Diagnostic ultrasound ( PDFDrive )

CHAPTER 3 Contrast Agents for Ultrasound 55
in the tissue as little as possible, thus enhancing the echo from
blood. More important, they change the nature of the echo from
blood in a way that allows them to be imaged selectively in real
time.
Blood Pool Agents
Free Gas Bubbles
Gramiak and Shah irst used bubbles to enhance the blood echo
in 1968. 3 hey injected agitated saline into the let ventricle during
an echocardiographic examination and saw strong echoes within
the lumen of the aorta. It was subsequently shown that these
echoes originated from free bubbles of air that came out of solution
either during agitation or at the catheter tip during injection. 4
Agitated solutions of compounds such as indocyanine green and
Renograin—already approved for intraarterial injection—were
also used. he application of free gas as a contrast agent was
conined to the heart, including evaluation of valvular insuiciency,
5 intracardiac shunts, 6 and cavity dimensions. 7 he fundamental
limitation of bubbles produced in this way is that they
are large, so they are efectively iltered by the lungs, and unstable,
so they go back into solution on the order of a second. Apart
from occasional use in the echocardiography laboratory to identify
shunts, free bubbles are rarely used as a contrast agent today.
Encapsulated Air Bubbles
To overcome the natural instability of free gas bubbles, various
shell coatings were developed to create a more stable particle
(Table 3.1). In 1980 Carroll and colleagues 8 encapsulated nitrogen
bubbles in gelatin and injected them into the femoral artery of
rabbits with VX2 tumors in the thigh. Although echo enhancement
of the tumor rim was identiied, the large diameter of the
coated bubbles (80 µm) precluded administration by an intravenous
route. he challenge to produce a stable encapsulated
microbubble of a comparable size to that of a red blood cell and
that could survive passage through the heart and the pulmonary
capillary network was irst met by Feinstein and colleagues in
1984, 9 who produced microbubbles by sonication of a solution
of human serum albumin and showed that it could be detected
in the let side of the heart ater a peripheral venous injection.
his agent was subsequently developed commercially as Albunex
(Mallinckrodt Medical, Inc., St. Louis, MO).
Another approach to stabilizing an air bubble is to add a
lipid shell upon dissolution of a dry powder. Levovist (Schering
AG, Berlin, Germany), is a dry mixture comprising 99.9%
microcrystalline galactose microparticles and 0.1% palmitic
acid. On dissolving in sterile water, the galactose disaggregates
into microparticles, which provide an irregular surface for the
adherence of microbubbles 3 to 4 µm in size. Stabilization of the
microbubbles takes place as they become coated with palmitic
acid, which separates the gas/liquid interface and slows their
dissolution. 18 he resulting microbubbles have a median bubble
diameter of about 3 µm with the 97th percentile at approximately
6 µm and are suiciently stable for transit through the pulmonary
circuit. he agent is chemically related to its predecessor Echovist
(Schering), a galactose agent that forms larger bubbles and
that has been used principally for visualization of nonvascular
ductal structures such as the fallopian tubes. 19,20 Numerous early
TABLE 3.1 Regulatory and Marketing Status of Some Current Ultrasound Contrast Agents as
of 2016
Name
Company/
Developer
Composition (Shell/Gas)
REGULATORY/MARKETING STATUS
Cardiology Indications
Radiology Indications
Deinity
SonoVue
Lumason
Lantheus Medical
Imaging 10 Lipid/perluoropropane Approved in United States,
Canada
Bracco 11
Phospholipid/sulfur Approved in European Union,
hexaluoride
Canada
Optison GE Healthcare 12 Sonicated albumin/
octaluoropropane
Sonazoid
Approved in European Union,
United States, Canada
Approved in Canada, China,
Australasia, Americas
Approved in 40 countries,
including European Union,
Canada, China, United
States
Suspended development
GE Healthcare and
Daiichi Sankyo 13 Lipid perluorobutane Clinical development Approved in Japan, Korea,
Norway
Clinical development in
European Union, United
States
biSphere Point Biomedical 14 Polymer bilayer/air Suspended development Suspended development
Imagify Acusphere 15 Polymer/perluorobutane Clinical development Suspended development
PESDA Porter 16 Sonicated albumin/ Not commercially developed Not commercially developed
perluorocarbon
BR55 Bracco 17 Lipopeptide VEGFR-2–
targeted/perluorocarbon
Clinical development
VEGFR, Vascular endothelial growth factor receptor.