(CCI) A major limitation of the use of ultrasound contrast agents is the problem that signals from the microbubbles are mixed with those from tissue, so that the distribution of the microbubbles is not optimally displayed either in Doppler or gray scale.
Coherent contrast imaging is a high frame rate implementation of inverting the phase of alternate sound pulses and summing the resulting echoes. The symmetrical signals from linear reflectors are cancelled leaving those from non-linear scatterers, with the advantage that the cancellation is performed without the need to transmit two pulses per image line so that bubble destruction is minimized. Coherent contrast imaging yields best results in the vascular phase of phospholipid microbubbles (such as Definity and SonoVue).

See also Coherence.

Harmonic B-mode imaging takes advantage of the non-linear oscillation of microbubbles. During harmonic imaging, the sound signal is transmitted at a frequency of around 1.5 to 2.0 MHz and received at twice this frequency. The microbubbles also reflect waves with wavelengths different from the transmitted one, the detectors can be set to receive only the latter ones and create only images of the contrast agent.
Using bandpass filters the transmitted frequency is separated from the received signal to get improved visualization of vessels containing ultrasound contrast agents (USCAs). The signal to noise ratio during the presence of microbubbles in tissue is four- to fivefold higher at the harmonic compared with the basic frequency.
Using harmonic B-mode imaging, harmonic frequencies produced by the ultrasound propagation through tissue have to be taken into account. The tissue reflection produces only a small amount harmonic energy compared to USCAs, but has to be removed by background subtraction for quantitative evaluation of myocardial perfusion.

See also Non-linear Propagation.

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.

(MI) The mechanical index is an estimate of the maximum amplitude of the pressure pulse in tissue. It is an indicator of the likelihood of mechanical bioeffects (streaming and cavitation). The mechanical index of the ultrasound beam is the amount of negative acoustic pressure within a ultrasonic field and is used to modulate the output signature of US contrast agents and to incite different microbubble responses.
The mechanical index is defined as the peak rarefactional pressure (negative pressure) divided by the square root of the ultrasound frequency.
The FDA ultrasound regulations allow a mechanical index of up to 1.9 to be used for all applications except ophthalmic (maximum 0.23). The used range varies from 0.05 to 1.9.
At low acoustic power, the acoustic response is considered as linear. At a low MI (less than 0.2), the microbubbles undergo oscillation with compression and rarefaction that are equal in amplitude and no special contrast enhanced signal is created. Microbubbles act as strong scattering objects due to the difference in impedance between air and liquid, and the acoustic response is optimized at the resonant frequency of a microbubble.
At higher acoustic power (MI between 0.2-0.5), nonlinear oscillation occurs preferentially with the bubbles undergoing rarefaction that is greater than compression. Ultrasound waves are created at harmonics of the delivered frequency. The harmonic response frequencies are different from that of the incident wave (fundamental frequency) with subharmonics (half of the fundamental frequency), harmonics (including the second harmonic response at twice the fundamental frequency), and ultra-harmonics obtained at 1.5 or 2.5 times the fundamental frequency. These contrast enhanced ultrasound signals are microbubble-specific.
At high acoustic power (MI greater than 0.5), microbubble destruction begins with emission of high intensity transient signals very rich in nonlinear components. Intermittent imaging becomes needed to allow the capillaries to be refilled with fresh microbubbles. Microbubble destruction occurs to some degree at all mechanical indices. A mechanical index from 0.8 to 1.9 creates high microbubble destruction. The output signal is unique to the contrast agent.

From Bracco Research S. A., Geneva, Switzerland
BG1135 is a polymer-shelled new ultrasound contrast agent under development. The air-filled microsphere has a rigid, 100 nm thick polymeric shell and a mean diameter of 2.9 μm with 99% less than 8 μm.
The destruction mechanism of BG1135 is unique among microbubbles. The microbubbles of BG1135 appear to acquire a small shell defect, allowing the filling gas to stream out and creating a new gas bubble, but leaving the old shell intact. No significant differences between the diameters of the shells can be measured before and after insonation even though the agent is fragmented.