(UCA / USCA) Ultrasonography is the most commonly performed diagnostic imaging procedure. The introduction of sonographic contrast media into routine practice modifies the use of ultrasound in a variety of clinical applications. USCAs consist of microbubbles filled with air or gases and can be classified according to their pharmacokinetics. Among the blood pool agents, transpulmonary ultrasound contrast agents offer higher diagnostic potential compared to agents that cannot pass the pulmonary capillary bed after a peripheral intravenous injection. In addition to their vascular phase, some USCAs can exhibit a tissue- or organ-specific phase.
The sonogram image quality is improved either by decreasing the reflectivity of the undesired interfaces or by increasing the backscattered echoes from the desired regions.

Different types of ultrasound contrast agents:
Ultrasound contrast agents act as echo-enhancers, because of the high different acoustic impedance at the interface between gas and blood. The enhanced echo intensity is proportional to the change in acoustical impedance as the sound beam crosses from the blood to the gas in the bubbles.

The ideal qualities of an ultrasound contrast agent:
A typical ultrasound contrast agent consists of a thin flexible or rigid shell composed of albumin, lipid, or polymer confining a gas such as nitrogen, or a perfluorocarbon. The choice of the microbubble shell and gas has an important influence on the properties of the agent.
Current generations of microbubbles have a diameter from 1 μm to 5 μm. The success of these agents is mostly dependent on the small size and on the stability of their shell, which allows passage of the microbubbles through the pulmonary circulation. Microbubbles must be made smaller than the diameter of capillaries or they would embolize and be ineffective and perhaps even dangerous.
The reflectivity of these microbubbles is proportional to the fourth power of a particle diameter but also directly proportional to the concentration of the contrast agent particles themselves.
Ultrasound contrast agents produce unique acoustic signatures that allow to separate their signal from tissue echoes and to depict whether they are moving or stationary. This enables the detection of capillary flow and of targeted microbubbles that are retained in tissues such as normal liver.
The new generation of contrast media is characterized by prolonged persistence in the vascular bed which provides consistent enhancement of the arterial Doppler signal. Contrast agents make it also possible to perform dynamic and perfusion studies. Targeted contrast imaging agents are for example taken up by the phagocytic cell systems and thus have liver/spleen specific effects.

See also Ultrasound Contrast Agent Safety, Adverse Reaction, Tissue-Specific Ultrasound Contrast Agent, and Bubble Specific Imaging.

Vascular ultrasound contrast agents are gas microbubbles with a diameter less than 10 μm (2 to 5 μm on average for most of the newer agents) to pass through the lung capillaries and enter into the systemic circulation. Air bubbles in that size persist in solution for only a short time; too short for systemic vascular use in medical ultrasound imaging. So the gas bubbles have to be stabilized to persist long enough and survive pressure changes in the heart.
Most vascular contrast media are stabilized against dissolution and coalescence by the presence of additional materials at the gas-liquid interface. In some cases, this material is an elastic solid shell that enhances stability by supporting a strain to counter the effect of surface tension. In other cases, the material is a surfactant, or a combination of two or more surfactants.
Typically the effective duration of vascular enhancement is a few minutes, after which the microbubbles dissipate. This rather short duration of vascular enhancement makes it easy to perform repeated dynamic studies. Intravenous vascular contrast agents will be used in imaging malignant tumors in the liver, kidney, ovary, pancreas, prostate, and breast. Tumor neovascularization can be a marker for angiogenesis, and Doppler signals from small tumor vessels may be detectable after contrast injection. Contrast agents are useful for evaluating vessels in a variety of organs, including those involved in renal, hepatic, and pancreatic transplants. If an area of ischemia or a stenosis is detected after contrast administration, the use of other more expensive imaging modalities, including CT and MRI, can often be avoided.

See also Acoustically Active Lipospheres.

Submicron ultrasound contrast agents are gas-filled, double-walled microspheres with a diameter smaller than 1 μm that rupture when exposed to ultrasound energy at megahertz frequencies. These agents differ from traditional ultrasound contrast microbubbles in that the submicron bubbles may serve as extravascular agents. They are small enough to travel through the lymphatic system and to be extravasated from tumor neovasculature. The detection of these agents is limited by their hard shell, which requires high-pressure ultrasound insonation for shell rupture and excitation of the gas bubble. After shell rupture, the gas diffuses rapidly from submicron sized agents. The optimal processing of each echo is important.

The earliest introduction of vascular ultrasound contrast agents (USCA) was by Gramiak and Shah in 1968, when they injected agitated saline into the ascending aorta and cardiac chambers during echocardiographic to opacify the left heart chamber. Strong echoes were produced within the heart, due to the acoustic mismatch between free air microbubbles in the saline and the surrounding blood.
The disadvantage of this microbubbles produced by agitation, was that the air quickly leak from the thin bubble shell into the blood, where it dissolved. In addition, the small bubbles that were capable of traversing the capillary bed did not survive long enough for imaging because the air quickly dissipated into the blood. Aside from agitated saline, also hydrogen peroxide, indocyanine green dye, and iodinated contrast has been tested. The commercial development of contrast agents began in the 1980s with greatest effort to the stabilization of small microbubbles.

The development generations by now:
To pass through the lung capillaries and enter into the systemic circulation, microspheres should be less than 10 μm in diameter. Air bubbles in that size range persist in solution for only a short time; too short for systemic vascular use.
The first developed agent was Echovist (1982), which enabled the enhancement of the right heart. The second generation of echogenic agents, sonicated 5% human albumin-containing air bubbles (Albunex), were capable of transpulmonary passage but often failed to produce adequate imaging of the left heart. Both Albunex and Levovist utilize air as the gas component of the microbubble.
In the 1990s newer developed agents with fluorocarbon gases and albumin, surfactant, lipid, or polymer shells have an increased persistence of the microspheres. This smaller, more stable microbubble agents, and improvements in ultrasound technology, have resulted in a wider range of application including myocardial perfusion.

See also First Generation USCA, Second Generation USCA, and Third Generation USCA.

In June 2007 Tyco International Ltd. completed the separation of its healthcare business, which is named Covidien. Mallinckrodt, Inc. is now part of Covidien Ltd. The company makes and distributes products for respiratory care; bulk and dosage pharmaceuticals, primarily for pain relief and addiction therapy; and imaging agents for magnetic resonance, ultrasound, x-ray, and nuclear medicine applications. With worldwide manufacturing and distribution facilities and sales offices, Mallinckrodt, Inc. sells its products worldwide.
Albunex was one of the first marketed ultrasound contrast agents. Currently, Mallinckrodt discontinued the manufacturing and development of ultrasound contrast agents.

Ultrasound Contrast Agents: