Ultrasonic imaging technique

(42) Date of commencement of the patent: 15. 6.1993 (45) Date of issue: 25. 1.1994 (51) Int.Cl.⁵ : A61B 8/00 (30) Priority:

27th 1.1983 US 461664 claimed.

(56) Documents:

US-PS4143554 US-PS 4265251 US-PS4315435 (73)

FINE STEVEN B.

90402 SANTA MONICA (US).

(54) METHOD OF GENERATING ULTRASONIC IMAGES (57) In a method of manufacturing a contrast agent injectable into the bloodstream of a subject for generating ultrasonic images, it is provided that a biocompatible liquid is irradiated with ultrasonic energy in the high frequency range of 5,000 to 30,000 Hz Microbubbles are generated with substantially uniform diameters of about 6 to 20 microns.

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The invention relates to a method for producing a contrast agent which can be injected into the bloodstream of a living being for generating ultrasound images.

There are various techniques for imaging parts of the animal or human body as a diagnostic or therapeutic aid. Some of these existing methods are described below.

One of the most well-known imaging techniques uses x-rays to visualize skeletal and other internal structures of animals and humans. However, there are a number of problems associated with the use of X-rays. First, different areas of the body are not resistant to X-rays. In addition, X-rays are dangerous if the amount of irradiation is excessively high; furthermore, the absorbed X-ray radiation has a cumulative effect throughout life. Finally, although X-rays can provide images of skeletal and other internal structures, they are relatively unsatisfactory for accurately imaging certain organ systems and blood vessels.

Another commonly used technique is angiography, in which a radiopaque contrast agent is injected into an artery. Because the contrast enhances the arteries it flows through, X-rays can be used to image large, distant arteries and their significant branches. However, angiography does not allow the visualization of underpilled, ischemic areas of the tissue or heart muscle or microcirculation. In addition, certain angiographic observations are based on measurements that vary depending on the device used, the placement and angle of lenses, the experience of the operator, and similar factors. Furthermore, angiography is invasive, requiring the use of a catheter in arteries rather than in veins. In addition to a required hospitalization, angiography can also be dangerous.

Another technique, often referred to as radio nuclide imaging, requires the injection of radioactive substances such as thallium into the bloodstream. This procedure does not require invasion of the arteries as in angiography, but requires the use of very expensive and complicated equipment. Furthermore, radio-nuclide imaging gives images of only a limited number of views of the heart, and these images can not be of excessive clarity. Furthermore, this type of radiation is cumulative over the lifetime and can be dangerous.

Recently, advances have been made in techniques of ultrasound imaging of various parts of the body. Applying these techniques to the heart is called echocardiography. An ultrasound scanner is used to generate and receive sound waves. The ultrasound scanner is placed on the body surface over the area to be imaged. The sound waves generated by the scanner are directed to the area to be imaged. The scanner then captures the sound waves reflected from the underlying area and converts that data into images.

Although such ultrasound scanners are known in the art, an overview will be given to better explain the present invention. When ultrasonic energy is transmitted through a substance, the acoustic properties of the substance depend on the speed of the transmissions and the density of the substance. Changes in the acoustic substance properties (or the acoustic resistance) are particularly pronounced at the boundary layers of various substances (i.e. H. Solids, liquids and gases. It follows that the change in acoustic properties as ultrasonic energy passes through various media alters the reflection characteristics, resulting in a more intense sound reflection signal received by the ultrasound scanner.

Earlier ultrasound imaging methods, such as echocardiograms, suffered from insufficient sharpness. For this reason, strong efforts have been made to improve the ultrasound scanners and associated equipment. In addition, beginning in 1968, contrast agents were injected into the bloodstream to obtain clearer and enhanced ultrasound images. The known contrast agents were liquids containing microbubbles, sometimes encapsulated with gelatin or saccharin, and sometimes by mechanical agitation, i. H. by hand shaking and mixing various liquids. Other known contrast agents are described in the article by J. Ophir u. a. Ultrasonic Backscatter from Contrast Produced by Collagen Microspheres at Ultrasonic Imaging by Academic Press, Inc. 1980, described.

The contrast agents themselves are strong sound wave reflectors because of the acoustic differences between the liquid and the micro-gas bubbles dissolved therein. When the contrast agent is injected and perfused through the microvasculature of the tissue, clearer images of that tissue can be produced. Despite the use of such contrast agents, the images produced, e.g. B. of the myocardial tissue, because of the variable size and durability of the known microbubbles, of a relatively low quality, highly variable and unquantifiable. In addition, the problem of air embolism toxicity has not been sufficiently researched.

From US-PS 4,265,251 it is further known in connection with the pressure measurement in the blood vessels to produce bubbles in a solution, wherein CO2 is introduced into the solution by means of a capillary tube. After the introduction of the CO2 bubbles, the solution, z. As a sugar solution, quickly

-2AT397 034B solidified, so that the bubbles are embedded in the resulting solid matrix. Particles of the matrix containing at least one vesicle are then introduced into the blood vessel where the matrix dissolves and the gas bubbles are released into the bloodstream.

The object of the present invention is to produce smaller and more uniform microbubbles in conjunction with the known contrast agents.

This object is achieved in that a biocompatible liquid is sonicated with ultrasonic energy in the high frequency range of 5000 to 30,000 Hz, wherein microbubbles are generated with substantially uniform diameters of about 6 to 20 gm.

The contrast agents of the present invention are (1) echo capable (ie capable of reflecting sound waves), (2) small enough to pass through such capillaries and to perfuse those tissues which were impracticable to known contrast agents injected into a peripheral vein.

This produces improved images of such tissues and organs, and allows for discrimination between well perfused and poorly perfused tissues. The new contrast agents are further quantifiable and reproducible.

The method of the present invention allows (1) the imaging of organ systems that could not be imaged using the known ultrasound techniques, and (2) the clearer and more detailed imaging of certain areas that were already visible by known methods.

In one embodiment of the present invention, the biocompatible liquid (e.g. B. 70 % Dextrose, 50% dextrose, 70% sorbitol, Renogratin-76, mixtures of these agents and the like. Like.) Of a high-frequency (5000 to 30000 Hz, preferably 20000 Hz) exposed to ultrasonic energy. As a result, microbubbles are produced with a diameter of approximately 6 to 20 gm. For ease of reference, microbubbles will be referred to as sonicated microbubbles hereinafter.

The contrast agent of the present invention is detected by a conventional ultrasonic scanner and converted into images as described above.

In addition to overcoming many of the problems associated with the prior art, the contrast agent produced in accordance with the invention makes it possible to produce novel images of various organ systems. Although the contrast agent of the present invention is applicable to various animal and human body organ systems, its novel features and advantages will be more fully understood from the following description applied to the production of myocardial tissue images and perfusion or blood flow patterns. The description and drawings are for illustration only. It is expressly understood that they are not intended to define the limits of the invention.

When reviewing the description and drawings, it should be noted that the heart is a pump that is supplied by many blood vessels. Over time, these can be partially or totally blocked, causing damage to the heart tissue. Information has been gained in the past about cardiac tissue using radio-nuclide imaging and surgery. The angiogram does not generate any direct tissue data, but it requires the drawing of inferences of the data obtained with respect to the large blood vessels and the wall movements of the heart.

The invention will be described below with reference to the accompanying drawings. 1 shows a schematic illustration of the use of an ultrasound scanner in echocardiography; and Figs. 2-5 are cross-sectional images of the heart enhanced by the use of contrast media flowing through the heart.

FIG. 1 is a schematic representation of the heart and the lungs and a scanner (10) and an imaging device (12) having ultrasonic scanner device. The device generates visible images of a predetermined area, in this case the heart region of a human body. Typically, the scanner is placed directly on the skin (14) over the area to be imaged (16). The scanner (10) contains various electronic components, including ultrasound transducers. The scanner (10) generates ultrasonic waves (18) which perform a sector scan of the cardiac region (16). The ultrasonic waves (18) are reflected from the various parts of the heart region (16), received by the generating transducer, and processed by known pulse echo techniques. After processing, signals are transmitted to the imaging device (12) for viewing (also known in the art).

After preparation of the patient and attachment of the scanner (10) containing the sonicated microbubble Konstrastmiltel invention, z. B. indicated by a brachial vein indicated generally at (24). The contrast medium flows through the vein (24) in the direction of the arrow (26) through the right venous side (28) of the heart (30), through the pulmonary artery (29) leading to the lungs (32), through the lungs (32). , through the capillaries (34), through the pulmonary vein (35) and finally into the left atrium (36) and the left ventricle (37) of the heart (30).

It has been found that when using sonicated microbubbles, images are generated which have strong contrast ranges. Without being bound by any theory, sonicated microbubbles result

In comparison with known contrast agents, the present invention has markedly clearer and more detailed images of myocardial tissue and microvessels.

In the following, Figs. 2 5, reference is made. There one can see a contrast echocardiogram resulting from the use of the sonicated microbubble contrast agent of the present invention. In the figures, a horseshoe-shaped part (50) represents the left ventricular wall muscle (or tissue) surrounding the left ventricular chamber (37). The microbubbles were injected into the pulmonary artery of a dog and crossed the capillary junction of the lung to enter the left atrium (36) and the left ventricular chamber (37), into the aorta through the coronary arteries and possibly into the left ventricular tissue (50) , which enhances the picture.

Specially 2 Figure 12 shows a two-dimensional echocardiogram (2-DE) image of the left ventricular chamber (37) and the left atrium (36) prior to introduction of the microbubbles. FIG. 3 Figure 10 shows the injection of 10 ml of a sonicated renografin / NaCl mixture through a fixed pulmonary artery catheter. As can be seen, the contrast agent appears in the left atrium (36) and flows into the left ventricle (37). In Fig. 4 a substantially complete shadowing of the left ventricular chamber (37) is achieved. In Fig. 5 the subsequent shading of the myocardial tissue (50) can be seen. This is because the contrast-carrying blood has flowed through the aorta into the coronary arteries that deliver the blood to the myocardial tissue (50). Thus, observations and diagnoses can be made with regard to the passage of blood through the lungs, to blood flow patterns, to the size of the left atrium, to the state of the mitral valve (separating the left atrium and the left ventricle), to ventricular dimensions in the left ventricular chamber and abnormalities in the wall movement. Upon ejection of the contrast agent from the left ventricle, the condition of the aortic valve can be analyzed as well as the percentage or percentage of volume ejected from the left ventricle. Finally, the contrast patterns in the tissue indicate which areas, if any, are not properly perfused.

In summary, such a pattern of images helps to diagnose unusual blood flow characteristics within the heart, valve capacity, chamber sizes, and wall motion, and provides a potential indicator of myocardial perfusion.

In the above example, the microbubbles are prepared from a mixture of Renographin-76, a relatively non-toxic, biocompatible, known radiopacifier, and a 1: 1 saline solution. This mixture was sonicated, d. H. exposed to radio frequency energy for 30 seconds through a 375 watt heating system sonicator. Such sonicators are known for other uses and typically emit ultrasonic energy at 20,000 Hz, although ultrasonic frequencies of 5,000 to 30,000 Hz or higher are possible within the scope of the present invention. Depending on the selected contrast agent, for. B. the mixture described above, sugar solutions od. Like., Different bubble sizes are generated, which is usually in the desired range of about 6 to 20 gm in diameter.

In addition to the scanner (10) briefly described above, there are other ultrasound scanners, such as those described for. B. in U.S. Patent Nos. 4,143,554 and 4,315,435, the disclosure of which is incorporated herein by reference. Basically, these patents relate to various techniques, including dynamic cross-section echography (DCE), for generating sequential two-dimensional images of cross-sectional slices of animal or human anatomy with ultrasonic energy at a frame rate sufficiently high to allow dynamic visualization of moving organs. Apparatus types used in DCE technology are commonly referred to as DCE scanners and transmit and receive short bursts of sound in the form of narrow bundles or lines. The reflected signal strength is a function of time, which is converted to a position using a nominal velocity of sound and reproduced on a CRT or other suitable device in a manner analogous to radar or sonar display. DCE can thus be used to produce images of many organ systems, including the liver, gallbladder, pancreas, and kidney, but is often used to visualize tissue and the major blood vessels of the heart. The invention includes these and other known scanners.

As noted above, in attempts to find a safe, reproducible and quantifiable contrast agent for use in reproducing an enhanced ultrasound image of the observed tissue, saccarine or gelatin-entrapped nitrogen or carbon dioxide microbubbles having an average size of approximately 75 μm, under pressure standing gas in liquids (eg. B. H2O2) and mechanically shaken mixtures of liquid solutions. Since the pulmonary artery capillaries have a diameter of 8 to 10 μm, the 75 μm trapped gas bubbles can not penetrate the capillary plug, requiring direct injection into the area to be imaged or arterial injection with the same risks as in the invasive procedure of angiography discussed above was. Furthermore, unlike those produced by sonication, the microbubbles produced by shaking various liquids have significant size differences. Different amounts of such non-entrapped, well-shaken microbubbles can

-4AT397 034B

Penetrate capillaries, but the current state of the art gives only qualitative data due to the lack of proper control of the ug variables. These contrast agents all work to some degree, but they have a number of problems, such as the inconsistent size of the bubbles. These and other problems are solved by the sonicated microbubbles of the present invention.

While the sonicated microbubbles are more uniform in size and provide enhanced images, the main problem associated with the introduction of air remains. The danger of injecting trapped or unentered microbubbles into the heart is that the vesicles may disintegrate and the proportion of vesicles dissolved air both in the arterial system (z. B. of the brain and kidneys) as well as in other microcirculation systems can become toxic.

Thus, it is clear that the particular contrast agent chosen depends on the purpose of the imaging. For example, the potential risk factors of an agent for diagnostic or therapeutic use should be considered. The size of the microbubbles should also be considered. If the bubbles are too large, they can not pass through the capillaries and cause a direct or arterial injection when the area to be imaged is behind the capillaries. On the other hand, too small a bubble does not reflect the sound waves emitted by the ultrasonic transducer.