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Contrast-Enhanced Ultrasound: Basic Technique in Liver and Kidney
Andrej Lyshchik, MD, PhD
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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

          1. Durot I et al: Contrast-enhanced ultrasound of malignant liver lesions. Abdom Radiol (NY). 43(4):819-847, 2018
          2. 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
          3. Wilson SR et al: CEUS LI-RADS: algorithm, implementation, and key differences from CT/MRI. Abdom Radiol (NY). 43(1):127-142, 2018
          4. Barr RG: How to develop a contrast-enhanced ultrasound program. J Ultrasound Med. 36(6):1225-1240, 2017
          5. Burrowes DP et al: Contrast-enhanced US approach to the diagnosis of focal liver masses. Radiographics. 37(5):1388-1400, 2017
          6. 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
          7. 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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          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

                  1. Durot I et al: Contrast-enhanced ultrasound of malignant liver lesions. Abdom Radiol (NY). 43(4):819-847, 2018
                  2. 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
                  3. Wilson SR et al: CEUS LI-RADS: algorithm, implementation, and key differences from CT/MRI. Abdom Radiol (NY). 43(1):127-142, 2018
                  4. Barr RG: How to develop a contrast-enhanced ultrasound program. J Ultrasound Med. 36(6):1225-1240, 2017
                  5. Burrowes DP et al: Contrast-enhanced US approach to the diagnosis of focal liver masses. Radiographics. 37(5):1388-1400, 2017
                  6. 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
                  7. 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