Factors Influencing a Good Image
On the technical side (Machine Settings):
- Gain
- Mechanical Index
- Dynamic Range
- Frame Rate
On the Contrast Media side:
- Dosage
- Injection Rate
- How slow (Cardiology)
- How fast (General Imaging)
- Concentration
- Mixing
On the patient side:
- Weight (BMI)
- Cardio circulation
- Metabolism
- Cardiac output
Let’s talk about Gain
Gain refers to the received signal amplification. For CEUS the gain usually is set very slightly above the noise floor so that before microbubbles arrive, the image is dark and with a “hint” (very low level) of noise. If the gain is set too low (image starts out too dark), weak microbubble signals are not detected and only signals from larger vessels are recorded. If the gain is set too high (image starts out bright and grainy even before the microbubbles arrive) the received echoes from the bubbles are clipped after a certain amplitude.
Acoustic shadowing is the depth-dependent reduction in ultrasound amplitude due to excessive scattering from microbubbles. The nearfield microbubbles obscure and “shadow” the far field ones. Acoustic shadowing is due to excessive dose of UCA or increased microbubble concentration. The UCA dose should be adapted to the patient and the clinical indication. CEUS is always performed with low MI to avoid bubble destruction and harmonic signal generation from tissues. Typically, modern high-end diagnostic ultrasound scanners should effectively suppress tissue signals at low MI’s over the entire depth to enhance the visualization of microbubbles.
What Is Background signal (noise)?
The use of a dual-image display format is essential in CEUS studies and it is recommended especially in examining small lesions. In this display format, a conventional B-mode low MI fundamental image and a bubble-only contrast image are displayed side-by-side. The reason this is useful is that the nonlinear image is almost completely black (before contrast administration and under ideal conditions) making it difficult to keep the lesion of interest in the image plane. Having the conventional image displayed simultaneously allows the operator to keep the lesion in the imaging plane. Using the B-mode image for guidance, place calipers on the target lesion on both screens simultaneously to facilitate enhancement characterization. It is also possible to overlay the contrast and low MI fundamental B-mode plane image. For quantitative studies, it is critical to maintain the transducer at the same place and avoid motion. Pronounced hyperechoic lesions may still be visible on the contrast image before the arrival of the agent. TIC will help to better define the wash-out characteristics in these cases. It should be noted that in most systems, the quality of the B-mode image in dual-image displays is inferior to that obtained with the same settings in non-contrast mode.
But, what does dynamic range have to do with my CEUS exam?
The compression or dynamic range of the ultrasound system also plays a key role in microbubble visualization. A small dynamic range is preferred in cases of very low signal and a wide dynamic range is preferred when the objective is to perform quantification (to avoid signal saturation). The dynamic range should be set to optimise the expected enhancement pattern. The dynamic range is the range of signal intensities to be displayed. A wide dynamic range increases the number of signal levels (“grey levels”), allowing for better differentiation between different degrees of enhancement. A small dynamic range will decrease the number of “colours” in the image and increases visual contrast but can limit the differentiation between areas of variable enhancement. For example, in a vascular metastatic lesion there is often a rim of increased signal surrounding the lesion. If the dynamic range is set too narrow – the rim will be displayed in the same “colour” as the lesion and the increased signal in this area may not be appreciated. Lowering the dynamic range will let the vessels stand out brighter, but it should not be too low that the gray or colorized bubble image suffers in contrast resolution. With a large dynamic range, the increased rim of signal can be better identified.
For visualisation of lesions with low perfusion, a narrow dynamic range is preferred. For perfusion quantification studies, a wide dynamic range should be used to avoid signal saturation. It should be noted that reducing the dynamic range can increase the apparent difference between lesional and parenchymal enhancement. If acquiring a series of cases whose appearances are to be compared, it may be advantageous to keep the dynamic range and other postprocessing settings constant.
Should I worry about the Frame Rate?
A frame rate ≥10 Hz is recommended for adequate visualization and recording of the wash-in patterns when characterizing focal liver lesions (FLL). The contrast wash-in may only be visualized for about a second in some highly vascularized lesions and is best appreciated using retrospective frame-by-frame cine review. Moreover, a high frame rate is also important during sweeps of the liver to detect lesions so as to avoid skipping significant regions of the organ 40 . However, increased frame rates can augment bubble destruction, and decreasing the frame rate in the late vascular phases will prolong the enhancement time.
What is Mechanical Index (MI) and why is it so important?
The Acoustic Pressure Amplitude (P) refers to the peak negative amplitude of the ultrasound pulse used for imaging. It is measured in Pa and is used in the calculation of the Mechanical Index (MI). The MI is an estimate of the maximum peak negative acoustic pressure in the tissue within the acoustic field scaled by the square root of the center frequency. MI is related to the likelihood of cavitation and the US Food and Drug Administration (FDA) limits the maximum MI to a value of 1.9 [when P is measured in MPa and frequency in MHz]. In addition to the MI, which refers to the highest value in the acoustic field, some manufacturers also estimate and display the MI at the focus zone or the percentage of maximum acoustic power that allows finer tuning of the acoustic energy delivered 40 . It is important to note that there is a direct linear relationship between P and the MI (within linear acoustics). Choosing the appropriate MI is important for effective CEUS because as summarized in 40 this parameter affects several processes relevant to image quality and microbubble behaviour. These parameters are listed below and discussed in more detail later.
- The degree and rate of microbubble destruction.
- The depth of ultrasound beam penetration.
- The ability to separate signals scattered from background tissue versus those scattered by microbubbles, since tissue scattering is linear at low amplitudes (low MIs) while microbubble scattering is non-linear at all amplitudes.
While the MI on-screen labelling is mandated by the FDA, manufacturers nonetheless use different calculations to arrive at this number. In practice, for contrast imaging, the number is not transferrable between machines. Thus, an optimal MI for a particular patient scanned with one machine may not be the same as for the same patient scanned with another.
Ok, enough theory. What about the practical examination (Step by step)?

Pre-contrast examination
The pre-contrast examination preparations include the identification of the best position of the patient, the identification of the target lesion and the optimal scan plane along the axis of the respiratory movements (usually longitudinal) to minimize out-of-plane motion from respiration. The optimal patient breathing position is determined and practiced with the patient prior to the contrast injection. Quiet breathing and breath suspension in neutral are preferred over breath hold in full inspiration or expiration.
Catheter
The best position of the patient should be determined during the pre-contrast examination and this may affect which arm is chosen for injection. In most circumstances, the cannula should be inserted in the left arm, preferably the antecubital vein, to avoid interaction of the injector with the right-sided examiner. Be aware of other important influencing factors, e. g., avoid the side of breast (or axillary) surgery to minimise the risk of worsening lymphedema.
Ideally, the diameter of the venous line should be 20 gauge or larger to minimize microbubble destruction during passage through the cannula, with its length as short as possible. Central line and port systems can be used as long as there is no filter requiring a high injection pressure. Their use will shorten contrast arrival time 48 .
In cases of difficult venous cannulation, US guided needle placement using a high frequency linear probe is recommended.
The catheter can be removed after exclusion of any kind of pseudoanaphylactic, e. g., 15 min after contrast injection.
3-way stopcock
A three-way stopcock may be valuable, especially if multiple injections are anticipated, as this facilitates sequential administration of the contrast material and then the saline flush, without removal of either syringe.
Injection
The injection bolus for SonoVue™ is given at about 1–2 ml/s. Avoid high pressure (risk of microbubble destruction). Immediately after injecting the contrast agent, a (5-) 10 ml saline bolus should be given to flush the line at about 2 ml/s 4 38 .
Central venous line and “port”
Central venous lines and ports may be used for CEUS if necessary if safety and aseptic requirements are met, but their use is discouraged if a peripheral vein can be accessed. Injecting UCAs through a central venous line or port requires a higher level of expertise to ensure a successful injection. Bubble disruption may also be increased necessitating a dose increase. The use of a central venous line requires a 3-way stopcock. Contrast arrival times are usually significantly shorter in case of a central-venous administration, a fact which might favour starting the timer earlier, at the beginning of the contrast injection.
Contrast agent dose
Using the optimal dose is important. Too high a contrast agent dose results in artefacts, particularly in the early phases of enhancement. These include acoustic shadowing, over-enhancement of small structures and signal saturation, which is also detrimental for quantification. On the other hand, too low a dose causes the concentration of microbubbles to be subdiagnostic in the late phase, challenging the detection of wash out. If the liver washes out early, the dose was probably too low or inherent significant intrahepatic shunting may prevent a longer enhancement time. Again, it is important to evaluate the status of the liver as being healthy or diseased. In difficult cases, a second (higher) dose may be administered, with no or only limited scanning in the early phases 40 to reduce bubble destruction. The exact dose depends on the UCA, ultrasound equipment (software version, transducer), type of examination, organ and target lesion, size and age of the patient and other factors.
For SonoVue™/Lumason™, 2.4 ml (1/2 vial) is recommended for most indications in the liver (detection, characterisation) but many investigators are now using 1.2 ml (this topic has been controversially discussed with co-authors and the reviewers).
For SonoVue™/Lumason™, 2.4 ml (1/2 vial) is the standard dose for most indications in the pancreas, spleen and kidney. For the pancreas, spleen and kidney, 1.2 ml often suffices. Depending on scanning conditions and depth of the lesion (organ) even lower doses can be used. For high frequency applications 4.8 ml is suggested. In particular, endoscopic ultrasound usually requires the complete vial of 4.8 ml 51 52 53 . For the extravascular (intraluminal) use only few drops diluted in normal saline solution are necessary. For Definity™ and Optison™ a standard dose is 0.2–0.3 ml for an adult. For Sonazoid™ a dose of 0.015 ml/kg (e. g., 0.5–1.0 ml) of the reconstituted suspension is recommended.
Repeated injection
Multiple injections of UCA are variably indicated and influenced mainly by the manufacturing of the different solutions and the volume needed to provide good visualization of the liver and a focal liver mass. SonoVue™/Lumason™, supplied in a 4.8 ml aliquot may allow for two or possibly three or four injections per vial, whereas Definity™, supplied in a 1.3 ml vial, which expands to 1.8 ml in solution may allow for multiple injections as needed (easily 6 or 7) as a standard bolus would generally be only 0.2–0.3 ml. For Sonazoid™ supplied in a 2 ml vial, a dose of 0.5–1.0 ml per injection (0.015 ml/kg) is recommended.
Repeated injection may occur in the following circumstances:
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There are additional nodules or observations, which require characterization.
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The initial injection may not provide the full answer to the characterization of a lesion, requiring a second injection to allow for assessment of missing information.
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A wash-out region may be identified on sweeps of the liver in either the PVP or the LP. Even if a corresponding nodule is not visible on the conventional B-mode images, arterial phase enhancement in the wash-out region can be characterized by re-injecting contrast material while keeping that region in the field of view.
For the first two indications above, the examiner usually should wait before reinjecting until the bubbles from the previous injection have disappeared or least greatly reduced, which usually requires 10 to 15 min for SonoVue™/Lumason™ and Definity™ also depending on patient age and constitution. The waiting period is much longer for Sonazoid™, the disappearance of bubbles may take longer than one hour. To expedite bubble destruction and reduce the delay for re-injection, continuous scanning at high MI, such as B-mode or colour Doppler can be performed including the heart and kidney. To assess arterial enhancement of a wash-out region that does not have a correlate on B-mode imaging, by comparison, the examiner should re-inject before bubbles have disappeared so as to maintain visibility of the wash-out region.
Continuous Infusion
Dynamic real-time characterization of focal liver masses with CEUS is best performed with a bolus technique. However, measurement of blood flow parameters for assessment of oncologic response to therapy is also possible with an infusion and the destruction-replenishment technique. The agent is, depending on the contrast agent, suspended in saline or other media and intravenously infused with controlled pressure, to avoid bubble destruction and at a constant rate to permit prolonged scanning. This technique provides a steady-state bubble concentration which can be used with the burst and replenish mode (manoeuvre) to generate multiple measurements. For Definity™, where bubble flotation is not usually an issue, the agent can be mixed in a 50 ml saline bag. For SonoVue™, a dedicated infusion pump is recommended. For more details see the EFSUMB guidelines 11 .
Contrast timer
All ultrasound scanners must have a visible timer. This timer should be started at the time of the beginning of the UCA injection for SonoVue™/Lumason™. With Definity™, no CA enters the body prior to the flush. The authors controversially discussed when to start the timer. Most (but not all) of the group agreed that the timer should be started at the beginning of the contrast injection. The application via a central venous line with much shorter arrival time is a good reason for this. It should be noted that in special situations (e. g., right heart insufficiency) contrast phases may appear at unusual time points including potential initial retrograde inflow via the liver vein.
Find a good compromise between the contrast dose and the equipment-specific settings.
Reference:
How to perform Contrast-Enhanced Ultrasound (CEUS)
Christoph F. Dietrich,1 Michalakis Averkiou,2 Michael Bachmann Nielsen,3 Richard G. Barr,4 Peter N. Burns,5 Fabrizio Calliada,6 Vito Cantisani,7 Byung Choi,8 Maria C. Chammas,9 Dirk-André Clevert,10 Michel Claudon,11 Jean-Michel Correas,12 Xin-Wu Cui,13 David Cosgrove,14 Mirko D’Onofrio,15 Yi Dong,16 JohnR. Eisenbrey,17 Teresa Fontanilla,18 Odd Helge Gilja,19 Andre Ignee,13 Christian Jenssen,20 Yuko Kono,21 Masatoshi Kudo,22 Nathalie Lassau,23 Andrej Lyshchik,17 Maria Franca Meloni,24 Fuminori Moriyasu,25 Christian Nolsøe,26 Fabio Piscaglia,27 Maija Radzina,28 Adrian Saftoiu,29 Paul S. Sidhu,30 Ioan Sporea,31 Dagmar Schreiber-Dietrich,32 Claude B. Sirlin,33 Maria Stanczak,17 Hans-Peter Weskott,34 Stephanie R. Wilson,35 Juergen Karl Willmann,36 Tae Kyoung Kim,37 Hyun-Jung Jang,37 Alexandar Vezeridis,38 and Sue Westerway39