Ultrasound is becoming the most popular among
the imaging modalities because of its low cost and non – reliability on ionising
radiation. Ultrasound is used to in various examinations to rule out pathologies
affecting the organs. Doppler ultrasound is used to detect blood flow in vessels
and tissue perfusion however, blood scatters ultrasound waves at diagnostic
transmission frequencies(2MHz – 15MHz) poorly(Postema & Gilja, 2011). Imaging blood flow and obtaining tissue perfusion information are relevant
in diagnostic purposes and hence markers are added to the blood to distinguish between
tissue and blood(Postema & Gilja, 2011) .
contrast – agents consisting of microbubbles of perfluorocarbon or nitrogen gas
encapsulated in biodegradable shells
designed to show sensitive blood flow in vessels and obtain tissue
perfusion information (Wilson, Greenbaum, & Goldberg, 2009), (Czarniecki, n.d.).
Contrast agents improve the echogenicity of blood and this improves the
visualisation of cardiac cavities, large vessels and tissue vascularity(“Contrast Enhanced Ultrasound | Bracco Imaging,” n.d.).
The contrast agents have no harmful effect on
the kidney, thyroid and is easily accessible as compared to contrast – enhanced
magnetic resonance imaging and contrast enhanced computerised tomography(Chung & Kim, 2014).
In contrast – enhanced ultrasound, contrast
agents are group as either first or second generation depending on the type of
gas present within the microbubble(Chung & Kim, 2014). First generation contrast agents use a high – mechanical -index technique
hence only intermittent scanning is possible since there is destruction of the
microbubble bubbles during continuous scanning over a long period(Chung & Kim, 2014). The use of second generation contrast agents involves low – mechanical
index techniques which enables continuous scanning without destruction to the
Contrast – enhanced ultrasound is used for
a variety of examinations and is gradually replacing the use of magnetic
resonant imaging and computerised tomography for certain examinations.
Principle of contrast – enhanced imaging
“Acoustic impedance is the physical
property of the tissue which describes how much resistance an ultrasound beam encounters
as it passes through the tissue”(Morgan, n.d.).
Acoustic impedance depends on the density and compressibility of the tissue and
velocity of sound wave. Therefore, if the density of the tissue increases, the
impedance also increases. The ability of ultrasound waves to travel from one
tissue to another depends on the difference in acoustic impedance between the
two tissues. If the difference is high the sound waves is reflected.
(Gramiak & Shah, 1968) made an accidental discovery of contrast agents, that the presence
of microbubbles in circulation significantly increases ultrasound intensity. Since
then different types of contrast agents have evolved(all of which generates a
suspension of microbubbles after being administered)(Tang et al., 2011).
Microbubbles of contrast agents must be
sufficiently small(3 – 5µm), “slightly smaller than the red blood cell”, (Wilson & Burns, 2010) to cross the capillary bed of pulmonary circulation and however big
enough such that they do not cross the vascular endothelium(Tang et al., 2011) . The
microbubbles are stabilised by coating of a biocompatible surfactant or polymer
commonly phospholipids or proteins to prevent the bubbles from rapidly
dissolving and/ or agglomerating. This coating both lowers the interfacial
tension at the bubble surface and provides a barrier to gas diffusion(Tang et al., 2011). Due
to the gas content of the microbubbles, they are highly compressible which
makes it more efficient scatters of ultrasound.
The microbubbles of contrast agents acts as
echo -enhancers using basically the same mechanism as echo – Reighley scattering
in diagnostic ultrasound; that is backscattering echo intensity is directly proportional
to the change in acoustic impedance between blood and microbubbles of contrast
agents(Calliada, Campani, Bottinelli, Bozzini, & Sommaruga, 1998). The difference in acoustic impedance at this interface is very
high and hence high amounts of incident ultrasound waves are reflected to the
transducer. But the acoustic wave reflection, though nearly complete, would not
be sufficient to cause strong acoustic enhancement because the microbubbles are
very small and are sparse in the circulation(Calliada et al., 1998). Moreover, reflectivity is proportional to the fourth power of a
particle diameter but also directly proportional to the concentration of the
particles themselves. Contrast agents hence are able to produce much stronger
backscatter than regular blood or tissue due to the substantial differences in
the compressibility and density between the gas microbubbles and the
surrounding blood(Dogra & Rubens, 2004).
The contrast agents are administered with
intravenous injection. Following injection, the
bubbles circulate throughout the vascular space and greatly increase the
amplitude of the scattered signals not only from large vessels and cavities but
also from the microvasculature, making imaging of tissue perfusion possible(Tang et al., 2011).
A suspension of bubbles
in water with dose ranging between 0.2 – 2ml in volume containing contains tens
of millions bubbles, almost comparable to the number of red blood cells in a
milliter of blood is injected in to a peripheral vein in the arm or hand(Wilson & Burns, 2010). The bolus
injection increases the echo from the blood by a factor of 500 – 1000. By
infusing the bubbles through a saline drip, a steady enhancement lasting up to
20minutes can be obtained(Wilson & Burns, 2010).
Ultrasound pulsations could be either
linear or non- linear with respect to the applied pressure, depending on the
magnitude of the incident ultrasound field(Dogra & Rubens, 2004). When applied pressure
magnitude is sufficiently large( >> 100kPa) microbubbles begins to
respond non – linearly(Dogra & Rubens, 2004).
The actual performance of contrast –
enhanced ultrasound requires contrast – specific software application on the
ultrasound machine. The equipment suppresses the signal from the background
tissue leaving only the signal from the microbubbles(Wilson et al., 2009). This
is accomplished by several techniques, the most common of them is “pulse
inversion” where two signals are transmitted through a single scan line with
the second being a mirror(inverted) image of the first. The two echoes from
both pulses are received by the transducer are summed. Since both echoes are
inverted copies of each other they cancel out to zero(produces no net signal) (Wilson & Burns, 2010), (Wilson et al., 2009). However,
nonlinear reflectors in the microbubbles produce echoes that are asymmetric
hence do not sum to zero(Wilson et al., 2009). The
nonlinear components in the microbubbles reinforce each other when summed
producing a strong harmonic signal(Wilson & Burns, 2010).
The mechanical index is defined as the peak
rarefactional pressure divided by the square root of the ultrasound frequency.
Mechanical index value is related to the insonation power of the microbubble
within the ultrasound field(Chung & Kim, 2014).
If the sound is transmitted at a low
mechanical index(MI), the microbubble population stay static, preserved which
enables several minutes of observation (Wilson & Burns, 2010). As the mechanical index increases, the microbubbles oscillate at
their resonance frequency linearly(MI < approximately 0.2) or nonlinearly(approximately 0.2 < MI < 0.5), however, if the mechanical index increases greater than 0.5, the microbubbles oscillate strongly and expand beyond their limit and this results in destruction of the bubbles(Chung & Kim, 2014). The destruction of bubbles facilitates the flash replenishment technique, where the bubbles can be visualised refilling the liver or tumour after destruction, which is optimal for visualising vessel morphology(Wilson & Burns, 2010). Contrast enhanced ultrasound images can be created from either the signals of nonlinear oscillations of the microbubbles or the signals from the microbubble destruction(Chung & Kim, 2014). Pitfalls Contrast – enhanced ultrasound imaging show high sensitivity but a poor specificity due to presence of pseudo - enhancement (false detection of contrast agent) produced by nonlinear wave propagation(Renaud, Bosch, van der Steen, & de Jong, 2015). History Contrast – enhanced ultrasound begun started in the 1960s when Gramiak and Shah observed a "cloud" of echoes from the aortic root after injecting saline through an intra- aortic catheter (Gramiak & Shah, 1968). Contrast enhancement was caused by the compressible gas core of saline which enabled the bubble to backscatter the ultrasound wave(Paefgen, Doleschel, & Kiessling, 2015). Those first saline bubbles used were not stable due to high surface tension(Paefgen et al., 2015). The injection of autologous blood at adequately rapid rate caused the formation of a more stable saline bubble(Kremkau, Gramiak, Carstensen, Shah, & Kramer, 1970), these bubble still lacked sufficient lifetime and definite structure. In 1990, the first stable commercially available and FDA approved ultrasound contrast agent was developed (Feinstein, Cheirif, Silverman, Heidenreich, & Dick, n.d.), Albunex, an albumin – coated and air filled microsphere(Paefgen et al., 2015). Requirement and types of contrast agents. The principal requirements for ultrasound contrast agents are (1) being easily introducible to the vascular system, (2) being stable for the duration of the ultrasound examination, (3) having low toxicity and (4) modifying acoustic properties of tissue to enhance image quality for good visualisation(Rumack, Wilson, Charboneau, & Levine, 2005). The technology adopted in contrast agents is that of encapsulated bubbles of gas that are smaller than red blood cells and therefore are capable of circulating freely in the systemic vasculature(Rumack et al., 2005).