WO1998003205A2

WO1998003205A2 - Enhanced ultrasound contrast imaging using inhaled gases

Info

Publication number: WO1998003205A2
Application number: PCT/US1997/012354
Authority: WO
Inventors: Steven C. Quay
Original assignee: Sonus Pharmaceuticals, Inc.
Priority date: 1996-07-19
Filing date: 1997-07-16
Publication date: 1998-01-29
Also published as: AU3665297A; WO1998003205A3

Abstract

Ultrasound imaging of the left cardiac chambers of the heart and other tissues is enhanced by inhalation of a gas or gas mixture during intravenous injection of an ultrasound contrast agent. Increased concentration of the inhaled gas in the lungs suppresses outgassing of the contrast agent in the lungs, maintaining high concentrations of the contrast agent in blood flowing to the left heart and other tissues.

Description

ENHANCED ULTRASOUND CONTRAST IMAGING USING INHALED GASES

RELATED APPLICATION

This application is a non-provisional application based on provisional application 60/022,528 filed July 1 9, 1 996.

Field of The Invention

This invention relates generally to enhancement of ultrasound contrast imaging by causing inhalation of gases. More specifically, the invention relates to ultrasound imaging of the left cardiac chambers of the heart or organs of the body receiving blood from the lungs, by intravenous administration of an ultrasound contrast agent in conjunction with inhalation of a gas or gas mixture.

Background of The Invention

Ultrasound imaging is a non-invasive method of imaging the organs and structures of human and animal subjects. The ultrasound image can be enhanced using ultrasound contrast agents. Various contrast agents for use in diagnostic ultrasound, including echocardiography, have been described. A review of the subject is found in Ophir and Parker, Ultrasound in Med. & Biol. (1 989), 1 5:31 9-333, although research has intensified since the publication of this article.

Prior efforts have investigated a variety of ways of introducing ultrasound contrast agents into the bloodstream. WO 95/33447 (Riess et al.) teaches the use of fluorocarbon containing emulsions. WO 95/07072 (Weitschies et al.) and WO 95/22994 (Heldmann et al.) describe using microparticles and microparticulate systems.

Other researchers have experimented with a variety of materials to form such microparticles. U.S. Patent No. 4,844,882 (Widder et al.) teaches the use of microspheres composed of proteins. U.S. Patent No. 4,957,656 (Cerny et al.) teaches the use of microspheres composed of human serum albumen. WO 95/32006 (Unger) focuses upon microparticles with liposome shells. In recent years, agents which include gaseous microbubbles or microbubble precursors (as opposed to completely solid or liquid agents) have become the subject of great interest, since these agents take advantage of the relatively high echogenicity of gases versus liquids or solids.

To enhance the performance of microbubbles as ultrasound contrast agents, numerous approaches have been disclosed. These approaches are generally directed to methods by which either the persistence of the bubbles is increased or the bubble size population is optimized. One approach that has proved very successful, has been to identify compounds which, as gases, are relatively more persistent in blood than air.

For example U.S. Pat. No. 5,393,524 (Quay) teaches a method for selecting and using gases as ultrasound agents whose solubility in air is higher than their solubility in blood. U.S. Pat No. 5,409,688 (Quay) discloses several such gaseous ultrasound contrast agents. U.S. Pat. No. 5,558,854 (Quay) specifically describes perfluoropentane and perfluorohexane as effective ultrasound contrast agents. Another approach has been to use compounds that are normally liquids at manufacturing temperatures, but which become gases inside the body. These compounds are then administered in the form of liquid-in-liquid dispersions. For example, U.S. Pat. Nos. 5,858,855 and 5,558,853 (both to Quay) teach the use of colloidal dispersions of ultrasonic contrast agents, wherein the dispersed liquid contrast agent has a boiling point at or below the body temperature of the organism to be studied. U.S. Pat. No. 5,595,723 (Quay) teaches methods of preparing such stable colloidal dispersions of ultrasound contrast agents.

The persistence of microbubbles produced using the above approaches permits intravenous administration of ultrasound contrast agents. Injected microbubbles travel through the bloodstream to the right heart, which may then be imaged. After being pumped through the right heart, the microbubbles travel to the lungs and then into the left cardiac chambers of the heart.

Unfortunately from the point of view of ultrasound imaging, the lungs are very efficient at outgassing blood. One result of this efficiency is that the size and number of microbubbles reaching the left heart or body is greatly diminished. As a result of this decrease in the number and size of the microbubbles reaching the left chambers of the heart, the intensity of the ultrasound signal is low.

Attempts to facilitate ultrasound imaging of the left heart have met with limited success. Experiments have shown that no enhancement of the ultrasound signal of the left heart occurs with inhalation in the absence of an ultrasound contrast agent. That is, gas inhalation alone has no effect as an ultrasound contrast agent. U.S. Patent 5,406,950 (Brandenburger et al.) does discuss ultrasound imaging of the left heart using gaseous contrast agents inhaled by the patient. In this patent however, the contrast agent is administered to the patient exclusively by inhalation. In light of this background, it would be desirable to identify a method for ultrasound imaging of the left heart and organs of the body using an ultrasound contrast agent which can travel through the lungs (i.e. the blood containing the contrast agent can travel through the lungs) without substantially diminishing the efficacy of the contrast agent.

Summary of The Invention

The present invention is directed to a method of performing diagnostic imaging wherein the efficacy of contrast agent in imaging the left heart is greatly increased. In the invention, a subject inhales a selected gas or gas mixture while microbubbles or microbubble precursors of a contrast agent are administered intravascularly. A component of the inhaled gas mixture can be a persistent gas, and can be preferably be the same gas contained in the ultrasound contrast microbubbles being administered into the blood stream.

The present invention can also be used to enhance a left heart and body organ ultrasound signal obtained using ultrasound contrast agents other than the gas microbubbles disclosed above. Other such ultrasound contrast agents include gas-containing micro- particles, including microparticles formed from human serum albumin, liposomes, or cross-linked polymers. In all cases, the agent will include a component which carries microbubbles or forms microbubbles in the blood stream. Detailed Description of The Invention

The invention provides an improvement in ultrasound imaging methods in which microbubbles are peripherally injected into a patient. Many types of such agents have been proposed and the improvement will be valuable with any agent which is subject to significant outgassing as it passes through the lungs. Specifically, the invention is a method of increasing the concentration of a gas in the lungs which will reduce the amount of outgassing by the blood carried agent. To ensure a complete understanding of the invention the following definitions are provided:

Surfactants: The group of amphiphilic materials which are manufactured by chemical processes or purified from natural sources or processes. These can be anionic, cationic, nonionic, and zwitterionic. Such materials are described in Emulsions: Theory and Practice, Paul Becher, Robert E. Krieger Publishing, Malabar, Florida, 1 965 which is hereby incorporated by reference.

Anionic Surfactants: A surfactant with a net negative charge.

Polvoxypropylene-Polvoxyethylene Glvcol Nonionic Block Copolvmers: The surfactants which are available from BASF

Performance Chemicals, Parsippanγ, New Jersey under the trade name Pluronic and which consists of the group of surfactants designated by the CTFA name of poloxamer 108, 1 88, 21 7, 237, 238, 288, 338, 407, 101 , 105, 122, 123, 124, 1 81 , 182, 183, 1 84, 21 2, 231 , 282, 331 , 401 , 402, 1 85, 21 5, 234, 235, 284, 333, 334, 335, and 403.

Fluorine-Containing Surfactant: A surfactant containing one or more fluorine atoms. Some, but not necessarily all, fluorine containing surfactants useful in this invention can be selected from the group consisting of: telomer B containing fluorinated surfactants available from Du Pont, Wilmington, DE under the Trade name of Zonyl (including Zonyl FSA, FSP, FSE, UR, FSJ, FSN, FSO, FSC, FSK, PEG, and TBS). The chemical formula of one particularly useful surfactant, PEG Telomer B, is given below:

F(CF₂CF₂)_x(CH₂CH₂O)_vH where x = 2, 3, 4, 5, 6, 7 and y = 1 -14. Other fluorine-containing surfactants useful under the present invention include fluorochemical surfactants from 3M Industrial Chemical Products Division, St. Paul, MN under the trade name of Fluorad (including FC-95, FC-98, FC- 99, FC-143, FC-1 70C, FC-171 , FC-430, FC-99, FC-100, FC-120, FC-129, FC-135, FC-431 , FC-740), the perfluoroalkylpoly(oxyethylene) surfactants described by Mathis et al. (J Am Chem Soc 106. 6162-61 71 (1 984), incorporated herein by reference), the fluoroalkylthio-etherpoly(oxyethylene) surfactants described by Serratrice et al. (J Chim Phvs 87, 1 969-1980 (1990), incorporated herein by reference), the perfluoroalkylated polyhydroxylated surfactants of Zarif et al. (J Am Oil Chem Soc 66, 1 51 5-1523 (1989), incorporated herein by reference), and the fluorosurfactants available from Atochem North America, Philadelphia, PA under the trade name of Forafac.

Other surfactants useful in the invention are disclosed in U.S. patent 5,595,723 and related patent U.S. 5,558,853 which are co- assigned to Sonus Pharmaceuticals Inc. and which are hereby incorporated by reference.

Biocompatible: Capable of performing functions within or upon a living organism in an acceptable manner, without undue toxicity or physiological or pharmacological effects. High Vapor Pressure Chemical: A chemical with a sufficiently high vapor pressure that colloidal dispersions of the chemical as a liquid contain, at the body temperature of an organism undergoing an ultrasound examination, a sufficient quantity of the chemical as a gaseous dispersion to provide a diagnostically useful alteration in the ultrasound data obtained during an examination.

Various biocompatible chemicals that form microbubbles are useful in the invention. Preferred compounds have a boiling point less than 40°C. Most preferred chemicals are fluorine-containing. Chemicals useful as ultrasound contrast agents which are objects of the present invention are disclosed in United States Patents 5,393,524; 5,409,688; 5,558,094 and 5,558,854 which are co- assigned to Sonus Pharmaceuticals Inc., and are hereby incorporated by reference. Examples of fluorine containing chemicals useful in the invention include dodecafluoroneopentane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, perfluorocyclopentane, perfluoroheptane, perfluorooctane, sulfur hexafluoride and mixtures thereof.

Fluorine-Containing Compounds: A compound containing at least one fluorine atom.

Emulsion: A colloidal dispersion of one immiscible liquid dispersed in another liquid in the form of droplets, whose diameter, in general, are between 100 and 3000 nm and which is typically optically opaque, unless the dispersed and continuous phases are refractive index matched. Such systems possess a limited stability, generally defined by the application or relevant reference system, which may be enhanced by the addition of amphiphilic materials or viscosity enhancers. Microemulsion: A stable liquid monophasic and optically isotropic colloidal dispersion of water and water-immiscible liquids stabilized by amphiphilic materials in which the dispersions have appreciable light scattering properties (meaning they can appear optically clear or milky but are reddish or yellowish if observed by transmitted light) and the diameters of the particles are, in general, between 5 and approximately 140 nm.

Aqueous Medium: A water-containing liquid which can contain pharmaceutically acceptable additives such as acidifying agents, alkalizing agents, antimicrobial preservatives, antioxidants, buffering agents, chelating agents, complexing agents, solubilizing agents, humectants, solvents, suspending and/or viscosity-increasing agents, tonicity agents, wetting agents or other biocompatible materials. The current invention can be used to improve the efficacy of ultrasound imaging in the body and particularly imaging the left heart. In the invention, the subject inhales a selected gas or gas mixture while an aqueous medium containing a contrast agent is injected into the bloodstream. The underlying principal of the method of the current invention is that repeated inhalation of the desired gas or gas mixture causes the level of that gas in the lungs to increase substantially. Elevated lung concentrations of the inhaled gas inhibits diffusion of contrast agent from the bloodstream into the lungs. The resulting non- depletion of microbubbles of contrast agent in blood flowing from the lungs enhances the image obtained of anatomical regions receiving this blood.

The inhaled gas mixture or any of its components can be persistent (i.e. have low blood solubility), and can be the same gas found in the injected ultrasound contrast microbubbles. C to C₁₀ fluorocarbon compounds, and sulfur hexafluoride, are among the inhaled gases which can work well in the present invention. Examples of fluorine containing chemicals useful in the invention include dodecafluoroneopentane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, perfluorocyclopentane, perfluoroheptane, perfluorooctane, and mixtures thereof

The inhalation gas may be administered using known methods. One such method is taught in U.S. Patent No. 5,487,380, which is incorporated herein by reference. This patent discloses an apparatus and method for administration of gaseous anaesthetic by inhalation, where the compound inhaled by the subject is rapidly absorbed into the bloodstream.

In the method of the invention, as the gas is inhaled, an aqueous medium is administered intravenously. In a preferred embodiment, the injected aqueous medium includes both microbubbles of ultrasound contrast agent and a fluorine-containing surfactant.

Emulsions of fluorine-containing surfactants are particularly useful as stabilizers of contrast agents for ultrasonic diagnostics.

Fluorosurfactants, particularly telomerized fluorosurfactants, stabilize those chemicals capable of forming microbubbles that provide strong ultrasound contrast signals as disclosed in U.S. Patent Nos. 5,558,853 and 5,558,855 (both to Quay, and incorporated herein by reference). Among the fluorine-containing surfactants used are synthetic surfactants. Preferred surfactants are fluorosurfactants, such as the Zonyl and the Fluorad brand series and polyoxypropylene-polyoxyethylene glycol nonionic block copolymers. Most preferred are the nonionic surfactants such as PEG Telomer B, and the anionic surfactants such as Fluorad FC-99.

Among injected fluorine-containing contrast agents used in the agent of the invention, those having good biocompatibility and a 5 boiling point less than 40 °C are preferred. As a result of their stability, perfluorocarbons are most preferred. Examples of these preferred chemicals include dodecafluoroneopentane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, perfluorocyclopentane, perfluoroheptane,

10 perfluorooctane, and mixtures thereof. The following list indicates that, for the preferred fiuorocarbon compounds, only those having fewer than eleven carbon atoms will have the necessary vapor pressure characteristics. The following list contains some of the fluorine-containing compounds which may be used with the present

1 5 invention:

Chemical M.W. B.P. C.Group

Propane, 2- (trifluoromethyl) - 1,1,1,3,3,3-hexafluoro 211 12.03 3 20 2-Butene, 3 -methyl 68 14.0 1

Methane, disilano 76.25 14.7 11

Ethyl nitrite 75.07 16.0 11

Ethyl amine 45.08 16.6 10 _ Tungsten hexafluoride 298 17.5 11 25 2, 3-Dimethyl-2-norbornano 140.23 19.0 li

Ethylene, 1, l-dichloro-2, 2-difluoro 133 19.0 3

Methane, bromo luoro 112.93 19.0 3 __ 1-Butene, 3-methyl 70.13 20.0 1 30 Borine, trimethyl 55.91 20.0 11

Fluorinert, FC-87 (3M Trade Mark) Unknown 20.0 3

Cyclopropane, 1,1-dimethyl 70.13 20.6 1 __ Acetaldehyde 44.05 20.8 7 35 Acetyl flouride 62.04 20.8 9

Borine, dimethyl, methoxy 71.19 21.0 11

Ethylene, 1, 2-dichloro- 1,2-difluoro 132.92 21.1 3 _{A t}- Ethylene, dichloro difluoro 132.92 21.1 3 40 Methane, difluoro-iodo 177.92 21.6 3

Diacetylene 50.08 22.0 1

Propylene, 2-chloro 76.53 22.6 3

Carvone- {d} 150.22 23.0 11 ._ Methane, trichloro luoro 137.37 23.7 3 45 l,3-Dioxolane-2-one, 4-methyl 102.09 24.2 1

Methane, dibromo difluoro 209.82 24.5 3

2-Pentanone, 4-atnino-4-methyl 115.18 25.0 10

Methane, chloro difluoro nitro 131.47 25.0 3

Propane, hepta luoro-1-nitro 215.03 25.0 3 Cyclopentene, 3 -chloro 102.56 25 0

1,4-Pentadιene 68.12 26 0

1, 5-Heptadiyne 92 14 26 0

3-Butene-2-one, , 4-phenyl {trans} 146.19 26 0 5 Propane , 1,1,2,, 2 , 3-Pentafluoro 134.06 26 0

2-Butyne 54 09 27 0

Ethane, 2,2-dιchloro- 1, 1, 1-trιfluoro 152 9 27 0

Cyclopentene, Octa luoro 211.05 27 0 10 l-Nonene-3-yne 122.21 27 0

2-Methyl butane 72.15 27 8

Butane, 2 -methyl 72.15 27 8

Ethane, 1, 2-dιchlorotrι luoro 152 9 28 .0

Ether, difluoromethyl 15 2,2,2-trιfluoroethyl 150.05 28 0

Cyclopropane, 1,2- d methyl (trans, 1} 70.13 28 0 1

Vinyl ether 70 28 .0 6

Cyclopropane, 1,2- 20 dimethyl (trans, dl) 70.13 29 0 1

Toluene, 2,4-dιamιno 122 17 29 0 2

1-Pentene, perfluoro 250 04 29 0 3

1-Butyne, 3-methyl 68.12 29 .5 1

1-Pentene 70.13 30 0 1 25 1-Pentene, 3,3,4,4,5,5,5- heptafluoro 196 30 .0 3

Ethylene, idotrifluoro 207 9 30 0 3

Styrene , 3 - fluoro 122 14 30 0 11

1-Pentene, 3-bromo 149 03 30 5 3 30 Pentane, perfluoro 288 04 30 5 3

Ethane, 1,2 -difluoro 66.05 30 7 3

Butane, 3-methyl, 1, 1, 1-trι luoro 126 12 31 .0 3

1-Butene, 2 -methyl 70.13 31 .2 1

Formic acid, methyl ester 60.05 31 .5 9 35 Methane sulfonyl chloride, trifluoro 168.52 31 .6 3

Ethane, 1, l-dichloro- l-fluoro 116 95 32 .0 3

Pentane, l- luoro 90.14 32. .0 3

Acetylene-dndo 277 83 32 0 3 40 Propane, 2-amιno 59.11 32. .4 10

Butane , l-fluoro 76.11 32 5 3

Methyl isopropyl ether 74.12 32 5 6

Propylene, 1-chloro 76.53 32, .8 3

Butyraldehyde, 2-bromo 151 33 0 3 45 2 -Butene, 2-chloro-

1,1,1,4,4, -hexafluoro 198.5 33, .0 3

1,3 -Butadiene, 1, 2, 3-trichloro 157 43 33 0 3

Butene, 2-chloro-

1,1, 1, 4, 4, 4 -hexafluoro 199 33 0 3 50 bis- (Dimethyl phosphino) amine 137 1 33 5 10

1, 3 -Butadiene, 2 -methyl 68.12 34 0 1

1 -Butene-3 -yne, 2-methyl 66.1 34 0 1

Isoprene 68..12 34 0 1

Methane, chloro dimtro 140.48 34. .0 3 55 Propane, 1,2-epoxy 58.08 34 3 6

Cyclopropane , ethyl 70.13 34. 5 1

Ethyl ether 74.12 34 5 6

Dimethyl disulfide, hexafluoro 202.13 34 6 11 _a - Ethylene, ι,2-dιchloro-l-fluoro 115 35. 0 3 60 Propane, 1, 2-dιchlorohexafluoro 220.93 35. .0 3

Ethyl vinyl ether 72.11 35 0 6

Propane , 2 -chloro 78.54 35 7 3

Methane, bromo-chloro- luoro 147.37 36 0 3 __ Piperidine, 2, 3,6-trιmethyl 127.23 36 0 11 65 1, 2, 3-Nonadecane tricarboxylic ac d, 2-hydroxy, tri ethylester 500.72 36 0 9

Dimethyl ethyl amine 73.14 36 0 10 __ n-Pentane 72.15 36. 1 1 70 2-Pentene (trans) 70.13 36 3 1

Cyclobutane , methyl 70.13 36 3 1

Ethyl methyl amine 59.11 36 7 10

2-Pentene {cis} 70.13 36 9 1

Cyclopropane, 1,2 -dimethyl {cis} 70.13 37 0 1 75 Ethylene, l,l-dιchloro 96.94 37 0 3

Propylene, 1-chloro-{ trans} 76.53 37 4 3

Ethylene, 1, l-dιchloro-2-fluoro 114.93 37 5 3 Methane, dichloro 84.93 40.0 3 Methane, iodo- 141.94 42.4 3 Ethane, 1,1-dichloro 98 57.3 3 perfluorohexane 338.05 58 3 perfluoroheptane 388.06 80-82 3 perfluorooctane 438.06 99-100 3

M.W. is molecular weight. B.P. is boiling point. C. Group is chemical group.

CHEMICAL GROUP DESIGNATION

I Aliphatic hydrocarbons and/or derivatives 2 Aromatic hydrocarbons and/or derivatives

3 Organic halides and/or derivatives

6 Ethers and/or derivatives

7 Aldehydes and/or derivatives

9 Carboxylic acids and/or derivatives 10 Amines and/of derivatives

II Miscellaneous

The chemicals useful in the invention can also be activated prior to injection. That is, where the chemicals are in liquid form (i.e. are in the form of a microbubble precursor), the formation of microbubbles can be accelerated and enhanced by, e.g. hypobaric activation methods. Such methods are known in the art and are, for example, disclosed in detail in WO 96/40282 (Sonus Pharmaceuticals, Inc). The phrase microbubble precursor is intended to encompass any form of agent which can produce or become a microbubble of the desired gas jn vivo.

Ultrasound imaging is conducted by methods well known in the art, see: Ophir and Parker, Ultrasound in Med. & Biol. (1989), 15:319-333. In addition, methods of harmonic imaging as described in U.S. Patent Nos. 5,410,516 and 5,540,909

(incorporated by reference herein) can be used with the method of the invention.

The general principles of the present invention may be more fully appreciated by reference to the following non-limiting example. Example 1 : Ultrasound Imaging of Baboon Purpose:

In order to evaluate efficacy of ultrasound imaging of the left ventricle of baboons using the process of the current invention, various contrast agents were injected as the subject inhaled a gas.

Procedures:

1 . Aqueous media containing the various contrast agents shown in Table 1 were prepared. 2. Within 5 minutes prior to injection of the aqueous media, anesthetized baboons began inhaling the corresponding gas mixture shown in Table 1 .

3. Immediately prior to injection, the syringe containing the aqueous media was activated as described in WO 96/40282. 4. The activated aqueous media was then intravenously injected via the lateral ear vein.

5. The baboon left ventricle was imaged with an ATL

Ultramark 9 ultrasound imaging system equipped with a 7.0 MHz transducer for producing gray scale enhancement of the left heart region. The gain was set to optimize the image between 20 and

100%.

Results:

Intravenous administration of contrast agent during inhalation enhanced the image of the left ventricle as shown below in TABLE 1 . Contrast results are reported on a relative scale: 5 + represents the highest contrast and 1 + represents the lowest contrast. TABLE 1

Intravenous Inhaled Contrast Administration Gas Mixture Results

2% dodecafluoropentane air 3 + emulsion air-filled microspheres air 1 +

2% dodecafluoropentane

5% DDFP/95% air 5 + emulsion perfluoropropane-filled

20% DDFP/80% air 4 + microspheres air-filled galactose 30% perfluorobutane

4 + microparticles /70%air perfluoropropane-filled air 3 + liposomes perfluoropropane-filled

10% perfluoropropane/air 4 + liposomes perfluoropropane-filled air 3 + liposomes perfluoropropane-filled 10% perfluorohexane/

4 + liposomes 20% perfluoropropane/air

No serious adverse effects were associated with administration of the gas or aqueous media.

The results shown in Table 1 demonstrate the enhancement of the ultrasound image by using the inhaled gas method. These results clearly demonstrate enhancement of ultrasound imaging of the left ventricle under a variety of contrast agent / inhaled gas combinations. Especially enhanced images were obtained where at

least one component of the inhaled gas mixture was the same as injected contrast agent. Although the invention has been described in some respects with reference to specified preferred embodiments thereof, many variations and modifications will be apparent to those skilled in the art. It is, therefore, the intention that the following claims not be given a restrictive interpretation but should be viewed to encompass

such variations and modifications that may be routinely derived from the inventive subject matter disclosed.

Claims

What is claimed is:

1 . A method of diagnostic imaging comprising the steps of:

(1 ) causing a subject to inhale at least one fluorine-

containing biocompatible gas;

(2) administering to said subject's bloodstream an agent

including microbubbles or microbubble precursors of a

fluorine containing chemical; and

(3) performing a diagnostic scan on an area of the body of

said subject to obtain an image enhanced by the

presence of said agent.

2. The method of claim 1 wherein the inhalation gas is selected

from the group consisting of dodecafluoroneopentane,

perfluoropropane, perfluorobutane, perfluoropentane,

perfluorohexane, perfluorocyclopentane, perfluoroheptane,

perfluorooctane and sulfur hexafluoride.

3. The method of claim 2 wherein the ultrasound contrast agent

includes a fluorinated surfactant.

4. The method of claim 3 wherein the ultrasound contrast agent

includes one or more chemicals selected from the group consisting of dodecafluoroneopentane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, perfluorocyclopentane, perfluoroheptane, perfluorooctane and sulfur hexafluoride.

5. A method of ultrasound imaging comprising the steps of:

(1 ) intravascularly administering a microbubble or microbubble precursor containing ultrasound contrast agent to a patient;

(2) causing inhalation of a biocompatible gas or gas mixture

in said patient, said gas or gas mixture being present in an amount effective to reduce the degree of outgassing from said microbubbles in the lungs; and

(3) performing an ultrasound scan on a partion of said patient into which said microbubbles have moved via the blood stream.

6. The method of claim 5 wherein the biocompatible gas and the contrast agent include one or more chemicals selected from the group consisting of dodecafluoroneopentane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane, perfluorocyclopentane, perfluoroheptane, perfluorooctane and sulfur hexafluoride.

7. The method of claim 6 wherein the contrast agent also includes a fluorine-containing surfactant.

8. The method of claim 7 wherein the surfactant is an anionic or a non-ionic surfactant.

9. A method of ultrasound imaging comprising the steps of: (1 ) intravascularly administering to a patient a biocompatible ultrasound contrast agent comprising microbubble precursors or microbubbles of a gas; (2) causing the inhalation by said patient of at least one chemical selected from the group consisting of dodecafluoroneopentane, perfluoropropane, perfluorobutane, perfluoropentane, perfluorohexane,

perfluorocyclopentane, perfluoroheptane, perfluorooctanje and sulfur hexafluoride in an amount and for a time adequate to decrease the amount of outgassing from said microbubbles in the lungs; and (3) performing an ultrasound scan on a portion of said

patient.

10. The method of claim 9 wherein the ultrasound scan is a harmonic imaging scan.

1 1 . The method of claim 9 wherein said portion includes the left heart of the patient.