One More Reason to Advocate for Contrast-Enhanced Ultrasound in Children: No Current Shortage of Ultrasound Contrast Agents

Contrast-enhanced ultrasound (CEUS) is a valuable tool to evaluate the pediatric patient as it offers many of the diagnostic benefits of other imaging modalities such as CT or MRI but avoids potential risks including radiation exposure and sedation. Furthermore, CEUS is portable and can be performed at the patient’s bedside, which is particularly important in critically ill children where transportation to the radiology department may be difficult. Currently, in the United States, only one ultrasound contrast agent is FDA-approved for use in pediatric patients for intravesical use for contrast-enhanced voiding urosonography (ceVUS) and for intravenous use for characterization of liver lesions and cardiac indications. However, off-label use has greatly expanded the applications of this technology to the betterment of patients.

Grayscale (left) and contrast-enhanced (right) ultrasound of the left kidney in a 3-year-old boy incidentally found to have a renal lesion on prior spine MRI. Images demonstrate a predominately cystic complex lesion (circle). On contrast-enhanced images, the cystic components are clearly demonstrated with faint enhancement of thin septations allowing characterization of the lesion as a minimally complex renal cyst (Bosniak type 2F). Normal diffuse homogenous enhancement is seen in the remainder of the left renal parenchyma (arrows). In this case, the use of contrast-enhanced ultrasound for lesion characterization prevented radiation exposure, which would be required for CT, and sedation, which would be required for MRI.

Multiple studies have shown the feasibility and value of CEUS in a wide variety of applications including evaluation of the neonatal brain in hypoxic-ischemic injury, intraoperative characterization of brain lesions for real-time assessment of resection margins, initial and follow-up evaluations in the setting of solid abdominal organ trauma, quantification of femoral head perfusion before and after developmental hip dysplasia reduction, and intraoperative ceVUS to visualize vesicoureteral reflux and assess the efficacy of bladder bulking agent injections and possible requirement for additional surgical procedures. This is to name just a few!

Additionally, CEUS has been utilized by Interventional Radiology departments in many troubleshooting situations including evaluation of vascular access/thrombosis, identifying solid tumor components for biopsy, visualizing non-solid abscess contents for accurate drain placement, and lymph node injection for evaluation of the lymphatic drainage pathways. Again, this is a limited list of uses! Essentially, any diagnostic or therapeutic situation that would benefit from real-time bedside evaluation of organs, lesions, vessels (or anything in the human body) could potentially benefit from CEUS.

Despite the widespread applications of CEUS, few centers regularly employ this technique or only use it in select cases. Concerns about contrast agent side effects, including anaphylaxis, have been consistently demonstrated to be minimal and lower than other contrast agents routinely utilized in imaging studies and the safety of ultrasound contrast agents has been continually proven over time. While appropriate monitoring and preparation for severe reactions is mandatory, this is not dissimilar to safety practices with CT and MRI contrast agents. Speaking of which, current CT contrast shortages and uncertain implications of gadolinium deposition with MRI contrast agents further bolster support for using CEUS as a first-line imaging modality.

Even after explaining the relatively high benefit-to-risk ratio in this patient population, advocates for CEUS continue to find resistance to broader use. Some obstacles to wider implementation include staff training and requirement of a radiologist during the CEUS, which is currently standard practice. Select institutions offer CEUS training courses for technologists and physicians to familiarize them with technique and workflow management. Like any new procedure, education, experience, and departmental support allow increasing confidence and ease of implementation. Despite adequate technologist and nursing staff familiarity, in this time of ever-growing imaging study volumes and hospital staffing shortages, requiring the physical attendance of a radiologist for a CEUS examination is less than ideal. However, this allows valuable support for the technologist and for the radiologist to communicate directly with the patient and family providing an immeasurable face-to-face interaction that cannot be replicated in the reading room.

To summarize, CEUS is an incredibly valuable tool in evaluating children with vast clinical applications, the list of which continues to grow over time. If you have a patient and ask yourself “could CEUS add information with high benefit-to-risk ratio,” the answer is often “yes.” But lack of widespread awareness and implementation lead to clinicians never asking that question or even considering the potential benefit of CEUS in pediatric patients. A growing community of Pediatric Diagnostic and Interventional Radiologists would like to change that in the future.

If you are using CEUS at your institution, what kind of scenarios (standard and unique) have you found CEUS to be helpful? If you are not using CEUS at your institution, what do you see as current obstacles? What would be required or helpful for you to implement in your practice?

Ryne Didier, MD, is a Pediatric Radiologist at the Children’s Hospital of Philadelphia (@CHOPRadiology). Her clinical and research interests include prenatal imaging and emerging ultrasound imaging techniques and applications.

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A Quick Introduction to Subharmonic Imaging and Pressure Estimation

Our imaging field has had access to commercial microbubble-based ultrasound contrast agents for well over twenty years by now. It is well established that these agents—combined with nonlinear contrast-specific imaging techniques—improve both the sensitivity and specificity of ultrasound diagnoses across a wide range of clinical applications.

There are currently 3 ultrasound contrast agents approved by the United States’ Food and Drug Administration (FDA) for cardiology and/or radiology applications: Optison (GE Healthcare, Princeton, NJ); Definity (Lantheus Medical Imaging, N Billerica, MA); and Lumason (marketed for more than a decade in Europe and elsewhere as SonoVue; Bracco Imaging, Milan, Italy). There are other contrast agents in commercial development around the world; in particular Sonazoid (GE Healthcare) and BR55 (Bracco Imaging). Very importantly, the safety profiles of all of these agents are also well established with a severe reaction rate of less than 0.01% (based on studies of millions of dosages injected worldwide), making them the safest of all contrast media used for imaging.

Flemming Forsberg, PhD

Ultrasound agents consist of billions of gas microbubbles (typically < 8 mm in diameter) that are each encapsulated by an outer shell for stability. Following an intravenous injection, the microbubbles can traverse the lung capillaries and circulate in the blood for 3–6 minutes (under continuous imaging—longer if intermittent imaging is employed), due to their size and the higher molecular weight gasses used as filling gasses (rather than just air as was used in earlier microbubble designs), which reduces diffusion back into solution.

The acoustic properties of the bubble filing gasses (specifically the compressibility) are very different from those of the surrounding blood (by six orders of magnitude). Hence, microbubble-based ultrasound contrast agents can enhance ultrasound signals markedly with echo signals being increased by up to 30 dB. This in turn enables signals from breast tumor neovascularity corresponding mainly to vessels 20–39 mm in diameter to be imaged.

Ultrasound contrast agents not only enhance the backscattered ultrasound signals, but at sufficient acoustic pressures (typically above 0.3 MPa) they also act as nonlinear oscillators. These oscillations generate significant energy components in the received echo signals, which span the range of possible frequency emissions from subharmonics through ultra-harmonic frequency components. These nonlinear bubble echoes can be separated from tissue echoes and used to create contrast-sensitive imaging modalities such as harmonic imaging (HI), which is commercially available on most state-of-the-art ultrasound scanners.

Multi-pulse imaging strategies, such as pulse-inversion imaging or pulse-amplitude modulation, can further improve the depiction of microvascularity compared to color Doppler imaging modes. However, HI suffers from reduced blood-to-tissue contrast resulting from second harmonic generation and accumulation in tissue. Hence, subharmonic imaging (SHI), transmitting at the fundamental frequency (f0) and receiving at the subharmonic (f0/2), becomes an attractive alternative because of the weaker subharmonic generation in tissue and the significant subharmonic scattering produced by some new contrast agents. Several ultrasound scanners (from GE Healthcare and Mindray) have now been released with commercial SHI software packages. A recent multi-center study of 3D SHI for characterizing suspicious breast lesions indicates that diagnostic accuracies up to 97% can be achieved.

Ultrasound contrast agents can be used not only as vascular tracers but also as sensors for noninvasive pressure estimation by monitoring subharmonic contrast bubble amplitude variations. This innovative technique, called subharmonic-aided pressure estimation (SHAPE), relies on the inverse linear correlation (r2 > 0.90) between the amplitude of the subharmonic signals and hydrostatic pressure (up to 186 mmHg) measured in vitro for most (but not all) commercial contrast agents. SHAPE offers the possibility of allowing pressure gradients in the heart and throughout the cardiovascular system as well as interstitial fluid pressure in tumors to be obtained noninvasively. Studies indicate that SHAPE can provide in vivo pressure estimates with errors of less than 5 mmHg in the left and right ventricles of patients. Moreover, a large multi-center clinical trial of using SHAPE to diagnose clinically significant portal hypertension in 178 subjects resulted in a sensitivity of 91% and a specificity of 82% and these subjects had a higher SHAPE gradient than participants with lower pressures (0.27 ± 2.13 dB vs -5.34 ± 3.29 dB; p<0.001) indicating SHAPE may indeed be a useful tool for the diagnosis of portal hypertension.

Flemming Forsberg, PhD, FAIUM, FAIMBE, is a Professor of Radiology at Thomas Jefferson University in Philadelphia, Pennsylvania. He also serves as a Deputy Editor of the Journal of Ultrasound in Medicine and as the Vice Chair of the American Institute of Ultrasound in Medicine’s (AIUM’s) Contrast-Enhanced Ultrasound Community (2021–2023).

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