CEUS: US examination performed after administration of microbubble-based contrast agent
APHE: Increased enhancement of focal lesion in arterial phase compared to normal surrounding parenchyma
Examiner Training Requirements
Appropriate training of paramount importance for successful CEUS examination
Most robust training guidelines developed by European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB)
US Contrast Agents
Lumason (sulfur hexafluoride lipid-type A microspheres, Bracco Diagnostics Inc., Monroe Township, NJ)
Marketed as SonoVue outside USA
Supplied as 25-mg vial of lipid-type A lyophilized powder and headspace fill of 60.7 mg sulfur hexafluoride
Reconstituted with 5 mL of sodium chloride 0.9% and can be used for several hours afterward
Definity (Perflutren Lipid Microsphere, Lantheus Medical Imaging Inc., N. Billerica, MA)
Supplied as 2-mL clear glass vial containing lipid blend and headspace fill of 6.52 mg/mL octafluoropropane
Vials activated by shaking for 45 seconds using proprietary VIALMIX activation device
Requires refrigerated storage
Optison (Perflutren protein-type A microspheres, GE Healthcare, Prinston, NJ)
Supplied as injectable suspension of protein-type A microspheres, 10 mg human albumin, and perflutren in 3-mL vials
Activation only requires gentle vial rotation to re-suspend microspheres
Requires refrigerated storage
Evidence for successful use in liver imaging lacking
Safety Considerations
Microbubble contrast agents generally well tolerated with only rare adverse events
US contrast agents have no known renal toxicity in approved doses
Large retrospective multicenter study of US contrast agent safety, including over 10,000 doses, showed severe allergic reactions in only 8 patients (0.01% incidence) and allergoid reactions in only 4 patients (0.006% incidence)
Study of 16,025 patients undergoing CEUS demonstrated 0.12% overall rate of adverse effects and 0.031% incidence of serious events, with no fatalities
In postmarketing surveillance of 1,651,451 patients exposed to SonoVue from 2001 to 2010, 0.013% incidence of serious adverse events and 0.0098% incidence of allergy-like or anaphylactoid reactions
Similar to CT and MR, all US contrast injections should be performed in appropriate settings and supervised by board-certified physician
Resuscitation equipment and trained personnel should be immediately available to patient during each contrast-enhanced examination
Contrast reactions should be managed in accordance to standard contrast guidelines as described in ACR Manual on Contrast Media
US Equipment
US scanners with appropriate software and hardware packages for CEUS must be used
US contrast agents visualized by separating soft tissue signal from microbubbles based on nonlinear resonance of microbubbles
Successful soft tissue cancellation in contrast mode produces near-complete disappearance of soft tissue signal in CEUS window, which is normal without presence of microbubbles
To minimize disruption of US contrast agent, CEUS imaging performed at low acoustic pressures with mechanical index (MI) ranging from 0.05-0.3
Patient Positioning
Patients should be in comfortable position, similar to routine US examination
Transducer positioned in approach whereby precontrast B-mode imaging best defines lesion with minimal out-of-plane motion with respiration
Acoustic window should allow target lesion to be continuously visible during entire examination
Contrast Administration
Recommended dose of US contrast agents for liver imaging is 2.4 mL of Lumason, 0.2 mL of Definity, or 1 mL for Optison
Several factors can influence dose of US contrast for particular examination
In patients with low BMI, dose of contrast could be decreased by 20-25% to avoid overenhancement
Imaging of very superficial liver lesions with higher frequency probes often requires doubling of contrast dose
Dose of contrast should be adjusted based on sensitivity of equipment used for CEUS examination
Contrast Injection
US contrast agent injection should be performed through 18- to 22-g IV line
Use of smaller caliber lines not recommended to prevent microbubble destruction
Injection through central venous lines and infusion ports is acceptable as long as all safety and aseptic requirements are met
Contrast bolus should be delivered over 2-3 seconds
Care should be taken to prevent increase in contrast syringe pressure, since this can destroy microbubbles within syringe, leading to reduced enhancement and image quality
Bolus of contrast should be immediately followed by 5-10 mL normal saline flush delivered at rate of ~ 2 mL/second
Contrast Timer
If contrast injection into IV line extension, scanner’s contrast timer usually applied
By convention, contrast timer started at end of contrast injection and simultaneous with onset of saline flush
Start of contrast timer should be kept consistent to avoid mistiming of contrast washout
Imaging Parameters
CEUS imaging should be performed in dual-screen format displaying low MI B-mode image alongside contrast-only display
This approach provides anatomic guidance and ensures target lesion kept within field of view during imaging
In dual screen-imaging, both B-mode and contrast images created using same low MI technique, which usually results in some degree of B-mode image quality degradation
Gain settings allow examiner to adjust both B-mode and CEUS signal amplification
Setting gain too low will result in significant signal loss
Setting gain too high will increase nonspecific image noise resulting in pseudoenhancement
Gain setting should be set as high as possible, providing adequate soft tissue suppression without displaying pseudoenhancement, so contrast mode image looks almost devoid of signal before arrival on contrast
Appropriate placement of focal zone another very important step to ensure high quality of imaging
Focal zone should be positioned just deep to target lesion for most US scanners
Liver and Kidney CEUS Protocol
Continuous insonation of large portions of highly vascular tissues (i.e., liver or renal parenchyma) will result in excessive destruction of microbubbles and substantial decrease in degree of contrast enhancement in late phase
To maximize benefits of real-time CEUS imaging and to preserve enough microbubbles to allow late contrast washout detection, CEUS protocols usually based on combination of continuous imaging in arterial phase and intermittent imaging in late phases
Liver CEUS best performed with adherence to following protocol
Imaging
Should be performed continuously from contrast injection at least until peak arterial-phase enhancement, which usually occurs 20-40 seconds after contrast injection
Alternatively, continuous imaging can be extended beyond peak AP enhancement until 60 seconds after contrast injection to determine presence of early washout
After 60 seconds, imaging should be performed intermittently (5-10 seconds every 30-60 seconds) to detect late washout and assess its degree
This technique will minimize microbubble destruction and improve ability to detect late washout and assess its degree
Image recording
Should be performed continuously from 1st bubble arrival through peak AP enhancement as minimum requirement
Optionally, cine loop can be continued beyond AP enhancement peak until 60 seconds after injection
After 60 seconds, recording of static images at 60 seconds and with every intermittent (every 30-60 seconds) acquisition thereafter will be sufficient to document and evaluate presence, timing, and degree of washout
Sweeping entire liver or kidney in late phase can help to identify additional areas of contrast washout
Renal CEUS protocol can be shortened with potential elimination of delayed CEUS imaging if lesion in question fully characterized during early phases
Technical Pitfalls and Challenges
One of the most important CEUS limitations is its inability to examine entire liver or both kidneys in arterial phase, since only part of organ (usually containing region of interest with focal observation) can be imaged with each US contrast injection
Imaging of multiple nodules often requires multiple injections and careful planning of patient positioning to maximize use of limited acoustic windows
Evaluation of focal observations in contralateral kidney often requires additional contrast injection
Repeat injection should be performed in accordance with contrast manufacturer guidelines
Some small lesions, usually < 10 mm, or lesions with subdiaphragmatic or very deep location can be challenging to visualize on CEUS
As a basic rule, if lesion difficult to clearly identify on precontrast B-mode imaging, it may be challenging to produce high-quality CEUS images
CEUS might also be limited in patients with high BMI and in patients with severe hepatic steatosis, mainly due to substantial signal attenuation
Selected References
Durot I et al: Contrast-enhanced ultrasound of malignant liver lesions. Abdom Radiol (NY). 43(4):819-847, 2018
Lyshchik A et al: Contrast-enhanced ultrasound of the liver: technical and lexicon recommendations from the ACR CEUS LI-RADS working group. Abdom Radiol (NY). 43(4):861-879, 2018
Wilson SR et al: CEUS LI-RADS: algorithm, implementation, and key differences from CT/MRI. Abdom Radiol (NY). 43(1):127-142, 2018
Barr RG: How to develop a contrast-enhanced ultrasound program. J Ultrasound Med. 36(6):1225-1240, 2017
Burrowes DP et al: Contrast-enhanced US approach to the diagnosis of focal liver masses. Radiographics. 37(5):1388-1400, 2017
Claudon M et al: Guidelines and good clinical practice recommendations for Contrast Enhanced Ultrasound (CEUS) in the liver - update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultrasound Med Biol. 39(2):187-210, 2013
Sidhu PS et al: The EFSUMB Guidelines on the Non-hepatic Clinical Applications of Contrast Enhanced Ultrasound (CEUS): a new dawn for the escalating use of this ubiquitous technique. Ultraschall Med. 33(1):5-7, 2012
Related Anatomy
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Related Differential Diagnoses
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References
Tables
Tables
KEY FACTS
Terminology
Available Contrast Agents
Principles of Image Formation
CEUS Protocol
TERMINOLOGY
Abbreviations
Arterial-phase hyperenhancement (APHE)
Definitions
CEUS: US examination performed after administration of microbubble-based contrast agent
APHE: Increased enhancement of focal lesion in arterial phase compared to normal surrounding parenchyma
Examiner Training Requirements
Appropriate training of paramount importance for successful CEUS examination
Most robust training guidelines developed by European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB)
US Contrast Agents
Lumason (sulfur hexafluoride lipid-type A microspheres, Bracco Diagnostics Inc., Monroe Township, NJ)
Marketed as SonoVue outside USA
Supplied as 25-mg vial of lipid-type A lyophilized powder and headspace fill of 60.7 mg sulfur hexafluoride
Reconstituted with 5 mL of sodium chloride 0.9% and can be used for several hours afterward
Definity (Perflutren Lipid Microsphere, Lantheus Medical Imaging Inc., N. Billerica, MA)
Supplied as 2-mL clear glass vial containing lipid blend and headspace fill of 6.52 mg/mL octafluoropropane
Vials activated by shaking for 45 seconds using proprietary VIALMIX activation device
Requires refrigerated storage
Optison (Perflutren protein-type A microspheres, GE Healthcare, Prinston, NJ)
Supplied as injectable suspension of protein-type A microspheres, 10 mg human albumin, and perflutren in 3-mL vials
Activation only requires gentle vial rotation to re-suspend microspheres
Requires refrigerated storage
Evidence for successful use in liver imaging lacking
Safety Considerations
Microbubble contrast agents generally well tolerated with only rare adverse events
US contrast agents have no known renal toxicity in approved doses
Large retrospective multicenter study of US contrast agent safety, including over 10,000 doses, showed severe allergic reactions in only 8 patients (0.01% incidence) and allergoid reactions in only 4 patients (0.006% incidence)
Study of 16,025 patients undergoing CEUS demonstrated 0.12% overall rate of adverse effects and 0.031% incidence of serious events, with no fatalities
In postmarketing surveillance of 1,651,451 patients exposed to SonoVue from 2001 to 2010, 0.013% incidence of serious adverse events and 0.0098% incidence of allergy-like or anaphylactoid reactions
Similar to CT and MR, all US contrast injections should be performed in appropriate settings and supervised by board-certified physician
Resuscitation equipment and trained personnel should be immediately available to patient during each contrast-enhanced examination
Contrast reactions should be managed in accordance to standard contrast guidelines as described in ACR Manual on Contrast Media
US Equipment
US scanners with appropriate software and hardware packages for CEUS must be used
US contrast agents visualized by separating soft tissue signal from microbubbles based on nonlinear resonance of microbubbles
Successful soft tissue cancellation in contrast mode produces near-complete disappearance of soft tissue signal in CEUS window, which is normal without presence of microbubbles
To minimize disruption of US contrast agent, CEUS imaging performed at low acoustic pressures with mechanical index (MI) ranging from 0.05-0.3
Patient Positioning
Patients should be in comfortable position, similar to routine US examination
Transducer positioned in approach whereby precontrast B-mode imaging best defines lesion with minimal out-of-plane motion with respiration
Acoustic window should allow target lesion to be continuously visible during entire examination
Contrast Administration
Recommended dose of US contrast agents for liver imaging is 2.4 mL of Lumason, 0.2 mL of Definity, or 1 mL for Optison
Several factors can influence dose of US contrast for particular examination
In patients with low BMI, dose of contrast could be decreased by 20-25% to avoid overenhancement
Imaging of very superficial liver lesions with higher frequency probes often requires doubling of contrast dose
Dose of contrast should be adjusted based on sensitivity of equipment used for CEUS examination
Contrast Injection
US contrast agent injection should be performed through 18- to 22-g IV line
Use of smaller caliber lines not recommended to prevent microbubble destruction
Injection through central venous lines and infusion ports is acceptable as long as all safety and aseptic requirements are met
Contrast bolus should be delivered over 2-3 seconds
Care should be taken to prevent increase in contrast syringe pressure, since this can destroy microbubbles within syringe, leading to reduced enhancement and image quality
Bolus of contrast should be immediately followed by 5-10 mL normal saline flush delivered at rate of ~ 2 mL/second
Contrast Timer
If contrast injection into IV line extension, scanner’s contrast timer usually applied
By convention, contrast timer started at end of contrast injection and simultaneous with onset of saline flush
Start of contrast timer should be kept consistent to avoid mistiming of contrast washout
Imaging Parameters
CEUS imaging should be performed in dual-screen format displaying low MI B-mode image alongside contrast-only display
This approach provides anatomic guidance and ensures target lesion kept within field of view during imaging
In dual screen-imaging, both B-mode and contrast images created using same low MI technique, which usually results in some degree of B-mode image quality degradation
Gain settings allow examiner to adjust both B-mode and CEUS signal amplification
Setting gain too low will result in significant signal loss
Setting gain too high will increase nonspecific image noise resulting in pseudoenhancement
Gain setting should be set as high as possible, providing adequate soft tissue suppression without displaying pseudoenhancement, so contrast mode image looks almost devoid of signal before arrival on contrast
Appropriate placement of focal zone another very important step to ensure high quality of imaging
Focal zone should be positioned just deep to target lesion for most US scanners
Liver and Kidney CEUS Protocol
Continuous insonation of large portions of highly vascular tissues (i.e., liver or renal parenchyma) will result in excessive destruction of microbubbles and substantial decrease in degree of contrast enhancement in late phase
To maximize benefits of real-time CEUS imaging and to preserve enough microbubbles to allow late contrast washout detection, CEUS protocols usually based on combination of continuous imaging in arterial phase and intermittent imaging in late phases
Liver CEUS best performed with adherence to following protocol
Imaging
Should be performed continuously from contrast injection at least until peak arterial-phase enhancement, which usually occurs 20-40 seconds after contrast injection
Alternatively, continuous imaging can be extended beyond peak AP enhancement until 60 seconds after contrast injection to determine presence of early washout
After 60 seconds, imaging should be performed intermittently (5-10 seconds every 30-60 seconds) to detect late washout and assess its degree
This technique will minimize microbubble destruction and improve ability to detect late washout and assess its degree
Image recording
Should be performed continuously from 1st bubble arrival through peak AP enhancement as minimum requirement
Optionally, cine loop can be continued beyond AP enhancement peak until 60 seconds after injection
After 60 seconds, recording of static images at 60 seconds and with every intermittent (every 30-60 seconds) acquisition thereafter will be sufficient to document and evaluate presence, timing, and degree of washout
Sweeping entire liver or kidney in late phase can help to identify additional areas of contrast washout
Renal CEUS protocol can be shortened with potential elimination of delayed CEUS imaging if lesion in question fully characterized during early phases
Technical Pitfalls and Challenges
One of the most important CEUS limitations is its inability to examine entire liver or both kidneys in arterial phase, since only part of organ (usually containing region of interest with focal observation) can be imaged with each US contrast injection
Imaging of multiple nodules often requires multiple injections and careful planning of patient positioning to maximize use of limited acoustic windows
Evaluation of focal observations in contralateral kidney often requires additional contrast injection
Repeat injection should be performed in accordance with contrast manufacturer guidelines
Some small lesions, usually < 10 mm, or lesions with subdiaphragmatic or very deep location can be challenging to visualize on CEUS
As a basic rule, if lesion difficult to clearly identify on precontrast B-mode imaging, it may be challenging to produce high-quality CEUS images
CEUS might also be limited in patients with high BMI and in patients with severe hepatic steatosis, mainly due to substantial signal attenuation
Selected References
Durot I et al: Contrast-enhanced ultrasound of malignant liver lesions. Abdom Radiol (NY). 43(4):819-847, 2018
Lyshchik A et al: Contrast-enhanced ultrasound of the liver: technical and lexicon recommendations from the ACR CEUS LI-RADS working group. Abdom Radiol (NY). 43(4):861-879, 2018
Wilson SR et al: CEUS LI-RADS: algorithm, implementation, and key differences from CT/MRI. Abdom Radiol (NY). 43(1):127-142, 2018
Barr RG: How to develop a contrast-enhanced ultrasound program. J Ultrasound Med. 36(6):1225-1240, 2017
Burrowes DP et al: Contrast-enhanced US approach to the diagnosis of focal liver masses. Radiographics. 37(5):1388-1400, 2017
Claudon M et al: Guidelines and good clinical practice recommendations for Contrast Enhanced Ultrasound (CEUS) in the liver - update 2012: a WFUMB-EFSUMB initiative in cooperation with representatives of AFSUMB, AIUM, ASUM, FLAUS and ICUS. Ultrasound Med Biol. 39(2):187-210, 2013
Sidhu PS et al: The EFSUMB Guidelines on the Non-hepatic Clinical Applications of Contrast Enhanced Ultrasound (CEUS): a new dawn for the escalating use of this ubiquitous technique. Ultraschall Med. 33(1):5-7, 2012
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