Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
INJECTION SYSTEM HAVING MICROBUBBLE-ENHANCED EXTRAVASATION DETECTION SYSTEM
Document Type and Number:
WIPO Patent Application WO/2009/042621
Kind Code:
A2
Abstract:
An injection system (101) includes a fluid delivery system for moving an injection medium along a flow path for injection thereof into a subject. The system (or a separate extravasation detection system(131)) has an ultrasound transducer (133) for detecting ultrasound energy reflected from inside the subject and an ultrasound contrast enhancement system for introducing microbubbles into the subject during the injection. The microbubbles increase reflectivity of one or more fluids in the subject to ultrasound energy, facilitating extravasation detection. A needle (143) or injection line may be constructed to produce the microbubbles during the injection, for example. In use, ultrasound is directed into the subject. Microbubbles are introduced into the subject during the injection to increase reflectivity of one or more fluids in the subject (181) to ultrasound. Ultrasound energy reflected from inside the subject is detected to obtain information indicative of whether or not the injection is extravasating or non-extravasating.

Inventors:
LAITENBERGER PETER G (GB)
POOLEY DAVID M (GB)
Application Number:
PCT/US2008/077420
Publication Date:
April 02, 2009
Filing Date:
September 24, 2008
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
MALLINCKRODT INC (US)
LAITENBERGER PETER G (GB)
POOLEY DAVID M (GB)
International Classes:
A61N7/00; A61M5/168
Domestic Patent References:
WO1999027981A11999-06-10
WO2002078771A12002-10-10
Foreign References:
US6231513B12001-05-15
US5271928A1993-12-21
US7047058B12006-05-16
US5733527A1998-03-31
GB2396221A2004-06-16
Attorney, Agent or Firm:
KINNEY, Anthony, R. et al. (675 McDonnell BoulevardHazelwood, Missouri, US)
Download PDF:
Claims:
What is claimed is:

1. An injection system for injecting an injection medium into a subject, the system comprising: a fluid delivery system for moving said injection medium along a flow path for injection into the subject; an ultrasound transducer for detecting ultrasound energy that has been directed into the subject after the energy has been reflected from inside the subject; and an ultrasound contrast enhancement system that introduces microbubbles into the subject during injection of the injection medium, wherein the microbubbles increase reflectivity of one or more fluids in the subject to the ultrasound energy.

2. An injection system as set forth in claim 1 , in combination with an injection medium in the reservoir, said microbubbles comprising a multiplicity of gas filled microspheres in the injection medium, the injection medium being one of an X-Ray contrast medium and an MRI contrast medium.

3. An injection system as set forth in claim 1 or 2, wherein the ultrasound contrast enhancement system comprises a flow restriction that produces microbubbles by generating a pressure drop in the injection medium as it moves along said flow path to the subject.

4. An injection system as set forth in claim 3, wherein ultrasound contrast enhancement system comprises a hypodermic needle, the needle being constructed to produce said microbubbles in the injection medium as the injection medium flows through the needle.

5. An injection system as set forth in claim 4, wherein the needle comprises a hollow shaft for delivery of the injection medium to the subject through the hollow shaft, the needle comprising one or more of the following: (a) a flow restriction in the shaft for producing said microbubbles; (b) an electrode in the shaft for facilitating a gas-generating reaction to produce said microbubbles; and (c) a gas-generating material in the shaft for producing said microbubbles.

6. An injection system as set forth in any one of claims 1 -5, wherein the ultrasound contrast enhancement system comprises a gas generating system that produces microbubbles that are entrained in the injection medium as the injection medium flows along the fluid flow path to the subject.

7. An injection system as set forth in any one of claims 1-6, wherein the ultrasound contrast enhancement system comprises a gas reservoir and a system for combining gas in the gas reservoir with the injection medium as the injection medium flows along the fluid flow path to the subject.

8. An injection system as set forth in claim 7, wherein said fluid delivery system further comprises an injection line in fluid communication with the reservoir containing the injection medium and the subject during the injection, said system for combining gas with the injection medium comprising a connector connecting a line from the gas reservoir to the injection line at a segment of the injection line that has a reduced cross sectional flow area so that gas is entrained in the injection medium by the Venturi effect.

9. An injection system as set forth in any one of claims 1-8, wherein the microbubbles have an average diameter of 10 μm or less.

10. An injection system as set forth in any one of claims 1-9, wherein the ultrasound transducer is a first ultrasound transducer, the ultrasound contrast enhancement system comprising a second ultrasound transducer for generating microbubbles in the subject.

11. An injection system as set forth in any one of claims 1-10, further comprising a disposable acoustic impedance matching device for coupling the ultrasound transducer to the subject's skin.

12. An injection system as set forth in any one of claims 1-11, further comprising a Doppler analysis system for distinguishing between frequency-shifted ultrasound energy detected by the transducer and non-frequency shifted ultrasound energy detected by the transducer.

13. An injection system as set forth in any one of claims 1-12, wherein the ultrasound contrast enhancement system is constructed to produce a concentration of microbubbles during injection of 0.1% or more.

14. An injection system as set forth in any one of claims 1-13, wherein the ultrasound contrast enhancement system is constructed to produce microbubbles at a rate of about 1.0 x 10 3 to about 1.0 X 10 9 microbubbles/mL

15. An injection system as set forth in claim 14, wherein the ultrasound contrast enhancement system is constructed to produce microbubbles at a rate of 0 1 x 10 6 to about 1.0 X 10 8 microbubbles/mL.

16. An extravasation detection system for monitoring injection of an injection medium into a subject's blood vessel to detect extravasation of the injection medium into tissue surrounding the blood vessel, the system comprising: an ultrasound transducer for detecting ultrasound energy that has been directed into the subject after the energy has been reflected from inside the subject; and an ultrasound contrast enhancement system that introduces microbubbles into the subject during injection of the injection medium, wherein the microbubbles increase reflectivity of one or more fluids in the subject to the ultrasound energy.

17 An extravasation detection system as set forth in claim 16, wherein the ultrasound contrast enhancement system comprises a hypodermic needle constructed to produce said microbubbles as the injection medium flows through the needle into the subject.

18 An extravasation detection system as set forth in claim 16 or 17, wherein the ultrasound contrast enhancement system is constructed to produce microbubbles during injection at a rate of about 1.0 x 10 3 to about 1.0 X 10 9 microbubbles/mL

19. A hypodermic needle for injecting an injection medium into a subject's blood vessel, the needle being constructed to produce microbubbles during the injection

20 A hypodermic needle as set forth in claim 19, wherein the needle comprises a hollow shaft for delivery of the injection medium through the needle, the needle further comprising one or more of the following: (a) a flow restriction in the shaft; (b) an electrode in the shaft for facilitating a gas-generating reaction to produce said microbubbles; and (c) a gas- generating material in the shaft for producing said microbubbles.

21. A hypodermic needle as set forth in claim 19 or 20, wherein the needle is constructed to produce microbubbles during injection at a rate of about 1 ,0 x 10 3 to about 1.0 X 10 9 microbubbies/mL

22. A hypodermic needle as set forth in any one of claims 19-21 , wherein the hypodermic needle is connected to a catheter.

23. A method of determining correct placement of an external conduit in a blood vessel, comprising: placing the conduit; passing liquid through the conduit; causing microbubbles to be present in the liquid downstream of the conduit mouth; transmitting ultrasound energy; and detecting reflected ultrasound energy.

24. A method as set forth in claim 23, wherein microbubbles are in a concentration of about 1.0 x 10 3 to about 1.0 X 10 9 microbubbles/mL.

25. A method as set forth in claim 23 or 24, wherein the liquid comprises an injection medium selected from an X-ray contrast medium or an MRI contrast medium.

26. A method as set forth in any one of claims 23-25, further comprising generating a pressure drop in the liquid as it flows from a reservoir containing a supply of the liquid.

27. A method as set forth in any one of claims 23-26, further comprising using an electrode to facilitate a gas-generating chemical reaction to produce said microbubbles during the injection

28. A method as set forth in any one of claims 23-26, further comprising using a gas-generating material to produce said microbubbles during the injection.

29. A method as set forth in any one of claims 23-26, further comprising causing gas to flow from a gas reservoir into the liquid during the injection.

30. A method as set forth in any one of claims 23-26, further comprising using an ultrasound transducer to form said microbubbles in one or more fluids inside the subject.

31. A method as set forth in any one of claims 23-30, wherein the detecting comprises using an ultrasound transducer to detect the reflected ultrasound energy, the method further comprising using a disposable acoustic impedance matching device to couple the ultrasound transducer to the subject's skin.

32. A method as set forth in any one of claims 23-230, wherein the detecting comprises using the Doppler Effect to distinguish frequency-shifted ultrasound energy reflections from non-frequency-shifted ultrasound energy reflections.

33. An injection line for injecting an injection medium into a subject, wherein the injection line is constructed to produce microbubbles.

34. An injection line as set forth in claim 34, wherein the injection line comprises one or more of: (a) a flow restriction; (b) an electrode for facilitating a gas-generating reaction; and (c) a gas-producing material in the injection line.

Description:

INJECTION SYSTEM HAVING MICROBUBBLE-ENHANCED EXTRAVASATION

DETECTION SYSTEM

FIELD OF INVENTION

[0001] The present invention relates generally to systems and methods for injecting a substance into a subject's blood vessel, and more particularly to systems and methods for automatically detecting extravasation of an injected substance into tissue surrounding the target blood vessel.

BACKGROUND

[0002] Substances may be injected into the blood vessels of people and animals for various reasons. For example, there are many different kinds of contrast media that are injected intravenously to enhance viewing of various internal soft tissue features in X-Rays, MRts and other imaging techniques. Other injection media, such as chemotherapies, pharmaceuticals, and some radiopharmaceuticals (i.e., pharmaceuticals that are radioactive), are injected for various diagnostic and therapeutic purposes.

[0003] Any injection of a substance to a target biood vessel poses a risk of extravasation (sometimes referred to as infiltration), wherein some or all of the injection medium is injected into the tissue surrounding the target blood vessel rather than the blood vessel itself, Extravasation may be caused by failure to properly position the tip of the injection needle inside the target blood vessel. Extravasation may also result from physiological limitations on the ability of the blood vessel to withstand the increased pressure associated with the injection. The consequences of extravasation vary depending on the nature of the injection medium. For example, extravasation may cause severe discomfort for the subject, may cause tissue damage, and may result in permanent injury in severe cases. The consequences of extravasation can also depend on the amount of the injection medium that escapes into the tissue surrounding the vessel. Accordingly, it is important to detect extravasation early, before a large volume of the injection medium invades the surrounding tissue. Early detection allows the injection to be interrupted to limit the consequences of the extravasation.

[0004] Automated injectors are now commonly used to inject the injection media into subjects, One advantage of automated injectors is that they free health care workers from the need to administer the entire injection manually. On the other hand, automated injectors make automated detection of extravasation more important. Without intervention, an automated injector can continue to inject the substance into the subject while extravasation is occurring, thereby increasing the severity of the extravasation. Further, when powerful

automated injectors are used to inject the injection medium under high pressure (as is commonly the case with bolus injections of contrast media, for example), extravasation needs to be detected quickly to limit the amount of the injection medium that is injected into the surrounding tissue. Thus, there is a need for systems that can quickly and reliably detect extravasation automatically to reduce the risk of extravasation and to reduce the need for health care workers to supervise injections and manually monitor for extravasation.

[0005] Various prior art extravasation sensors are available to detect extravasation. For example, optical, thermal, pressure, ultrasound, and electrical impedance sensors have all been used to detect extravasation. A key factor in the reliability of an extravasation detector is the sensitivity of its extravasation sensor(s) to conditions that are indicative of extravasation. Thus, many prior art ultrasound extravasation detection systems use an acoustic impedance matching gel to couple an ultrasound sensor to the subject's skin. Although the gel increases sensitivity of the ultrasound sensor by providing better acoustic coupling of the sensor to the subject, the fact that the sensor contacts the subject raises concerns about the sanitation of reuse of the sensor with another subject. Thus, the ultrasound sensor has to be discarded after use with a single subject to eliminate the possibility that reuse of the sensor will spread pathogens or other contaminants. However, replacing the discarded ultrasound sensor after each use increases costs.

[0006] Ultrasound extravasation detection systems can aiso be difficult for health care workers to use. Not only is application of the impedance matching gel cumbersome, but some expertise may be required of the health care worker to interpret the information generated by the sensor. This requires additional training and/or use of more highly skilled people to use the ultrasound detection system. Further, low signal to noise ratios can plague ultrasound based extravasation detectors because there is little contrast between the reflectivities (also known as echogenicities) associated with the injection media and other features at the injection site. Thus, the difference between the response of the ultrasound sensor to a successful injection and an extravasating injection can be slight. This makes it difficult to detect extravasation with an ultrasound sensor, particularly in the early stages of the extravasation.

[0007] Health care workers can also obtain information about the likelihood of extravasation by periodically palpating the tissue surrounding the injection site during the injection to check for swelling or increases in tissue firmness, Many prior art extravasation detectors interfere with or hinder manual palpation of the injection site because the sensor(s) of the extravasation detector limit the healthcare worker's access to the tissue surrounding the injection site, such as by being applied to the subject's skin at the injection site so as to cover the tissue surrounding the injection site.

[0008] Thus, there is a need for systems and methods yielding improved extravasation detection capabilities.

SUMMARY

[0009] One aspect of the present invention is an injection system for injecting an injection medium into a subject. The system has a fluid delivery system for moving said injection medium along a flow path for injection into the subject. The system also has an ultrasound transducer for detecting ultrasound energy that has been directed into the subject after the energy has been reflected from inside the subject. An ultrasound contrast enhancement system introduces microbubbles into the subject during injection of the injection medium. The microbubbles increase reflectivity of one or more fluids in the subject to the ultrasound energy.

[0010] Another aspect of the invention is an extravasation detection system for monitoring injection of an injection medium into a subject's blood vessel to detect extravasation of the injection medium into tissue surrounding the blood vessel. The system has an ultrasound transducer for detecting ultrasound energy that has been directed into the subject after the energy has been reflected from inside the subject. The detection system also includes an ultrasound contrast enhancement system that introduces microbubbles into the subject during injection of the injection medium. The microbubbles increase reflectivity of one or more fluids in the subject to the ultrasound energy.

[0011] Another embodiment of the invention is a hypodermic needle for injecting an injection medium into a subject's blood vessel. The needle is constructed to produce microbubbles during the injection.

[0012] Another embodiment of the invention is an injection line for injecting an injection medium Into a subject's blood vessel. The injection line is constructed to produce microbubbles during the injection.

[0013] In another embodiment of the invention is a method of monitoring injection of an injection medium into a subject's blood vessel to detect extravasation of the injection medium into tissue surrounding the blood vessel. The method includes directing ultrasound energy into the subject. Microbubbles are introduced into the subject during injection of the injection medium. The microbubbles increase reflectivity of one or more fluids in the subject to the ultrasound energy. Ultrasound energy reflected from inside the subject is detected to obtain information indicative of whether or not the injection is an extravasating injection or a non-extravasating injection.

[0014] Another embodiment of the invention includes a method of determining correct placement of an external conduit in a blood vessel. The method comprises placing the conduit, passing liquid through the conduit, causing microbubbles to be present in the liquid

downstream of the conduit mouth, transmitting ultrasound energy, and detecting reflected ultrasound energy,

BRIEF DESCRIPTION OF THE DRAWIhJGS

[0015] FIG. 1 is a schematic illustration of one embodiment of an injection system of the present invention;

[0016] FIG. 2 is a schematic illustration of part of one embodiment of a needle of the present invention that is constructed to produce microbubbles;

[0017] FIG. 3A is a schematic illustration of part of a subject's body during a non- extravasating injection;

[0018] FIG. 3B illustrates a signal from an ultrasound transducer of the injection system indicative of ultrasound echoes from inside the subject during the non-extravasating injection;

[0019] FIG. 4A is a schematic illustration similar to Fig. 3A showing a pool of extravasated fluid in the subject;

[0020] FIGS. 4B and 4C are similar to Fig. 3B and illustrate signals corresponding to additional echo returns from the pool of extravasated microbubble-containing fluid (Fig. 4B shows the entire signal and Fig. 4C shows echoes from the pool in isolation);

[0021] FIG. 5 is a schematic illustration of part of one embodiment of a needle comprising an electrode for producing microbubbles;

[0022] FlG. 6 is a schematic illustration of part of one embodiment of a needle comprising a gas-generating material for producing microbubbles;

[0023] FIG. 7 is a schematic illustration of part of one embodiment of a flexible catheter that is constructed to produce microbubbles;

[0024] FIGS. 8 and 8A are schematic illustrations of one embodiment of an injection system that entrains gas from a gas reservoir into an injection line used to deliver the injection medium to a subject to enhance ultrasound contrast;

[0025] FiG. 9 is a schematic illustration of one embodiment of an injection system comprising an ultrasound transducer for forming microbubbles to enhance ultrasound contrast at an injection site; and

[0026] FlG. 10 is a schematic illustration of one embodiment of an injection system containing a supply of an injection medium including a multiplicity of gas-filled microspheres.

[0027] Corresponding reference characters indicate corresponding parts throughout the drawings.

DETAILED DESCRIPTION

[0028] Referring to the drawings, first to Fig. 1 , an automated injection system of the present invention, generally designated 101, is shown schematically in the process of injecting an injection medium (not shown in Fig. 1) into a subject's blood vessel 103. The subject 102 can be any organism having a vascular system, including a human or other animal.

[0029] As depicted in Fig. 1, the injection system 101 includes a fluid delivery system, generally designated 105, for moving the injection medium along a fluid flow path 107 for injection into the subject. In this particular embodiment, the system 105 comprises an automated power injector 109, which is generally conventional except as noted. The injector 109 is a syringe pump and includes a reservoir 111 defined by a barrel 113 of the syringe for containing a supply of the injection medium and a motor 117 that drives a piston 119 in the barrel to expel the injection medium from the reservoir 111 into the subject through an injection line 121 that is in fluid communication with the reservoir and the subject 102 during the injection. Although the fluid delivery system 105 shown in Fig. 1 includes a syringe pump, other types of injection mechanisms, including manual injection systems can be used instead within the scope of the invention. Likewise, the flow path may have different configurations and lengths and be defined in different ways than shown in Fig. 1 within the scope of the invention.

[0030] The injection medium can be any flowable substance that is to be injected into the subject's blood vessel 103. The injection medium may be a substantially homogenous fluid (e.g., a liquid solution) or it may be a heterogeneous flowable substance (e.g., a colloid or emulsion). The injection medium may be a contrast medium that is used to enhance contrast of features in an X-Ray, MRI, nuclear imaging, and optical imaging, or other non-ultrasound imaging procedure. In one embodiment, the injection medium comprises a radio-opaque substance (e.g., iodine, barium, gadolinium) for X-ray contrast. In another embodiment, the injection medium comprises a paramagnetic substance {e.g., gadolinium) for MR! contrast, in still another embodiment, the injection medium comprises a radioisotope {e.g., Technetium- 99) for conducting any of various diagnostic and/or therapeutic procedures in the field of nuclear medicine. In another embodiment, the injection medium comprises a pharmaceutical (e.g., a chemotherapeutic substance).

[0031] The injection system 101 includes an ultrasound extravasation detection system, generaily designated 131. The extravasation detection system 131 comprises at least one ultrasound transducer 133 operable to detect ultrasound energy after it has been directed into the subject 102 and reflected (i.e., echoed) from inside the subject. In the embodiment shown in Fig. 1 , the extravasation detection system 131 comprises a single transducer 133 that directs the ultrasound into the subject 102 and then detects ultrasound echoes returned from inside the subject. It is also possible to use one transducer to generate the ultrasound energy and a different transducer to detect the echoes without departing from

the scope of the invention. The ultrasound transducer 133 may be applied to the subject's skin downstream (relative to the direction of blood flow in the target blood vessel) from the injection site 175, as shown in Fig. 1 , to facilitate manual palpation of the injection site by a health care worker to monitor for swelling, tissue firmness, or other signs of extravasation. It is also contemplated that the extravasation detection system may comprise multiple ultrasound transducers. For example, the transducer may be one of a phased array of transducers included in a single ultrasound sensor. In another embodiment, the transducer may be one of an array of ultrasound transducers distributed over the outer surface of the subject's skin (e.g., downstream from the injection site 175) to facilitate localization of features inside the subject 102 by the detection system.

[0032] The extravasation detection system 131 also includes an ultrasound contrast enhancement system 141. The ultrasound contrast enhancement system 141 introduces a multiplicity of microbubbles (not shown) into the subject 102 during the injection. In general, microbubbles are small gas-filled volumes distributed in the fluid. Any short-lived bubbles generated will improve the signal strength. The average diameter of the microbubbles are typically less than about 10 μm so that they will pass through small vessels such as the capillary bed of the lung and reach the heart. In one embodiment, the microbubbles are between about 1 μm and about 10 μm. In one example, the microbubbles are between about 2 μm and about 5 μm. The microbubbles are effective to increase reflectivity (sometimes referred to as echogenicity) of one or more fluids in the subject 102 to the ultrasound energy. Although, conventional injection systems may produce a few microbubbles at the injection site {e.g., due to minor flow perturbations associated with use of the injection system) any microbubbles produced thereby are insufficient to significantly increase in the reflectivity of any fluids at the injection site, as evidenced by the ultrasound echo returns that have been obtained from injection sites when using conventional injection systems. In contrast, the injection system 101 shown in Fig. 1 introduces enough microbubbies into the subject 102, so that the microbubbles collectively raise reflectivity of one or more fluids in the subject from a level that is about the same as the soft tissue surrounding the target blood vessel 103 and other fluids (e.g., blood and naturally occurring interstitial fluids) at the injection site to a level that is substantially higher, thereby providing significant ultrasound contrast between the microbubble-containing fluids and other soft tissue features at the injection site. Signal strength (output voltage) will increase with the presence of microbubbles, In one embodiment of the invention, for example, the ultrasound contrast enhancement system 141 is operable to produce a concentration of microbubbles of at least about 0.1% (e.g., 1.0 x 10 3 microbubbles/mL). In another embodiment of the invention, the ultrasound contrast enhancement system 141 has a capacity to produce microbubbles at a rate of between about 1.0 x 10 3 microbubbles/mL to about 1.0 X 10 9 microbubbles/mL. In one

example, the ultrasound contrast enhancement system 141 produces microbubbles at a rate of between about 0.1 x 10 θ to about 1.0 X 10 9 microbubbles/mL. in another example, the ultrasound contrast enhancement system 141 produces microbubbles at a rate of between about 0.1 x 10 6 to about 1.0 X 10 8 microbubbles/mL The microbubble size may vary dependant on the manner in which they are generated. In one embodiment, the microbubbles have an average diameter of 5 μm to 15 μm. In another embodiment, the microbubbles have an average diameter of 5 μm to 10 μm. In another embodiment, the the microbubbles have an average diameter of 10 μm or less.

[0033] There are various ways that microbubbles can be introduced into the subject 102 within the scope of the present invention. For example, the injection system 101 shown in Fig. 1 comprises a needle 143 for piercing the subject's skin to establish fluid communication between the injection medium reservoir 111 and the inside of the subject 102. The needle 143 is constructed to produce microbubbles during the injection. As shown in Fig. 2, for instance, the needle 143 comprises a hollow tubular shaft 145 defining a passage for delivery of the injection medium to the subject 102 through the shaft. Further, the needle 143 comprises a flow restriction 147 in the shaft. The purpose of the flow restriction 147 is to create a pressure drop in the injection medium as it flows through the shaft 145 of the needle 143. The pressure drop causes gas dissolved in the injection medium to come out of solution and/or produces cavitation in the injection medium, thereby forming the microbubbles.

[0034] Generally, the flow restriction 147 comprises an obstruction to flow through the shaft 145 of the needle 143. As shown in Fig. 2, for example, the obstruction can comprise an annular member 149 extending radially inward from the inner surface 151 of the shaft 145 toward the center of the shaft to define an orifice having a reduced cross sectional flow area. Flow restrictions may be designed using resonator methods similar to a reed or a configuration that produces eddy currents and pressure differentials like a whistle. In one embodiment of the invention, for example, the shaft 145 defines a cross sectional flow area A1 (e.g., a substantially uniform cross sectional flow area along the length of the shaft and the flow restriction 147 defines a reduced cross sectional flow area A2. The flow restriction can have other constructions without departing from the scope of the invention. The flow restriction 147 shown in Fig. 2 is located adjacent the tip 155 of the needle 143. However, the flow restriction can be located elsewhere in the injection system 101 (e.g., upstream in the needle 143 or in the injection line 121 ) without departing from the scope of the invention.

[0035] The extravasation detection system 131 also includes a processor 161 that receives signals from the ultrasound transducer 133 that are indicative of the reflected ultrasound energy. In the embodiment shown in the drawings, the processor 161 receives the signals over a transmission line 163 connecting the processor to the transducer 133. However, the ultrasound transducer 133 may be in wireless communication with the processor

161 without departing from the scope of the invention. The processor 161 preferably includes an analysis system for analysis of the signals from the transducer 133 by the processor to yield information about one or more features inside the subject. Some examples of the types of analysis that may be performed by the processor are set forth below and in the description of operation of the injection system 101. Alternatively, the processor 161 may simply output the unanalyzed signals received from the transducer 133 in a form that can be interpreted by a health care worker, such as a visual display (not shown), within the scope of the invention.

[0036] In one embodiment, the processor's 161 analysis system identifies ultrasound echoes returned by microbubble-containing fluids inside the subject 102. The processor's 161 analysis system may also have the ability to automatically characterize injections as being extravasatiπg or non-extravasating, based at least in part on the signals received from the transducer 133. If the processor 161 is operable to characterize the injection automatically, it may also activate an extravasation alarm (e.g., display a visual warning and/or sound an auditory warning) indicating that It has characterized an injection as an extravasating injection. In Fig. 1 , for example, the extravasation alarm comprises an LED warning light 165 under the control of the processor 161. The processor 161 may automatically interrupt the injection upon characterizing the injection as being an extravasating injection. For example, in the embodiment shown in Fig. 1 , the injector 105 is at least partially under the control of the processor 161 so that the processor can automatically shut the injector off (e.g., by interrupting power supplied to the motor 117 via a power line 167) to limit extravasation of additional fluids.

[0037] The processor 161 optionally includes a Doppler analysis system. Although not required to practice the invention, Doppler ultrasound systems are desirable because they can distinguish frequency-shifted ultrasound echoes (which are from moving objects) from non-shifted echoes (which are generated by stationary objects). Thus, the optional Doppler ultrasound analysis system can facilitate determination of whether microbubble-containing fluids in the subject 102 (e.g., the injection medium) are moving or stationary. If Doppler analysis indicates that the microbubble-containing fluids are moving, this indicates that such fluids are in the target blood vessel 103. Conversely, if they are not moving, or not moving enough to produce an echo having a sufficient frequency shift, this indicates that such fluids are in the tissue surrounding the target blood vessel 103.

[0038] In one embodiment, the ultrasound transducer 133 is coupled to the subject 102 by placing a disposable acoustic impedance matching device 171 on the outer surface of the subject's skin and contacting the impedance matching device with the ultrasound transducer 133, For example, the impedance matching device 171 may be a disposable pad that facilitates transfer of the ultrasound energy between the subject and the transducer. Suitable disposable impedance matching devices are already known to those skilled in the art

and do not need to be described further. The disposable impedance matching device 171 provides a physical barrier between the subject 102 and the ultrasound transducer 133, thereby alleviating sanitation concerns associated with reuse of the ultrasound transducer with another subject. The reduced coupling efficiency that may be associated with the impedance matching device 171 (relative to the efficiency that can be attained with a gel) is offset by the additional ultrasound contrast provided by the microbubbles (in combination with the Doppler analysis if that option is used) so that the extravasation detection system 131 is sufficiently sensitive to extravasation notwithstanding the physical barrier between the transducer 133 and the subject 102.

[0039] Except as noted, the injection system 101 operates in substantially the same way as a conventional injection system. To operate the injection system shown in Fig. 1 , for instance, a health care worker places the disposable impedance matching device on the outer surface of the subject's skin a short distance (e.g., a few centimeters or a few inches) downstream of the injection site. The ultrasound transducer 133 is placed in contact with the disposable impedance matching device 171 so that the impedance matching device is a barrier to contact between the transducer and the subject 102. The health care worker also pierces the subject's skin with the needle 143 and inserts the tip 155 of the needle into the subject 102 with the aim of positioning the needie tip in the target blood vessel 103.

[0040] Injection of fluids into the subject 102 begins after the needle 143 is inserted into the subject. An optional test injection may be conducted before injecting the injection medium into the subject 102. During the test injection, a relatively harmless test substance (e.g., physiological saline solution) is injected through at least the needle 143 for the purpose of confirming that the needle tip 155 is in the target blood vessel 103. When the health care worker is ready to start injecting the injection medium, the automated injector injects the injection medium into the subject 102 through the injection line 121 , which includes the needle 143.

[0041] The ultrasound contrast enhancement system 141 introduces the microbubbles into the subject during injection of the injection medium into the subject, as described above. The system 141 may also introduce microbubbles into the subject during the optional injection of the test solution into the subject. In the embodiment of Fig. 2, for example, the flow restriction 147 in the needle 143 generates a pressure drop when the injection medium and test solution flow through the shaft 145 of the needle. The pressure drop may be as little as from 100-ρsi (7 bars) to 90-psi (6 bars). The pressure drop produces microbubbles by causing dissolved gas in the injection medium (or test solution) to come out of solution and/or by producing cavitation. The microbubbles are then introduced into the subject 102 by the needle 143 along with the injection medium or test solution.

[0042] The microbubbles increase reflectivity of the fluids that contain them to ultrasound, facilitating use of the extravasation detection system 141 to detect extravasation. In one embodiment, for example, a pulse of ultrasound energy is directed into the subject 102 and a time-varying signal from the ultrasound transducer 133 indicates the strength of ultrasound echoes returned from inside the subject as a function of elapsed time. The processor 161 monitors a series of such time-varying signals from the transducer 133 during the injection to detect any extravasation. The ultrasound energy may be emitted as a beam that is swept through the subject (e.g., by use of a phased array of transducers) to scan the interior of the subject. However, scanning is not required.

[0043] Figure 3A shows a subject's limb 181 , including soft tissue 183, a bone 185, and the target blood vessel 103 in cross section during a non-extravasating injection. Figure 3B is a schematic illustration of the time-varying signal from the transducer after a pulse of ultrasound energy is directed into the subject 102 during the non-extravasating injection. The signal has one subset of signals 191 corresponding to ultrasound echoes returned by the microbubbles present in the target blood vessel 103 and another subset of signals 193 corresponding to echoes returned by the bone 185. Figures 4A-4C illustrate how the time varying signal (Fig. 4B) from the transducer 133 is changed by a pool 187 of extravasated microbubble-containing fluid (shown Fig. 4A) in the soft tissue 183 surrounding the target blood vessel 103 at the injection site 175. In addition to the signal subsets 191, 193 representing echoes from the target blood vessel 103 and the bone 185, the signal shown in Fig. 4B includes an additional signal subset 195 corresponding ultrasound echoes returned by the pool 187 of extravasated microbubble-containing fluid. (The microbubbles are not shown in the pool 187 because of their extremely smail size.) The prominence of the additional signal subset 195 is enhanced significantly because of the presence of the microbubbles in the pool 187 of extravasated fluid.

[0044] The processor 161 may analyze the signals from the transducer 133 by comparing them to a baseline signal to determine whether or not any of the microbubble- containing fluid (e.g., the injection medium) is in the tissue 183 surrounding the target blood vessel 103. The baseline signal may be a signal received from the transducer before the start of the injection, a signal received from the transducer during a test injection, a signal received from the transducer 133 at the start of an injection before any fluids have been extravasated (e.g., as shown in Fig. 3B), or a reference signal. For example, by subtracting the first signal (Fig. 3B) from the second signal (Fig. 4B), the processor 161 may generate a difference signal (Fig. 4C) representing substantially only the subset of signals 195 associated with the pool 187 of extravasated fluid. In this way, the processor 161 can monitor for extravasation by periodically subtracting a baseline signal (e.g., a signal corresponding to the start of the injection or another reference signal) from the signals it receives from the transducer 133

during the injection. The processor 161 can characterize the injection as an extravasatlng injection if it determines that more than a threshold amount microbubble-containing fluid is in the tissue 183 surrounding the target blood vessel 103.

[0045] If the processor 161 includes the optional Doppler analysis system, the processor may use the Doppler Effect to detect the relatively strong frequency-shifted echo returns from the microbubble-containing fluids that are successfully injected into the target blood vessel 103. Doppler analysis can filter out any non-shifted echo returns to isolate echo returns from the microbubble-containing fluids moving within the target blood vessel 103. Successful injection of microbubble-containing fluid into the target blood vessel will cause the level of these frequency-shifted echo returns to increase after the start of the injection. On the other hand, the frequency-shifted signals will not include echo returns from any extravasated microbubble-containing fluids (e.g., in the pool 187 shown in Fig. 4A), which are not moving enough to produce the same frequency shift produced by flow in the target blood vessel. Thus, the processor 161 can monitor for extravasation by periodically checking signals received from the transducer 133 to confirm that the level of frequency-shifted echo returns generally corresponds to the rate at which microbubble-containing fluid is being injected in the subject 102. The processor 161 may characterize the injection as an extravasating injection if the frequency-shifted echo returns remain below an expected level associated with the injection rate for too much time.

[0046] The processor 161 can perform Doppler analysis of the signals with or without the non-Doppler ultrasound analysis. For example, the processor 161 may compare the level of frequency-shifted echo returns determined by Doppler analysis to the level of total echo returns or the level of non-shifted echo returns to determine the amount of higher-contrast microbubble-containing fluid in the target blood vessel 103 relative to the amount that is stationary and presumably in the surrounding tissue 183.

[0047] The processing methods described above are only a few examples of the many processing methods that may be used to characterize the injection as extravasating or non- extra vasating. Thus, those skilled in the art will recognize that other processing methods are within the scope of the invention. Moreover, the methods of this invention do not require that any analysis be conducted by the processor; a medical practitioner may interpret information provided by the processor 161 (e.g., in a visual display) to monitor for extravasation.

[0048] If and when the processor 161 characterizes an injection as an extravasating injection it may automatically activate the extravasation warning system 165 and automatically interrupt the injection. In the embodiment shown in Fig. 1, for instance, the processor turns on the warning light 165 to alert health care workers to the possible extravasation and also interrupts power supplied to the motor 117 of the injector 105 to stop the injection. In other

Page U of 20

embodiments, the processor 161 activates the warning system 165 without interrupting the injection, or vice-versa.

[0049] Because the ultrasound transducer 133 is remote from the injection site 175 in the embodiment shown in Fig. 1, the health care worker may manually palpate the injection site 175 at any time during the injection process, including during the optional test injection and during the injection of the injection medium. Thus, one embodiment of the method includes manually palpating the injection site 175 during injection of the test medium and/or injection medium to confirm that the needle 143 is properly positioned in the target blood vessel 103 and/or that there is no swelling or other tactile indication of extravasation.

[0050] When the injection is complete, the needle 143 is withdrawn from the subject 102 and the disposable impedance matching device 171 is discarded. The steps of the method may be repeated with another subject using a new disposable matching device 171 , but reusing the same ultrasound transducer 133.

[0051] Figures 5 and 6 show other embodiments of needles that are constructed to produce microbubbies. The needle 201 shown in Fig. 5 has an electrode 203 in the shaft 245 to produce the microbubbies. The electrode 203 may provide localized heating of the injection medium that produces microbubbies during the injection. Alternatively or additionally, the electrode 203 may produce microbubbies by facilitating a gas-producing chemical reaction during the injection. In Fig. 5, the electrode 203 is positioned adjacent the tip 255 of the needle 201 , but it could be located elsewhere within the scope of the invention.

[0052] Figure 6 shows a needle 301 that includes a gas-generating system 303 to produce gas in the needle during the injection to form the microbubbies. For example, the gas generating system 303 may comprise a gas-producing material 305 in the needle 301. In the particular embodiment shown in Fig. 6, a layer of gas-producing material 305 is provided on the inner surface 351 of the shaft 345. Various materials are suitable for use as the gas- producing material 305 in the needle 301.

[0053] Figure 7 shows a flexible catheter 401 for injecting an injection medium into the subject 102 without using a needle to introduce the injection medium into the target blood vessel 103, As is generally known, flexible catheters may be threaded through the subject's vascular system to inject the injection medium into the subject 102 at a location that is remote from the point where the catheter penetrates the subject's skin. The catheter 401 is constructed to produce microbubbies in much the same manner as the needles 143, 201 , 301 discussed above. The embodiment shown in Fig. 7, for example, includes a flow restriction 403, an electrode 405, and a gas-producing material 407 in the catheter 401. Production of microbubbies by each of the flow restriction 403, electrode 405, and gas-producing material 407 in the catheter is substantially the same as it is for the needles 143, 201, 301. Although the catheter 401 shown in Fig. 7 has multiple microbubble-producing constructions or devices

403, 405, 407, it is understood that any combination of one or more of these constructions can be used in a catheter within the scope of the invention.

[0054] Any one of the needles 201, 301 or catheter 401 described above and shown in Figs. 5-7 can be used with the injection system 101 in place of the needle 143 shown in Fig. 2 to produce the microbubbles that are introduced into the subject 102 by the ultrasound contrast enhancement system. Operation of the injection system is substantially the same as described above in each case, except for the mechanism(s) of microbubble formation. Also, in the case of the catheter 401, the catheter may be thread some distance through the target blood vessel so that the injection site is remote from the point of entry of the catheter into the subject. In this case the health car© worker has to determine where the terminal end of the catheter is located to position the transducer properly relative to the injection site.

[0055] Figure 8 shows another embodiment of an injection system 501 of the present invention, which is substantially the same as the injection system 101 discussed above, except as noted. The ultrasound contrast enhancement system 541 does not use a needle that is constructed to produce microbubbles. instead, a conventional needle 543 is used and the ultrasound contrast enhancement system 541 comprises a gas reservoir 545 in fluid communication with the injection line 121. The gas reservoir 545 is used to contain a supply of gas to be combined with the injection medium in the injection line 121 during the injection to form the microbubbles. Suitable gases that may be used for this purpose include carbon dioxide, nitrogen, and the like. The gas reservoir 545 may be pressurized to induce flow of the gas into the injection line 121 during the injection. However, in the embodiment shown in Fig. 8, the gas reservoir 545 is substantially unpressurized. The injection line 121 comprises a section 549 having a reduced cross sectional flow area that entrains gas from the gas reservoir 545 into the injection medium using the Venturi effect. As best shown in Fig. 8A, for instance, a line 551 from the gas reservoir 545 may be connected to the injection line 121 by a Venturi effect T connector 553. The pressure drop in the injection line 121 at the reduced cross sectional flow area 549 draws gas from the gas reservoir 545 into the injection line where it forms microbubbles that are entrained in the flow of the injection medium through the injection line 121. The injection system 501 operates in substantially the same manner as the injection system 101 described above, except that the microbubbles are formed by entraining gas in the injection line 121 farther upstream of the injection site 175 than the needle 543.

[0056] Figure 9 shows still another embodiment of an injection system 601 of the present invention, which is substantially the same as the injection system 101 shown in Fig. 1 , except as noted. The injection system 601 also uses a conventional needle 543 and uses another ultrasound transducer 603 to generate the microbubbles. In the illustrated embodiment, the microbubble producing ultrasound transducer 603 is incorporated in a patch 605 applied to the subject's skin at the injection site 175 and controlled by the processor 161

via line 629 for communication between the transducer 603 and the processor. The ultrasound transducer 603 may be positioned elsewhere within the scope of the invention, including upstream of injection site 175 in the injection system 601 or elsewhere along the target blood vessel 103 without departing from the scope of the invention. Use of the injection system 601 is substantially as described above except that the microbubbles are produced using the ultrasound transducer 605 to direct high-energy ultrasound energy into the subject 102 or into fluids in the fluid delivery system. The ultrasound energy produces microbubbles by causing dissolved gases to come out of solution and/or by producing cavitation in the localized pressure drops associated with the troughs of the acoustic waves.

[0057] Another embodiment of an injection system 701 of the present invention is shown in Fig. 10. The injection system 701 is substantially the same as the injection system 101 shown in Fig. 1 , except as noted, in contrast to the other injection systems 101 , 501, 601 described herein, the injection system 701 does not form a significant quantity of microbubbles during the injection. Instead, the injection system 701 introduces microbubbies into the subject by including them in the supply of injection medium 703 (shown in the reservoir 111 in Fig. 10). In particular, the injection medium 703 comprises a multiplicity of gas-filled microspheres (not shown) distributed through the injection medium. Those skilled in the art will know how to manufacture suitable gas-filied microspheres that are sufficiently stable for transport to the medical facility in the injection medium and that are safe for administration to a subject. Suitable microspheres are already commercially used to make ultrasound contrast media. The needle can be a conventional needle 543, as shown in Fig. 10. Except for the inclusion of the gas-filied microspheres, the injection medium is substantially the same as described above. In particular, the injection medium may comprise any of the non-ultrasound contrast agents, radioisotopes, or pharmaceuticals listed above, in addition to the gas-filled microspheres. Operation of the injection system is substantially as described above in connection with the injection system shown in Fig. 1, except that the microbubbles are introduced into the subject by virtue of their already being in the injection medium when the injection begins.

[0058] When introducing elements of the present invention or the preferred embodiments thereof, the articles "a", "an", "the", and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "including" and "having" are intended to be inclusive and mean that there may be additional elements other than the listed elements.

[0059] As various changes could be made in the above constructions and methods without departing from the scope of the invention, it is intended that all matter contained in the above description and shown in the accompanying drawings be interpreted as illustrative and not in a limiting sense.