In recent years, contrast-enhanced ultrasound (CEUS) has emerged as a promising way to image children for certain indications. Unlike CT, fluoroscopy and nuclear medicine, CEUS is free from radiation and doesn’t require sedation, which is often needed for pediatric patients undergoing MR.

HealthCare Business News checked in with Dr. Kassa Darge, radiologist-in-chief at the Children’s Hospital of Philadelphia department of radiology, to discuss the state of CEUS today.

HCB News: You were an early adopter of contrast enhanced ultrasound (CEUS), can you tell us why you were initially interested in administering these exams?
Dr. Kassa Darge: My interest in CEUS began in the mid ‘90s when I was working in Germany. The initial idea was to try to replace the X-ray voiding cystourethrography with the use of ultrasound contrast agent and ultrasound scan. This meant — particularly 25 years ago — a significant reduction of radiation exposure to young children who are more vulnerable to the damage irradiation causes. I started with exploring the feasibility of using contrast ultrasound and initiated a comparative study with the X-ray voiding cystourethrography. The result was more than we expected. Not only was contrast ultrasound comparable to the X-ray voiding cystourethrography, but it exceeded in terms of detection of vesicoureteric reflux in children. Indeed, on average you found more than 10% of vesicoureteric reflux when using ultrasound with contrast than the fluoroscopic study. This was a great motivation to push for this study, now called contrast enhanced voiding urosonography (ceVUS) in Europe.

HCB News: Can you describe some of the best pediatric use cases for CEUS?
KD: There are a number of excellent pediatric use cases for CEUS. Let me start with the intracavitary administration of ultrasound contrast agent for the detection of vesicoureteric reflux. This not only replaces the X-ray fluoroscopic study voiding cystourethrography (VCUG) but also allows a more comfortable examination for the pediatric patient and a positive family experience. Why comfortable? The child can be in different positions when being scanned. The child can void in physiological positions — either sitting on a potty, preferably one that makes music when peeing is initiated, or in the case of a boy, can stand and pee in a urinal while being scanned from the back. The parents can access their child very closely. They can lie on the examination table with their child or sit close to them and hold them. That the ultrasound modality is diagnostically better than the X-ray one is the icing on the cake. A more sensitive and more comfortable test delivering a positive patient and family experience.

A second-best practice example is the case of an incidental liver lesion in a child. The default practice in the past is to refer the child to have a CT or an MR scan. What is the disadvantage of doing so? CT means significant radiation exposure, MR entails, for younger children in particular, sedation or anesthesia, with their own disadvantages. In addition, both are more expensive and not as easy as ultrasound to schedule. However, the use of contrast ultrasound allows just-in-time study with real-time dynamic imaging that delivers definite diagnosis, leaving out CT or MR. It is not hard to imagine the positive experience this diagnostic test will deliver to the patients and families.

HCB News: CEUS is beneficial for patients, particularly pediatric patients, because it uses no radiation. Are there other reasons why it may be preferable over other imaging techniques?
KD: For one imaging modality to be regarded equal or better, the driving force is the comparable diagnostic results. All other ancillary stuff is secondary. If the former is fulfilled an imaging modality will struggle to be used in place of the existing ones. In the case of contrast ultrasound in children, in many comparisons it is equal to or better than the conventional imaging modalities in terms of its diagnostic capability. In addition to this main advantage there are a number of additional ones as follows.

– Pediatric patients, particularly those younger than 7 years, often require sedation or anesthesia to carry out an MR exam. This adds complexity to the imaging service: coordination of scheduling, space for pre- and post-sedation/anesthesia care, specialized personnel, more MR room time, and higher study cost. Furthermore, the potential negative effects of sedation/anesthesia on the developing brain cannot be ignored. If an MR study with sedation/anesthesia can be replaced by contrast US, the advantage is enormous.

– Safer imaging practice for children is strongly advocated by the “Image Gently” campaign. The campaign has resulted in a significant reduction in radiation exposure to children by advocating for the implementation of various processes and methods to lower radiation exposure, including low-dose CT and pulsed fluoroscopy. Contrast US goes further by eliminating radiation completely when it fully replaces a diagnostic imaging study that uses ionizing radiation.

- A positive patient and family experience is particularly important in pediatric imaging. Children require more ancillary comfort measures than adults to conduct a study. Often the child’s parent or guardian is present for the examination and therefore their needs are also taken into consideration. Thus, it is necessary to satisfy the requirements of not one but two or three persons. Compared to fluoroscopy, CT or MR studies, US can offer a more child-friendly environment by virtue of having a small imaging transducer and without an associated equipment enclosure surrounding the patient. Parents or guardians are also able to access their child much more easily. An ultrasound scan can be performed with the child in different positions, including with a parent or guardian holding the child or on the exam bed with the child.

– The fact that contrast US can be carried out at the bedside has enormous implications. This avoids transporting children from an intensive care unit (ICU) to a CT or MR scanner, a benefit that is particularly useful for very ill children with multiple medical support devices. Bedside contrast US exams also open up new indications for CEUS in the ICU that can positively impact the management of the patients (e.g., monitoring brain perfusion).

HCB News: You founded CHOP's Center of Pediatric Contrast Ultrasound (CPCU) in 2017. Can you tell us what the center does and why you saw a need for it?
KD: The idea to establish the CPCU stemmed from the need to consolidate all the efforts in advancing an important, impactful and practice-changing diagnostic modality for children. The mission of the CPCU is to support the implementation of various clinical indications for CEUS in our institution, to support basic science and clinical pediatric contrast ultrasound research and to advance at a local, national and international level pediatric-focused contrast ultrasound education. All these three points have been realized and are continually expanding through the leadership and support of the CPCU. The CPCU has a director — a pediatric radiologist (Susan Back, M.D.) and a sonographer (Laura Poznick, RDMS) thus encompassing all essential professionals to push forward this modality. At CHOP the CPCU has been instrumental in the implementation of CEUS in the intravenous route, de facto from head to toe; the intravesical administration, primarily for vesicoureteric reflux; multiple interventional uses, and recently the novel intralymphatic use. The CPCU has been instrumental in the establishment and support of two basic science pediatric-focused contrast ultrasound research groups that have animal labs for research supported by ultrasound Ph.D. researchers as well as many clinical studies including four using investigational drug approvals (INDs) from the Food and Drug Administration. Lastly, the educational impact has been significant. Pre-COVID the CPCU held monthly in-person workshops at CHOP with live exams but since last year converted to webinars. The first 2 have been well attended and successful. The CPCU has been instrumental in training over 200 pediatric radiologists and sonographers and supporting the initiation of contrast ultrasound in more than 50 pediatric centers in the United States.

HCB News: Is it fair to say that many providers were slow to adopt CEUS? If so, is that still the case?
KD: Before the ultrasound contrast agent in 2016 many providers were slow in implementing off-label use of CEUS. Once the approval came through, we found, through a national survey, that the main bottleneck in advancing pediatric CEUS was the lack of available educational opportunities to start the method. We changed this by implementing through the CPCU educational opportunities, as well as by organizing educational sessions on CEUS at the Society of Pediatric Radiology (SPR) and AIUM annual meetings. Certainly, the COVID-19 pandemic has added a damper to the advancement like many other issues, but it is now picking up.

HCB News: What is the reimbursement situation like for CEUS?
KD: With the approval of the ultrasound contrast agent Lumason, the reimbursement possibility came about. Both the intravenous and intracavitary exams in children are reimbursed. There is a detailed reimbursement explanation of the website of the International Contrast Ultrasound Society (ICUS)

HCB News: Ultrasound contrast has a black box on its label, indicating a high risk of adverse events. Why is there controversy around that?
KD: In 2007 the FDA mandated a black box warning on the package insert of approved UCA in the United States. This black box warning described the possibility of serious cardiopulmonary reactions, including fatalities, following the use of any of the UCAs. A black box warning (or boxed warning) is the strictest labeling requirement that the FDA can issue for medical products. It aims to alert the public and healthcare providers regarding the possibility of serious adverse reactions associated with the use of that product, including serious injury or death. While black box warnings are an important tool for informing the public and can decrease use of medical products in high-risk populations, they may also discourage the use of medical products in people who would benefit from them. The boxed warning for UCA was issued in response to spontaneous reports of a small number of serious adverse events that occurred in adults after UCA administration in the early years of its introduction. However, the reported serious adverse events were not definitely attributed to UCA, and some were later ascribed to underlying medical conditions and/or other medication. Since the issue of the black box warning, cumulative relevant scientific literature continues to show that UCA have a very safe profile. Currently there is an ongoing citizen petition initiative from the ICUS for the removal of the boxed warnings from the UCA product labels.

HCB News: Many CEUS advocates have petitioned to have the black box removed. Has there been any progress on that front?
KD: ICUS submitted a citizen petition in September 2018, updated in August 2020, for the removal of the boxed warnings from the UCA product labels. We are still waiting for the FDA response.

HCB News: For providers who are interested in learning more about CEUS, or introducing the exam at their facility, what resources can you recommend?
KD: A number of very useful resources are available on adult contrast US, but only a few on pediatric contrast US. Information on adult contrast US can still have a lot of utility for pediatric applications. Useful resources include the ICUS website which offers comprehensive information on contrast US, including specific information on setting up a CEUS lab, protocols, guidelines, coding and payment, and an ICUS sonographer policy. The European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) website presents comprehensive guidelines and recommendations for CEUS of the liver and non-hepatic applications as well as dynamic CEUS for quantification of tumor perfusion. The World Federation for Ultrasound in Medicine and Biology (WFUMB) website offers an open access publication on “How to perform CEUS.” The Contrast-Enhanced Ultrasound Taskforce of the Society for Pediatric Radiology (SPR) website has information dedicated to pediatric contrast US as well as illustrative examples. Courses of variable length and depth on pediatric contrast US are offered at various meetings, including SPR, ICUS, European Society of Paediatric Radiology (ESPR), American Institute of Ultrasound (AIUM), Radiological Society of North America (RSNA), Society of Radiologists in Ultrasound (SRU) and EFSUMB, among others. More in-depth courses focused on pediatric contrast US are helpful in providing intensive and hands-on experience that speeds the ability to start a pediatric contrast US service. For instance, King’s College in London, under the auspices of the Euroson School and the British Medical Ultrasound Society (BMUS), hosts a comprehensive pediatric contrast US course every 1–2 years. The Center for Pediatric Contrast Ultrasound (CPCU) at Children’s Hospital of Philadelphia hosts almost monthly one-day intensive workshops encompassing in vitro and phantom demonstrations as well as live patient exams. Due to the pandemic the CPCU has converted its courses to virtual webinars.