabling the bubble to backscatter the applied US wave.


US contrast agents (UCA) consist of microscopic bubbles of gas enclosed in thin flexible shell.

The types of gas and shell material used differ depending on the brand of contrast agent.

The microbubbles are generally 1-4 micrometers in size (smaller than a red blood cell) making them small enough to flow easily through the circulation, but large enough so they remain inside the blood vessels.

Depending on their composition, injection method and dose, microbubbles can be detected in circulation from several minutes, up to 60 minutes after which their gas core diffuses out of the shell and the components are cleared by the reticuloendothelial system.

When high frequency sound waves from an ultrasound probe hit them, they oscillate and reflect a non-characteristic echo.

Generally the UCA is given as an injection and only lasts a short time in the body. If longer times are required, UCA may be given through a drip to maintain a steady infusion of contrast.


First generation

First generation contrast agents contained microbubbles of air that were dissolved
in blood when exposed to acoustic pressure in the ultrasound field and were
therefore present in the bloodstream for a limited time. The generation of
ultrasound contrast agents is categorized according to type of gas within the
microbubbles shells.
e.g. : Levovist consisted of air within a shell of galactose micro particles (99.9%) palmic acid (0.1%).

Second Generation

In second generation contrast agents the air in the microbubbles is replaced by a more inert and slowly diffusing gas such as perfluorocarbon, nitrogen gas or sulfur hexafluoride stabilized in a phospholipid membrane.

The bubble oscillate when exposed to the ultrasound beam (they are being compressed by the effect of positive pressure created by the ultrasound waves and they expand in the negative pressure phase).
e.g. : SonoVue consist of sulfur hexafluoride within a phospholipid shell.

Sonazoid consist of perflorobutane within a hydrogenated egg phosphatidylserine Definity consist of octafluoropropane gas within a lipid shell Optison consist of octafluoropropane within a albumin shell.


Blood pool contrast agent

The main objective in developing standardized ultrasound contrast agents was to obtain products that pass through the lungs, making contrast imaging of the entire vascular system possible after intravenous injection (blood-pool agents).

Most products available or in development today fall into this category. Ideally, blood-pool contrast agents should be transported freely in the bloodstream without leaving the vascular bed or accumulating in specific tissues Some of these contrast agents do not move perfectly freely with the bloodstream, but have some tissue-specific affinity.

This means that they accumulate in specific tissues—e.g., the reticuloendothelial cells in the liver and spleen—at the end of the vascular phase. This effect has been described for Levovist.

Tissue specific contrast agent

These are contrast agents that have a high affinity to specific tissues or molecular structures and which therefore accumulate specifically in these tissues.
It improves the assessment of certain organs like liver, kidney, pancreas, prostate and ovary by improving the acoustic differences between normal and abnormal portion of organs.
Currently, no tissue-specific contrast agents are available for use in humans, but several substances are in preclinical development.

Drug delivery system

The shells of ultrasound contrast agents can be used not only for the transport of gases or air, but can also transport drugs in the body. The release of these drugs then takes place locally, either through nonspecific rupture of the shell after specific binding to the target tissue (target-specific microbubbles) or by selective local rupture of the freely circulating microbubbles in the target area (e.g., by exposure to ultrasound). Systems of this type can be used for the transport of conventional drugs or even of DNA or RNA fragments (e.g., antisense molecules).

Oral contrast agent

These are actually negative contrast agents, as they do not produce echogenicity, but eliminate the interfering echogenicity in the gastrointestinal tract caused by the presence of air.
At present, the sole product approved for this purpose is only available in the United States (SonoRx).
The drinkable liquid contains cellulose fibers that adsorb the air that causes interference, thus allowing overlap-free examination of organs behind the gastrointestinal tract.

Intracavitary contrast agent

These were generally developed as blood-pool contrast agents; however, the administration route is not intravenous, but rather by catheter or needle into a body cavity.
Established indications are contrast hysterosalpingosonography to assess the patency of the tubes when investigating fertility, and voiding urosonography to investigate vesicoureterorenal reflux, particularly in children.


•There are two forms of contrast-enhanced ultrasound, untargeted (used in the clinic today) and targeted (under preclinical development). The two methods slightly differ from each other.

1)  Untargeted Contrast enhanced US

     Untargeted microbubbles, such as the  SonoVue, Optison, or Levovist, are injected intravenously into the systemic circulation in a small bolus.

  The microbubbles will remain in the systemic circulation for a certain period of time.

  During that time, ultrasound waves are directed on the area of interest. When microbubbles in the blood flow past the imaging window, the microbubbles’ compressible gas cores oscillate in response to the high frequency sonic energy field.

The more common method dynamic evaluation of the vascularity of a target lesion, most commonly in the liver or kidney, may be useful in diagnosis used to measure organ perfusion, which can be useful in diagnosing diffuse processes (e.g. cirrhosis)

Vascular CEUS contrast agents demonstrate distinct enhancement phases much like CT and MRI contrast media: arterial phase (up to 25 s post injection) portal venous phase (25-45 s post injection) late phase (at least 2 minutes post injection) 10


Microbubbles targeted with ligands that bind certain molecular markers that are expressed by the area of imaging interest are still injected systemically in a small bolus.

Microbubbles theoretically travel through the circulatory system, eventually finding their respective targets and binding specifically Ultrasound waves can then be directed on the area of interest.

If a sufficient number of microbubbles have bound in the area, their compressible gas cores oscillate in response to the high frequency sonic energy field.

Advantages of Contrast Enhanced US

To get better-quality images of an abnormality seen on a regular ultrasound, CT scan, or MRI
To monitor a known abnormality for changes in size or appearance
To image organs after trauma, infection, or suspected masses
To monitor the liver for hepatocellular carcinoma (a type of liver cancer) in patients with cirrhosis (scarring of the liver)
To image the liver or urinary system in patients who are allergic to the contrast used in CT or MRI
To check how open a blood vessel is, or to look for clots in a vein
To differentiate a gallbladder tumor from benign sludge

Disadvantages of Contrast Enhanced US

Microbubbles don’t last very long in circulation. They have low circulation residence times because they either get taken up by immune system cells or get taken up by the liver or spleen, even when they are coated with polyethylene glycol.
Microbubbles burst at low ultrasound powers (or mechanical indices), which is the measure of the acoustic power output of the ultrasound imaging system.
Increasing mechanical index increases image quality, but there are tradeoffs with microbubble destruction. There do not appear to be any significant harmful effects observed with the high mechanical index impulses used to clear microbubbles from the microcirculation in humans.

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