Olivia Bottinelli

Ultrasound contrast agents: Basic principles

INTRODUCTION Ultrasonography lacked substances to be administered to patients to improve or increase the diagnostic yield, which is peculiar considering that contrast agents have long been used with all the other imaging techniques. Fortunately some contrast agents, most of them consisting in gas microbubbles, have been recently introduced for ultrasound imaging too: this review will focus on their history, behavior, current applications and future developments. Echocontrast agent research is in progress and many new agents are expected to be marketed this and next year, to be added to Levovist by Schering AG (Berlin, Germany), to enhance the ultrasound signal safely and effectively. No definitive conclusions can be drawn yet on the actual merits of each contrast agent, but all of them seem to be both effective and safe, meaning that their future success will depend on the relative cost-effectiveness and peculiarities. THE BASIC PRINCIPLES OF ECHOCONTRAST AGENTS The microbubbles act as echo-enhancers by basically the same mechanism as that determining echo-scattering in all the other cases of diagnostic ultrasound, namely that the backscattering echo intensity is proportional to the change in acoustic impedance between the blood and the gas making the bubbles. The different acoustic impedance at this interface is very high and in fact all of the incident sound is reflected, even though not all of it will of course go back to the transducer. But the acoustic wave reflection, though nearly complete, would not be sufficient to determine a strong US enhancement because the microbubbles are very small and are sparse in the circulation. Moreover, reflectivity is proportional to the fourth power of a particle diameter but also directly proportional to the concentration of the particles themselves. SECOND HARMONIC IMAGING As we said above, the microbubbles reached by an ultrasound signal resonate with a specific frequency depending on microbubble diameter. However, the main resonance frequency is not the only resonance frequency of the bubble itself and multiple frequencies of the fundamental one are emitted, just like in a musical instrument. These harmonic frequencies have decreasing intensity, but the second frequency, known as the second harmonic, is still strong enough to be used for diagnostic purposes. The theoretical advantage of the harmonic over the fundamental frequency is that only contrast agent microbubbles resonate with harmonic frequencies, while adjacent tissues do not resonate, or else their harmonic resonation is very little. Thus, using a unit especially set to produce ultrasounds at a given frequency (3.5 MHz) and receive an ultrasound signal twice as powerful (7 MHz) it will be possible to show the contrast agent only, without any artifact from the surrounding anatomical structures, with a markedly improved signal-to-noise ratio. A similar effect to digital subtraction in angiography can thus be obtained, even though through a totally different process. Moreover, second harmonic imaging permits to show extremely small vessels (down to 40 microm) with very slow flow, which would be missed with a conventional method. B-mode imaging can also depict the microbubbles in the myocardium suppressing nearly all the artifacts from cardiac muscle motion. Recently a peculiar behavior of microbubbles has been observed which may permit contrast agent detection even in capillaries. This method is variously known as sonoscintigraphy, loss of correlation, stimulated acoustic emission and transient scattering. The contrast agent microbubbles reached by an ultrasound beam powerful enough explode producing a strong and very short backscatter echo which is read by the unit as a Doppler signal and results in a color pixel where the individual microbubble exploded. CONCLUSIONS The microbubble contrast agents developed and introduced as safe and effective echo-enhancers in present-day clinical practice will open up new oppurtunities

The latest in ultrasound: three-dimensional imaging. Part II

INTRODUCTION The three-dimensional (3D) reconstruction of ultrasound images has become a widespread option in ultrasound equipment. Specific softwares have become available and 3D reconstruction feasible since the early 1990s, particularly since 1994. POSSIBLE CLINICAL APPLICATIONS Several clinical applications are feasible in all parenchymatous organs (mainly the liver and prostate), hollow viscera (e.g. the bladder and gallbladder), peripheral vessels (supra-aortic trunks and limb vessels) and central (the aorta and iliac arteries) or cerebral vessels. Moreover, tumoral vessels in parenchymatous organs can be reconstructed, and even the fetus in the uterine cavity, with excellent detailing. The recent introduction of echocontrast agents and second harmonic imaging has permitted to study normal and abnormal peripheral, central and parenchymatous vessels, with similar patterns to those obtained with digital angiography. The spatial relationships between the vascular structures of the liver, kidney and placenta were studied with 3D ultrasound angiograms. The applications of this new technique include the analysis of vascular anatomy and the potential assessment of organ perfusion. THE LATEST APPLICATIONS--INTRAVASCULAR STUDIES: Some catheters with an ultrasound transducer in the tip have been tested for intravascular studies. Just like conventional transducers, they provide two-dimensional (2D) images which are then postprocessed into longitudinal 3D or volume reconstructions. The former resemble angiographic images and can be viewed 3D rotating the image along its longitudinal axis. Volume images, which are more complex and slower to obtain, can be rotated on any spatial plane and provide rich detailing of the internal vascular lumen. The clinical importance of intravascular ultrasound with 3D volume reconstructions lies in the diagnosis of vascular conditions and the assessment and monitoring of intravascular interventional procedures--e.g. to detect inaccurate deployment of intravascular stents and endoluminal grafts during the maneuver. Three-dimensional reconstructions involve geometric data assembly and volumetric interpolation of a spatially related sequence of tomographic cross sections generated by an ultrasound catheter withdrawn at a constant rate through a vascular segment of interest, resulting in the display of a straight segment. Therefore particular care is needed and there are some useful hints to avoid mistakes. CONCLUSIONS Three dimensional reconstructions of B-mode and color Doppler images are no longer a work in progress and their clinical importance and possible applications are both established and ever-increasing. On the other hand, independent of the different types of energy used, also computed tomography and magnetic resonance 3D reconstructions are very useful from a clinical viewpoint and they have become an established routine technique for both these methods. It is very likely that 3D volume reconstructions in ultrasound will find numerous applications in the near future. They may help to increase the diagnostic confidence and to facilitate diagnosis, intraprocedure monitoring in interventional radiology and follow-up and also to reduce the number of invasive examinations with iodinated contrast agents. This could result in cutting the cost and duration of the most expensive examinations. New, although invasive, applications can be hypothesized for intravascular or intraluminal catheters with an ultrasound transducer inside.

Contrast enhancing agents in ultrasonography: Clinical applications

INTRODUCTION As ultrasound remains a poorly sensitive method, echocontrast agents make a real difference. At least 29 echocontrast agents are currently on trial worldwide; their chemical composition, mechanisms of action and possible clinical applications are different. The state of the art of echocontrast agents is discussed: their established applications, those expected in the near future and finally their hypothetical, ideal applications. POTENTIAL CLINICAL APPLICATIONS An extravascular and a vascular domain can be considered. The former includes the gastrointestinal tract and body cavities--both the normal (bladder, uterus, tubes and so on) and the abnormal (abscesses, fistulas, pericardium, peritoneum and so on) ones. Echocontrast agents can: (1) create or improve an acoustic window; (2) distend some organs and fill them with a liquid, with homogenous attenuation of the ultrasound beam; (3) displace the air-containing intestinal loops; (4) depict the walls, the shape and the contours of a normal or abnormal cavity; (5) detect abnormal communications, fistulas and drainages; and (6) evaluate the amount of fluid in the pleural, pericardial or peritoneal cavities. As for vascular applications, this domain sees the highest number of echocontrast agents on trial or on the market. The best know of them are: Levovist (Schering AG, Berlin, Germany), BR1 (Bracco, Milan, Italy) and EchoGen (Abbott, USA). All these act by enhancing arteries, veins and capillaries. The clinical applications validated in clinical trials mainly regard studies in intracranial and neck vessels and the vascularity of upper and especially lower limbs of renal vessels. Tumor macrovascularity (and in the future, hopefully microvascularity) can also be studied in parenchymatous and/or glandular organs, as well as in intra- and extra-abdominal parenchymatous organs in the periskeletal soft tissues. Clinical validation has also been obtained in the follow-up of tumors submitted to ablation therapy (chemoembolization, ethanol injection, thermal ablation) and in echocardiography, both for morphological studies in the cardiac cavities and for the cardiac wall perfusion. CONCLUSIONS In a subgroup of 513 out of 1275 patients examined Europe-wide, the contrast agent Levovist increased the diagnostic confidence from 27.4 +/- 22.5 to 77.2 +/- 22.5%. Such data encourage further trials to validate current preliminary results.

Selection of patients for carotid endarterectomy: the role of ultrasound.

Stroke is the third leading cause of death in the western world and the major cause of disability among the middle aged and elderly populations. Carotid artery stenosis is the single most important risk factor for stroke. The North American Symptomatic Carotid Endarterectomy Trial and the European Carotid Surgery Trial have demonstrated that the risk of stroke is reduced by surgery in patients with high grade stenosis. Carotid plaque morphology also plays an important role; plaques which are ulcerated and echolucent are associated with a higher risk of stroke. Arteriography has long been regarded as the gold standard diagnostic tool for evaluation of carotid artery disease, but it is an invasive and costly technique which carries the risk of potentially serious complications. Doppler ultrasound can provide functional and anatomical information on vessel stenosis and plaque morphology at sub-millimetric resolutions and is an inexpensive and noninvasive tool. Color and spectral Doppler ultrasound are now recognized as the best screening tests for carotid artery stenosis. The evidence for its use as the sole diagnostic imaging modality prior to carotid endarterectomy is examined. The recent availability of ultrasound contrast agents helps to distinguish between pseudo- and true occlusions, improves ultrasound images and should help to reduce operator variability.

Clinical usefulness of color Doppler enhancement in the assessment of the liver and the portal system

Both the sensitivity and the specificity of imaging techniques in the study of focal hepatic lesions are relatively low (33–66%) [1]; ultrasonography is no exception. Defining the region(s) of interest (ROI) is sometimes difficult with both conventional and color Doppler sonography. Thus, approaching the study of liver vessels and of the portal system may be difficult because venous flow is often slow, poor, deep, or within an organ with high US beam absorption because of associated diffuse hepatopathy. The Doppler system must be sensitive enough to detect even very slow flows: this has been partly achieved in the latest equipment which has just been, or will soon be, marketed. However, the necessary increase in gain may worsen image quality dramatically, making the image useless for diagnostic purposes, because of the thickness of the organ under examination. Moreover, respiratory artifacts and, in the segments near the great vessels of the heart, pulsatile artifacts are common [2, 3].

Ultrasound of the Hand

Perfect knowledge of the complex anatomy of the structures involved and high-frequency probes are necessary for the application of ultrasound (US) in musculoskeletal imaging. Thanks to the introduction of “small parts” or “superficial soft tissue” probes with high frequency (over 7.5 MHz), the US study of small structures in very superficial sites is increasingly used in clinical practice because it provides answers to very specific diagnostic queries.