Flemming Forsberg

Ultrasound contrast agents: A review

During the past 25 years, many attempts have been made to establish effective ultrasound contrast agents for both cardiac and noncardiac applications. The ideal ultrasound contrast agent would be: (a) nontoxic; (b) injectable intravenously; (c) capable of passing through the pulmonary, cardiac and capillary circulations; and (d) stable for recirculation. A variety of potential ultrasound contrast agents have been or are now under development. Present and future ultrasound contrast agents should provide for increased diagnostic capabilities in a variety of normal and abnormal vessels and organs throughout the body. These agents will enhance tumor vascularity, delineate areas of ischemia, as well as improve visualization of vascular stenosis. Future developments with modification of ultrasound equipment should increase the capabilities of these agents to improve imaging as well as Doppler sensitivity.

Subharmonic imaging of contrast agents

Ultrasound contrast agents promise to improve the sensitivity and specificity of diagnostic ultrasound imaging. It is of great importance to adapt ultrasound equipment for optimal use with contrast agents e.g., by exploiting the nonlinear properties of the contrast microbubbles. Harmonic imaging is one technique that has been extensively studied and is commercially available. However, harmonic imaging is associated with problems, due to second harmonic generation and accumulation within the tissue itself. Given the lack of subharmonic generation in tissue, one alternative is the creation of subharmonic images by transmitting at the fundamental frequency (fo) and receiving at the subharmonic (fo/2). Subharmonic imaging should have a much better lateral resolution and may be suitable for scanning deep-lying structures owing to the higher transmit frequency and the much smaller attenuation of scattered subharmonic signals. In this paper, we will review different aspects of subharmonic imaging including implementation, in-vitro gray-scale imaging and subharmonic aided pressure estimation.

Guidelines and Good Clinical Practice Recommendations for Contrast Enhanced Ultrasound (CEUS) in the Liver – Update 2012

Initially, a set of guidelines for the use of ultrasound contrast agents was published in 2004 dealing only with liver applications. A second edition of the guidelines in 2008 reflected changes in the available contrast agents and updated the guidelines for the liver, as well as implementing some non-liver applications. Time has moved on, and the need for international guidelines on the use of CEUS in the liver has become apparent. The present document describes the third iteration of recommendations for the hepatic use of contrast enhanced ultrasound (CEUS) using contrast specific imaging techniques. This joint WFUMB-EFSUMB initiative has implicated experts from major leading ultrasound societies worldwide. These liver CEUS guidelines are simultaneously published in the official journals of both organizing federations (i.e., Ultrasound in Medicine and Biology for WFUMB and Ultraschall in der Medizin/European Journal of Ultrasound for EFSUMB). These guidelines and recommendations provide general advice on the use of all currently clinically available ultrasound contrast agents (UCA). They are intended to create standard protocols for the use and administration of UCA in liver applications on an international basis and improve the management of patients worldwide.

Characterization of ultrasound contrast microbubbles using in vitro experiments and viscous and viscoelastic interface models for encapsulation

Zero-thickness interface models are developed to describe the encapsulation of microbubble contrast agents. Two different rheological models of the interface, Newtonian (viscous) and viscoelastic, with rheological parameters such as surface tension, surface dilatational viscosity, and surface dilatational elasticity are presented to characterize the encapsulation. The models are applied to characterize a widely used microbubble based ultrasound contrast agent. Attenuation of ultrasound passing through a solution of contrast agent is measured. The model parameters for the contrast agent are determined by matching the linearized model dynamics with measured attenuation data. The models are investigated for its ability to match with other experiments. Specifically, model predictions are compared with scattered fundamental and subharmonic responses. Experiments and model prediction results are discussed along with those obtained using an existing model [Church, J. Acoust. Soc. Am. 97, 1510 (1995) and Hoff et al., J. Acoust. Soc. Am. 107, 2272 (2000)] of contrast agents.

Ultrasonic characterization of the nonlinear properties of contrast microbubbles

The nonlinear properties of microbubble contrast agents have been used to create contrast-specific imaging modalities such as harmonic imaging and subharmonic imaging. Thus, a better understanding of the nonlinear performance of contrast microbubbles may enhance the diagnostic capabilities of medical ultrasound (US) imaging. The first and second harmonic, the 1/2 order subharmonic and the 3/2 order ultraharmonic components in spectra of scattered signals from Optison microbubbles insonified at 2 and 4 MHz have been investigated using an in vitro laboratory pulse-echo system. The development of these signal components over time is quite different for 2-MHz insonification compared to 4-MHz insonification. Scattered subharmonic and ultraharmonic signals are much more time-dependent than first and second harmonic echoes. The dependence of the first and second harmonic, subharmonic and ultraharmonic components on acoustic pressure for 2-MHz insonification is similar to that for 4-MHz insonification. The first and second harmonic components increase linearly with acoustic pressure (in double logarithmic scales) and the subharmonic and ultraharmonic amplitudes undergo rapid growths in the intermediate acoustic pressure range and much slower increases at both lower and higher acoustic pressures.

Classification of ultrasonic B-mode images of breast masses using Nakagami distribution

The Nakagami distribution was proposed recently for modeling the echo from tissue. In vivo breast data collected from patients with lesions were studied using this Nakagami model. Chi-square tests showed that the Nakagami distribution is a better fit to the envelope than the Rayleigh distribution. Two parameters, m (effective number) and /spl alpha/ (effective cross section), associated with the Nakagami distribution were used for the classification of breast masses. Data from 52 patients with breast masses/lesions were used in the studies. Receiver operating characteristics were calculated for the classification methods based on these two parameters. The results indicate that these parameters of the Nakagami distribution may be useful in classification of the breast abnormalities. The Nakagami distribution may be a reasonable means to characterize the backscattered echo from breast tissues toward a goal of an automated scheme for separating benign and malignant breast masses.

Pressure dependence of subharmonic signals from contrast microbubbles.

Noninvasive pressure estimation in heart cavities and in major vessels would provide clinicians with a valuable tool for assessing patients with heart and vascular diseases. Some microbubble-based ultrasound contrast agents are particularly well suited for pressure measurements because their substantial compressibility enables microbubbles to vary significantly in size in response to changes in pressure. Pressure changes should then affect reflectivity of microbubbles after intravenous injection of a contrast agent. This has been demonstrated with a galactose-based contrast agent using 2.0-MHz ultrasound tone bursts. Preliminary results indicate that, over the pressure range of 0-186 mmHg, the subharmonic amplitude of scattered signals decreases by as much as 10 dB under optimal acoustic settings and the first and second harmonic amplitudes decrease by less than 3 dB. An excellent correlation between the subharmonic amplitude and the hydrostatic pressure suggests that the subharmonic signal may be utilized for noninvasive detection of pressure changes.

Power Doppler Assessment of Vascular Changes During Fracture Treatment With Low-Intensity Ultrasound

Objective. To study the use of power Doppler sonography for assessing changes in vascularity during treatment of fracture sites with low‐intensity ultrasound. Methods. In 6 dogs (3 pairs), subcutaneous dissection of the midshaft of the ulna allowed symmetrical osteotomies to be made with a reciprocation saw. Three dogs were treated and 3 were used as controls. The fracture site was subjected to 1.5‐MHz low‐intensity ultrasound (30 mW/cm2) for 20 minutes daily from a therapeutic ultrasonic device. Gray scale sonography was performed to evaluate the fracture site. Power Doppler sonography was used to assess flow patterns at the fracture site and surrounding soft tissue. A sonographic contrast agent was administered intravenously. The dose was 0.2 mL/kg. Results. Power Doppler sonography showed an increase in flow around the fracture site in the treated dogs compared with that in control dogs. Color pixel values on day 7 were 3‐fold higher in treated legs than control legs and on day 11 were 33% higher in treated legs than control legs. Enhancement after contrast agent administration was consistently higher in treated legs than control legs. Conclusions. Power Doppler sonography showed increased vascularity around the fracture sites in treated dogs with and without contrast agent administration.

Subharmonic Imaging with Microbubble Contrast Agents: Initial Results

The subharmonic emission from insonified contrast microbubbles was used to create a new imaging modality called Subharmonic Imaging. The subharmonic response of contrast microbubbles to ultrasound pulses was first investigated for determining adequate acoustic transmit parameters. Subharmonic A-lines and gray scale images were then obtained using a laboratory pulse-echo system in vitro and a modified ultrasound scanner in vivo. Excellent suppression of all backscattered signals other than from contrast microbubbles was achieved for subharmonic A-lines in vitro while further optimization is required for in vivo gray scale subharmonic images.

Clinical applications of ultrasound contrast agents

Within the last decade safe and practical ultrasound contrast agents have been introduced. Most of these are based on gas-filled microbubbles, which markedly enhance Doppler signals and, in some cases, also gray-scale images. The clinical improvements expected from ultrasound contrast is reviewed. Tissue-specific contrast agents constitute another area of potential clinical significance. One particular agent is taken up by the reticulo-endothelial system and produces so-called acoustic emission signals when imaged. An introduction to the unique clinical applications of acoustic emission is given. Harmonic imaging is a new contrast-specific imaging modality, which utilizes the nonlinear properties of some agents in an attempt to alleviate current limitations of ultrasound contrast studies. Examples of harmonic images are presented.