Surgery – Diagnostic testing – Detecting nuclear – electromagnetic – or ultrasonic radiation
Reexamination Certificate
1999-10-25
2001-11-13
Casler, Brian L. (Department: 3737)
Surgery
Diagnostic testing
Detecting nuclear, electromagnetic, or ultrasonic radiation
Reexamination Certificate
active
06315730
ABSTRACT:
This invention relates to ultrasound imaging, more particularly to the use of ultrasound imaging in measuring tissue perfusion.
It is well known that contrast agents comprising dispersions of gas microbubbles are particularly efficient backscatterers of ultrasound by virtue of the low density and ease of compressibility of the microbubbles. Such microbubble dispersions, if appropriately stabilised, may permit highly effective ultrasound visualisation of, for example, the vascular system and tissue microvasculature, often at advantageously low doses.
Measurements of tissue perfusion are of importance in, for example, tumour detection, tumour tissue typically having different vascularity from healthy tissue, and studies of the myocardium, e.g. to evaluate the blood supply thereto. Whilst contrast agent detection using current ultrasound imaging techniques may provide information as to whether particular organs or regions thereof are perfused or not, it does not readily permit quantification of levels of perfusion. Such information, which is useful in assessing whether a patient is at risk owing to low perfusion and so may benefit from preventative methods and/or treatment, must currently be obtained using radioisotopic imaging techniques such as scintigraphy, positron emission tomography or single photon emission computed tomography. These techniques all involve injection of radioactive substances, with potential safety risks for both the patient and medical staff, and use of expensive imaging equipment; this inevitably prohibits their widespread use.
The present invention is based on the finding that ultrasound imaging involving ultrasound-induced destruction or modification of contrast agents may be used to give a measure of tissue perfusion, thereby permitting ready and inexpensive measurement of relative rates of tissue perfusion in any tissue susceptible to ultrasound imaging.
There is currently a limited body of prior art pertaining to ultrasound imaging involving contrast agent destruction. It is stated in U.S. Pat. No. 5425366 that certain types of microparticulate ultrasound contrast agents, for example gas-containing polymer microcapsules, may be visualised by colour Doppler techniques despite being essentially motionless, e.g. as a result of uptake by the reticuloendothelial system. It is proposed that the relatively high irradiation energy levels associated with colour Doppler investigations cause the microparticles to burst, thereby generating Doppler-sensitive signals described as “acoustically stimulated acoustic emission”, although it seems more likely that in practice the detector interprets the discontinuity in the backscattered signal as a motion event and generates an appropriate display. It will be appreciated that since this technique is concerned exclusively with detection of essentially motionless contrast agent microparticles it is inherently inapplicable to measurement of rates of perfusion.
U.S. Pat. No. 5456257 describes detection of coated microbubble contrast agents in the bodies of patients by applying pulses of ultrasound irradiation at energy levels sufficient to destroy the coated microbubbles and identifying microbubble destruction events using phase insensitive detection (e.g. envelope detection) and differentiation of echoes received from successive ultrasound transmissions. Following the first transmission, acoustic energy emanating from microbubble destruction sites is received by an ultrasonic transducer and the resulting signal waveform is subject to amplitude detection; echoes received from a subsequent transmission are detected in similar manner and signals from the two reception periods are differentiated on a spatial basis. Typically the signals derived from the second reception period are subtracted from those derived from the first reception period to generate signals emanating from microbubble destruction events to the exclusion of other signals; thresholding may be applied to eliminate variations arising from tissue movements and flowing fluids. Whilst signals may be processed using sustain Systems and/or by counting events in a given region of the body over a period of time, thereby giving an indication of bulk flow of contrast agent-containing blood in, for example, the chambers of the heart, there is no suggestion that the technique may be used in quantifying capillary blood flow within tissue, i.e. of measuring perfusion.
The present invention similarly uses a first high energy ultrasound pulse or series of pulses to destroy or discernibly modify a recognisable amount of the contrast agent within a target region, but rather than employing subsequent pulses to detect background signals to be subtracted from the first detection sequence the invention uses the subsequent pulses to detect the flow of “fresh” or unmodified contrast agent (and therefore blood) into the target region. This permits determination of parameters such as vascular blood volume fraction, mean transit time and tissue perfusion with respect to local vascular state within the target region. The initial high energy pulse or pulses may, for example, be used to clear a closely defined target region of detectable contrast agent so that a sharp front of further contrast agent, which is readily detectable and quantifiable by ultrasound imaging, then flows into this region. The ability to generate sharp fronts of moving contrast agents in target regions of interest renders the method of substantial advantage over previous attempts to estimate wash-in rates of contrast agents into tissue immediately following injection, since the front of injected contrast agent will inevitably be smoothed or smeared out by passage through the lungs and heart. Alternatively the initial pulse or pulses may be used to modify the echogenicity of the contrast agent, for example by activating a contrast agent in precursor form so as to produce a rise in echogenicity in the target region. The time course of echogenicity change during and after ultrasound exposure may give information about local vascular state, e.g. regional blood volume and perfusion. For example, the wash-out rate of contrast agent, having been activated by ultrasound exposure, may be determined and thus used to map perfusion.
Thus, according to one aspect of the present invention, there is provided a method of measuring tissue perfusion in a human or non-human animal subject which comprises administering an effective amount of an ultrasound contrast agent to said subject, irradiating tissue in a target region with at least one pulse of ultrasound having energy sufficient to destroy or discernibly modify the echogenic properties of a recognisable amount of the contrast agent in said target region, and ultrasonically detecting and quantifying the rate of flow of either further contrast agent into said target region or modified contrast agent out of said target region.
Viewed from another aspect the invention provides the use of an ultrasound contrast agent in the manufacture of a diagnostic material for use in a method of measuring tissue perfusion in a human or non-human animal subject, said method comprising administering an effective amount of said ultrasound contrast agent to said subject, irradiating tissue in a target region with at least one pulse of ultrasound having energy sufficient to destroy or discernibly modify the echogenic properties of a recognisable amount of the contrast agent in said target region, and ultrasonically detecting and quantifying the rate of flow of either further contrast agent into said target region or modified contrast agent out of said target region.
A wide range of ultrasound contrast agents may be employed in accordance with the method of the invention; most commonly these contrast agents will be gas-containing or gas-generating. Representative examples of such contrast agents include microbubbles of gas stabilised (e.g. at least partially encapsulated) by a coalescence-resistant surface membrane (for example gelatin, e.g. as described in WO-A-8002365), a filmogenic protein (for exa
Eriksen Morten
Frigstad Sigmund
Hoff Lars
Østensen Jonny
Casler Brian L.
Imam Ali M.
Nyomed Imaging AS
Ronning, Jr. Royal N.
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