Ultrasound is becoming the most popular amongthe imaging modalities because of its low cost and non – reliability on ionisingradiation. Ultrasound is used to in various examinations to rule out pathologiesaffecting the organs. Doppler ultrasound is used to detect blood flow in vesselsand tissue perfusion however, blood scatters ultrasound waves at diagnostictransmission frequencies(2MHz – 15MHz) poorly(Postema & Gilja, 2011).
Imaging blood flow and obtaining tissue perfusion information are relevantin diagnostic purposes and hence markers are added to the blood to distinguish betweentissue and blood(Postema & Gilja, 2011) . Ultrasoundcontrast – agents consisting of microbubbles of perfluorocarbon or nitrogen gasencapsulated in biodegradable shellsdesigned to show sensitive blood flow in vessels and obtain tissueperfusion information (Wilson, Greenbaum, & Goldberg, 2009), (Czarniecki, n.d.).Contrast agents improve the echogenicity of blood and this improves thevisualisation of cardiac cavities, large vessels and tissue vascularity(“Contrast Enhanced Ultrasound | Bracco Imaging,” n.d.).
The contrast agents have no harmful effect onthe kidney, thyroid and is easily accessible as compared to contrast – enhancedmagnetic resonance imaging and contrast enhanced computerised tomography(Chung & Kim, 2014). In contrast – enhanced ultrasound, contrastagents are group as either first or second generation depending on the type ofgas present within the microbubble(Chung & Kim, 2014). First generation contrast agents use a high – mechanical -index techniquehence only intermittent scanning is possible since there is destruction of themicrobubble bubbles during continuous scanning over a long period(Chung & Kim, 2014). The use of second generation contrast agents involves low – mechanicalindex techniques which enables continuous scanning without destruction to themicrobubbles Contrast – enhanced ultrasound is used fora variety of examinations and is gradually replacing the use of magneticresonant imaging and computerised tomography for certain examinations.Principle of contrast – enhanced imaging “Acoustic impedance is the physicalproperty of the tissue which describes how much resistance an ultrasound beam encountersas it passes through the tissue”(Morgan, n.d.
).Acoustic impedance depends on the density and compressibility of the tissue andvelocity of sound wave. Therefore, if the density of the tissue increases, theimpedance also increases. The ability of ultrasound waves to travel from onetissue to another depends on the difference in acoustic impedance between thetwo tissues. If the difference is high the sound waves is reflected. (Gramiak & Shah, 1968) made an accidental discovery of contrast agents, that the presenceof microbubbles in circulation significantly increases ultrasound intensity.
Sincethen different types of contrast agents have evolved(all of which generates asuspension of microbubbles after being administered)(Tang et al., 2011). Microbubbles of contrast agents must besufficiently small(3 – 5µm), “slightly smaller than the red blood cell”, (Wilson & Burns, 2010) to cross the capillary bed of pulmonary circulation and however bigenough such that they do not cross the vascular endothelium(Tang et al.
, 2011) . Themicrobubbles are stabilised by coating of a biocompatible surfactant or polymercommonly phospholipids or proteins to prevent the bubbles from rapidlydissolving and/ or agglomerating. This coating both lowers the interfacialtension at the bubble surface and provides a barrier to gas diffusion(Tang et al., 2011).
Dueto the gas content of the microbubbles, they are highly compressible whichmakes it more efficient scatters of ultrasound. The microbubbles of contrast agents acts asecho -enhancers using basically the same mechanism as echo – Reighley scatteringin diagnostic ultrasound; that is backscattering echo intensity is directly proportionalto the change in acoustic impedance between blood and microbubbles of contrastagents(Calliada, Campani, Bottinelli, Bozzini, & Sommaruga, 1998). The difference in acoustic impedance at this interface is veryhigh and hence high amounts of incident ultrasound waves are reflected to thetransducer. But the acoustic wave reflection, though nearly complete, would notbe sufficient to cause strong acoustic enhancement because the microbubbles arevery small and are sparse in the circulation(Calliada et al.
, 1998). Moreover, reflectivity is proportional to the fourth power of aparticle diameter but also directly proportional to the concentration of theparticles themselves. Contrast agents hence are able to produce much strongerbackscatter than regular blood or tissue due to the substantial differences inthe compressibility and density between the gas microbubbles and thesurrounding blood(Dogra & Rubens, 2004).
The contrast agents are administered withintravenous injection. Following injection, thebubbles circulate throughout the vascular space and greatly increase theamplitude of the scattered signals not only from large vessels and cavities butalso from the microvasculature, making imaging of tissue perfusion possible(Tang et al., 2011). A suspension of bubblesin water with dose ranging between 0.2 – 2ml in volume containing contains tensof millions bubbles, almost comparable to the number of red blood cells in amilliter of blood is injected in to a peripheral vein in the arm or hand(Wilson & Burns, 2010). The bolusinjection increases the echo from the blood by a factor of 500 – 1000.
Byinfusing the bubbles through a saline drip, a steady enhancement lasting up to20minutes can be obtained(Wilson & Burns, 2010). Ultrasound pulsations could be eitherlinear or non- linear with respect to the applied pressure, depending on themagnitude of the incident ultrasound field(Dogra & Rubens, 2004). When applied pressuremagnitude is sufficiently large( >> 100kPa) microbubbles begins torespond non – linearly(Dogra & Rubens, 2004). The actual performance of contrast –enhanced ultrasound requires contrast – specific software application on theultrasound machine. The equipment suppresses the signal from the backgroundtissue leaving only the signal from the microbubbles(Wilson et al.
, 2009). Thisis accomplished by several techniques, the most common of them is “pulseinversion” where two signals are transmitted through a single scan line withthe second being a mirror(inverted) image of the first. The two echoes fromboth pulses are received by the transducer are summed. Since both echoes areinverted 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 asymmetrichence do not sum to zero(Wilson et al., 2009). Thenonlinear components in the microbubbles reinforce each other when summedproducing a strong harmonic signal(Wilson & Burns, 2010).
The mechanical index is defined as the peakrarefactional pressure divided by the square root of the ultrasound frequency.Mechanical index value is related to the insonation power of the microbubblewithin the ultrasound field(Chung & Kim, 2014). If the sound is transmitted at a lowmechanical index(MI), the microbubble population stay static, preserved whichenables several minutes of observation (Wilson & Burns, 2010). As the mechanical index increases, the microbubbles oscillate attheir resonance frequency linearly(MI < approximately 0.2) ornonlinearly(approximately 0.
2 < MI < 0.5), however, if the mechanicalindex increases greater than 0.5, the microbubbles oscillate strongly andexpand beyond their limit and this results in destruction of the bubbles(Chung & Kim, 2014). The destruction of bubbles facilitates the flash replenishmenttechnique, where the bubbles can be visualised refilling the liver or tumourafter destruction, which is optimal for visualising vessel morphology(Wilson & Burns, 2010). Contrast enhanced ultrasound images can be created from either thesignals of nonlinear oscillations of the microbubbles or the signals from themicrobubble destruction(Chung & Kim, 2014). Pitfalls Contrast – enhanced ultrasound imaging showhigh sensitivity but a poor specificity due to presence of pseudo - enhancement (false detection of contrastagent) produced by nonlinear wave propagation(Renaud, Bosch, van der Steen, & de Jong, 2015). History Contrast – enhanced ultrasound begunstarted in the 1960s when Gramiak and Shah observed a "cloud" of echoes fromthe aortic root after injecting saline through an intra- aortic catheter (Gramiak & Shah, 1968).
Contrast enhancement was caused by the compressible gas core ofsaline which enabled the bubble to backscatter the ultrasound wave(Paefgen, Doleschel, & Kiessling, 2015). Those first saline bubbles used were not stable due to highsurface tension(Paefgen et al., 2015). The injection of autologous blood at adequately rapid rate causedthe formation of a more stable saline bubble(Kremkau, Gramiak, Carstensen, Shah, & Kramer, 1970), these bubble still lacked sufficient lifetime and definitestructure. In 1990, the first stable commercially available and FDA approvedultrasound 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 ultrasoundcontrast agents are (1) being easily introducible to the vascular system, (2)being stable for the duration of the ultrasound examination, (3) having lowtoxicity and (4) modifying acoustic properties of tissue to enhance imagequality for good visualisation(Rumack, Wilson, Charboneau, & Levine, 2005). The technology adopted in contrast agentsis that of encapsulated bubbles of gas that are smaller than red blood cellsand therefore are capable of circulating freely in the systemic vasculature(Rumack et al., 2005).