Safety of Ultrasound Contrast Agents in Pediatric Patients With Sickle Cell Disease and Trait.

Ultrasound contrast agent (UCA) use is increasing. Recent isolated reports observed a rise in pain-related adverse events with the intravenous administration of the UCA Definity in adults with sickle cell disease. To date, no studies have investigated the incidence of similar adverse events with UCA Lumason or Optison. We describe our experience regarding the safety of Lumason and Optison in children with sickle cell disease and trait who underwent contrast-enhanced ultrasound exams in our department with intravenous, intravesical, and other intracavitary routes. No pain-related or other adverse events were observed in this pediatric population with any route of UCA administration.

Imaging of anorectal malformations: where are we now? Abdominal imaging task force of the European Society of Paediatric Radiology.

Anorectal and cloacal malformations are a broad mix of congenital abnormalities related to the distal rectum and anus. Confusion exists between all the forms in this large and heterogeneous group. The spectrum includes everything from anal stenosis, ventral anus, anal atresia (with and without fistula) and the full spectrum of cloacal malformations. Imaging in these conditions is done through the whole armamentarium of radiologic modalities, with very different imaging strategies seen across the centres where these conditions are managed. In 2017, the European Society of Paediatric Radiology (ESPR) abdominal imaging task force issued recommendations on the imaging algorithm and standards for imaging anorectal malformations. This was followed by further letters and clarifications together with an active multispecialty session on the different imaging modalities for anorectal malformations at the 2018 ESPR meeting in Berlin. Through this paper, the abdominal task force updates its guidelines and recommended imaging algorithm for anorectal malformations.

Ultrasound contrast agents: microbubbles made simple for the pediatric radiologist.

The ability to provide prompt, real-time, easily accessible and radiation-free diagnostic assessments makes ultrasound (US) one of the most versatile imaging modalities. The introduction and development of stable microbubble-based ultrasound contrast agents (UCAs) in the early 1990s improved visualization of complex vascular structures, overcoming some of the limitations of B-mode and Doppler imaging. UCAs have been used extensively in the adult population to visualize vasculature and to evaluate perfusion and blood flow dynamics in organs and lesions. Since the first observations that air bubbles within a liquid can generate a strong echogenic effect, to the early makeshift approaches with agitated saline, and later to the development of industrially produced and federally approved UCAs, these agents have evolved to become both clinically and commercially viable. Perhaps the most exciting potential of UCAs is being uncovered by current research that explores the use of these agents for molecular imaging and therapeutic applications. As contrast-enhanced ultrasound (CEUS) becomes more widely available, it is important for pediatric radiologists to understand the physics of the interaction between the US signal and the microbubbles in order to properly utilize them for the highest level of diagnostic imaging and interventions. In this article we introduce the composition of UCAs and the physics of their behavior in US, and we offer a brief history of their development over the last decades.

Contrast-enhanced ultrasound for musculoskeletal indications in children.

The increasing use of contrast-enhanced ultrasound (CEUS) has opened exciting new frontiers for musculoskeletal applications in adults and children. The most common musculoskeletal-related CEUS applications in adults are for detecting inflammatory joint diseases, imaging skeletal muscles and tendon perfusion, imaging postoperative viability of osseous and osseocutaneous tissue flaps, and evaluating the malignant potential of soft-tissue masses. Pediatric musculoskeletal-related CEUS has been applied for imaging juvenile idiopathic arthritis and Legg-Calvé-Perthes disease and for evaluating femoral head perfusion following surgical hip reduction in children with developmental hip dysplasia. CEUS can improve visualization of the capillary network in superficial and deep tissues and also in states of slow- or low-volume blood flow. In addition, measurements of blood flow imaging parameters performed by quantitative CEUS are valuable when monitoring the outcome of treatment interventions. In this review article we present current experience regarding a wide range of CEUS applications in musculoskeletal conditions in adults and children, with emphasis on the latter, and discuss imaging techniques and CEUS findings in musculoskeletal applications.

Pediatric contrast-enhanced ultrasound: shedding light on the pursuit of approval in the United States.

For two decades, pediatric contrast US has been well accepted throughout Europe and other parts of the world outside the United States because of its high diagnostic efficacy and extremely favorable safety profile. This includes intravenous (IV) administration, contrast-enhanced US (CEUS) and the intravesical application, contrast-enhanced voiding urosonography (ceVUS). However, the breakthrough for pediatric contrast US in the United States did not come until 2016, when the U.S. Food and Drug Administration (FDA) approved the first pediatric indication for a US contrast agent. This initial approval covered the use of Lumason (Bracco Diagnostics, Monroe Township, NJ) for the evaluation of focal liver lesions via IV administration in children. A second pediatric indication followed shortly thereafter, when the FDA extended the use of Lumason for assessing known or suspected vesicoureteral reflux via intravesical application in children. Both initial pediatric approvals were granted without prospective pediatric clinical trials, based instead on published literature describing favorable safety and efficacy in children. Three years later, in 2019, the FDA approved Lumason for pediatric echocardiography following a clinical trial involving a total of 12 subjects at 2 sites. The story of how we achieved these FDA approvals spans more than a decade and involves the extraordinary dedication of two professional societies, namely the International Contrast Ultrasound Society (ICUS) and the Society for Pediatric Radiology (SPR). Credit also must be given to the FDA staff for their commitment to the welfare of children and their openness to compelling evidence that contrast US is a safe, reliable, radiation-free imaging option for our pediatric patients. Understanding the history of this approval process will impact the practical application of US contrast agents, particularly when expanding off-label indications in the pediatric population. This article describes the background of the FDA's approval of pediatric contrast US applications to better illuminate the potential pathways to approvals of future indications.

Contrast-enhanced genitosonography and colosonography: emerging alternatives to fluoroscopy.

Imaging plays a crucial role in evaluating newborns and infants with cloacal and urogenital malformations. Contrast-enhanced genitosonography (ceGS) and contrast-enhanced colosonography (ceCS) are sensitive and radiation-free alternatives to fluoroscopic genitography and colography for diagnosis and surgical planning. These imaging techniques are performed by instilling a US contrast agent into specific body cavities to define the genitourinary and colorectal anatomy. This review article presents the experience with ceGS and ceCS applications in children, focusing on the background, examination technique, and interpretation of imaging findings, as well as strengths and weaknesses compared to conventional techniques.

Contrast-enhanced ultrasound of transplant organs - liver and kidney - in children.

Ultrasound (US) is the first-line imaging tool for evaluating liver and kidney transplants during and after the surgical procedures. In most patients after organ transplantation, gray-scale US coupled with color/power and spectral Doppler techniques is used to evaluate the transplant organs, assess the patency of vascular structures, and identify potential complications. In technically difficult or inconclusive cases, however, contrast-enhanced ultrasound (CEUS) can provide prompt and accurate diagnostic information that is essential for management decisions. CEUS is indicated to evaluate for vascular complications including vascular stenosis or thrombosis, active bleeding, pseudoaneurysms and arteriovenous fistulas. Parenchymal indications for CEUS include evaluation for perfusion defects and focal inflammatory and non-inflammatory lesions. When transplant rejection is suspected, CEUS can assist with prompt intervention by excluding potential underlying causes for organ dysfunction. Intracavitary CEUS applications can evaluate the biliary tract of a liver transplant (e.g., for biliary strictures, bile leak or intraductal stones) or the urinary tract of a renal transplant (e.g., for urinary obstruction, urine leak or vesicoureteral reflux) as well as the position and patency of hepatic, biliary and renal drains and catheters. The aim of this review is to present current experience regarding the use of CEUS to evaluate liver and renal transplants, focusing on the examination technique and interpretation of the main imaging findings, predominantly those related to vascular complications.

Starting a pediatric contrast ultrasound service: made simple!

The addition of contrast US to an existing pediatric US service requires several preparatory steps. This overview provides a guide to simplify the process. Initially, it is important to communicate to all stakeholders the justifications for pediatric contrast US, including (1) its comparable or better diagnostic results relative to other modalities; (2) its reduction in procedural sedation or anesthesia by avoiding MRI or CT; (3) its reduction or elimination of radiation exposure by not having to perform fluoroscopy or CT; (4) the higher safety profile of US contrast agents (UCA) compared to other contrast agents; (5) the improved exam comfort and ease inherent to US, leading to better patient and family experience, including bedside US exams for children who cannot be transported; (6) the need for another diagnostic option in light of increasing demand by parents and providers; and (7) its status as an approved and reimbursable exam. It is necessary to have an UCA incorporated into the pharmacy formulary noting that only SonoVue/Lumason is currently approved for pediatric use. In the United States this UCA is approved for intravenous administration for cardiac and liver imaging and for vesicoureteric reflux detection with intravesical application. In Europe and China it is only approved for the intravesical use in children. All other applications are off-label. The US scanner needs to be equipped with contrast-specific software. The UCA has to be prepared just before the exam and it is important to strictly follow the steps as outlined in the packaging inserts in order to prevent premature destruction of the microbubbles. The initial training in contrast US is best focused on the frontline staff actually performing the US studies; these might be sonographers, pediatric or interventional radiologists, or trainees. It is important from the outset to educate the referring physicians about contrast US. It is helpful to participate in existing contrast US courses, particularly those with hands-on components.

Contrast-enhanced ultrasound of the kidneys and adrenals in children.

Pediatric applications of contrast-enhanced ultrasound (CEUS) are growing. Evaluation of the kidneys and adrenal glands in children using intravenous administration of US contrast agents, however, is still an off-label indication. Pediatric CEUS applications for kidneys are similar to those in adults, including ischemic disorders, pseudo- versus real tumors, indeterminate lesions, complex cystic lesions, complicated pyelonephritis, and abscesses. CEUS applications for evaluation of adrenal glands in children are limited, mainly focusing on the assessment and follow-up of adrenal trauma and the differentiation between an adrenal hemorrhage and a mass. This review addresses the current experience in pediatric CEUS of the kidneys and adrenal glands. By extrapolating the established knowledge for US contrast evaluations in the adult kidney to the pediatric context we can note opportunities for CEUS clinical use in children.

Contrast-enhanced ultrasound: a comprehensive review of safety in children.

Contrast-enhanced ultrasound (CEUS) has been increasingly used in pediatric radiology practice worldwide. For nearly two decades, CEUS applications have been performed with the off-label use of gas-containing second-generation ultrasound contrast agents (UCAs). Since 2016, the United States Food and Drug Administration (FDA) has approved the UCA Lumason for three pediatric indications: the evaluation of focal liver lesions and echocardiography via intravenous administration and the assessment of vesicoureteral reflux via intravesical application (contrast-enhanced voiding urosonography, ceVUS). Prior to the FDA approval of Lumason, numerous studies with the use of second-generation UCAs had been conducted in adults and children. Comprehensive protocols for clinical safety evaluations have demonstrated the highly favorable safety profile of UCA for intravenous, intravesical and other intracavitary uses. The safety data on CEUS continue to accumulate as this imaging modality is increasingly utilized in clinical settings worldwide. As of August 2021, 57 pediatric-only original research studies encompassing a total of 4,518 children with 4,906 intravenous CEUS examinations had been published. As in adults, there were a few adverse events; the majority of these were non-serious, although very rarely serious anaphylactic reactions were reported. In the published pediatric-only intravenous CEUS studies included in our analysis, the overall incidence rate of serious adverse events was 0.22% (10/4,518) of children and 0.20% (10/4,906) of all CEUS examinations. Non-serious adverse events from the intravenous CEUS were observed in 1.20% (54/4,518) of children and 1.10% (54/4,906) of CEUS examinations. During the same time period, 31 studies with the intravesical use of UCA were conducted in 12,362 children. A few non-serious adverse events were encountered (0.31%; 38/12,362), but these were most likely attributable to the bladder catheterization rather than the UCA. Other developing clinical applications of UCA in children, including intracavitary and intralymphatic, are ongoing. To date, no serious adverse events have been reported with these applications. This article reviews the existing pediatric CEUS literature and provides an overview of safety-related information reported from UCA uses in children.

Contrast-enhanced ultrasound of the spleen, pancreas and gallbladder in children.

Gray-scale and color/power Doppler ultrasound (US) are the first-line imaging modalities to evaluate the spleen, gallbladder and pancreas in children. The increasing use of contrast-enhanced ultrasound (CEUS) as a reliable and safe method to evaluate liver lesions in the pediatric population promises potential for imaging other internal organs. Although CEUS applications of the spleen, gallbladder and pancreas have been well described in adults, they have not been fully explored in children. In this manuscript, we present an overview of the applications of CEUS for normal variants and diseases affecting the spleen, gallbladder and pancreas. We highlight a variety of cases as examples of how CEUS can serve in the diagnosis and follow-up for such diseases in children. Our discussion includes specific examination techniques; presentation of the main imaging findings in various benign and malignant lesions of the spleen, gallbladder and pancreas in children; and acknowledgment of the limitations of CEUS for these organs.

Contrast-enhanced voiding urosonography, part 1: vesicoureteral reflux evaluation.

Contrast-enhanced voiding urosonography (ceVUS) is a well-established, sensitive and safe ultrasound (US) modality for detecting and grading vesicoureteral reflux (VUR) and urethral imaging in children. Nearly three decades of remarkable advances in US technology and US contrast agents have refined ceVUS's diagnostic potential. The recent approval of Lumason/SonoVue in the United States, Europe and China for pediatric intravesical applications marked the beginning of a new era for this type of contrast US imaging. Consequently, the use of ceVUS in children has expanded to multiple places around the globe. In the first part of this review article, we describe the current experience in the use of ceVUS for VUR evaluation, with an emphasis on historical background, examination technique, image interpretation and diagnostic accuracy. In the second part, we will present the role of ceVUS for urethral imaging in children.

Contrast-enhanced voiding urosonography part 2: urethral imaging.

Ultrasound (US) has been increasingly used as an important imaging tool to assess the urethra in children. The earliest reports of pediatric urethral sonography involved imaging the urethra in a non-voiding state, during physiological voiding of urine, and after instillation of saline. The introduction of US contrast agents has continued to improve visualization of urethral anatomy. Contrast-enhanced US of the urethra can be performed during the voiding phase of a standard contrast-enhanced voiding urosonography (ceVUS) exam or with retrograde instillation of a contrast agent, depending on the exam indication. Both techniques are well tolerated by children and provide accurate information about urethral pathology and periurethral soft tissues. This article reviews the technical aspects and imaging findings of urethral pathologies in children using contrast-enhanced US, both by the voiding and retrograde instillation techniques.

Intraoperative Contrast-Enhanced Ultrasound Imaging of Femoral Head Perfusion in Developmental Dysplasia of the Hip: A Feasibility Study.

OBJECTIVES: Developmental dysplasia of the hip (DDH) is one of the most common developmental deformities of the lower extremity. Although many children are successfully treated with a brace or harness, some require intraoperative closed or open reduction and spica casting. Surgical reduction is largely successful to relocate the hip; however, iatrogenic avascular necrosis is a major source of morbidity. Recent research showed that postoperative gadolinium-enhanced magnetic resonance imaging (MRI) can depict hip perfusion, which may predict a future incidence of avascular necrosis. As contrast-enhanced ultrasound (CEUS) assesses blood flow in real time, it may be an effective intraoperative alternative to evaluate femoral head perfusion. Here we describe our initial experience regarding the feasibility of intraoperative CEUS of the hip for the assessment of femoral head perfusion before and after DDH reduction. METHODS: This single-institution retrospective Institutional Review Board-approved study with a waiver of informed consent evaluated intraoperative hip CEUS in children with DDH compared to postoperative contrast-enhanced MRI. Pediatric radiologists, blinded to prior imaging findings and outcomes, reviewed both CEUS and MRI examinations separately and some time from the initial examination both independently and in consensus. RESULTS: Seventeen patients had 20 intraoperative CEUS examinations. Twelve of 17 (70.6%) had prereduction hip CEUS, postreduction hip CEUS, and postreduction gadolinium-enhanced MRI. Seven of 12 (58.3%) were evaluable retrospectively. All CEUS studies showed blood flow in the femoral epiphysis before and after reduction, and all MRI studies showed femoral head enhancement after reduction. The CEUS and MRI for all 7 patients also showed physeal blood flow. CONCLUSIONS: Contrast-enhanced ultrasound is a feasible intraoperative tool for assessing adequate blood flow after hip reduction surgery in DDH.

European Society of Paediatric Radiology abdominal imaging task force: recommendations for contrast-enhanced ultrasound and diffusion-weighted imaging in focal renal lesions in children.

Contrast-enhanced ultrasound (CEUS) and diffusion-weighted imaging (DWI) are safe, repeatable imaging techniques. The aim of this paper is to discuss the advantages, technical factors and possible clinical applications of these imaging tools in focal renal lesions in children.

Intracavitary contrast-enhanced ultrasonography in children: review with procedural recommendations and clinical applications from the European Society of Paediatric Radiology abdominal imaging task force.

Contrast-enhanced ultrasonography (US) has become an important supplementary tool in many clinical applications in children. Contrast-enhanced voiding urosonography and intravenous US contrast agents have proved useful in routine clinical practice. Other applications of intracavitary contrast-enhanced US, particularly in children, have not been widely investigated but could serve as a practical and radiation-free problem-solver in several clinical settings. Intracavitary contrast-enhanced US is a real-time imaging modality similar to fluoroscopy with iodinated contrast agent. The US contrast agent solution is administered into physiological or non-physiological body cavities. There is no definitive list of established indications for intracavitary US contrast agent application. However, intracavitary contrast-enhanced US can be used for many clinical applications. It offers excellent real-time spatial resolution and allows for a more accurate delineation of the cavity anatomy, including the internal architecture of complex collections and possible communications within the cavity or with the surrounding structures through fistulous tracts. It can provide valuable information related to the insertion of catheters and tubes, and identify related complications such as confirming the position and patency of a catheter and identifying causes for drainage dysfunction or leakage. Patency of the ureter and biliary ducts can be evaluated, too. US contrast agent solution can be administered orally or a via nasogastric tube, or as an enema to evaluate the gastrointestinal tract. In this review we present potential clinical applications and procedural and dose recommendations regarding intracavitary contrast-enhanced ultrasonography.

European Society of Paediatric Radiology abdominal imaging task force: statement on imaging in very early onset inflammatory bowel disease.

Very early onset inflammatory bowel disease (VEO-IBD) is defined as disease presenting before the age of 6. These children require a tailored imaging approach because conventional imaging studies can be difficult to perform at such a young age. Unlike inflammatory bowel disease in older children and adults, colonic disease predominates in VEO-IBD, and small-bowel disease is rare. Distinguishing Crohn disease from ulcerative colitis is challenging both clinically and on histology. Radiology offers the greatest utility for detecting small-bowel disease because it helps to distinguish the two main disease entities and guide clinical management. Small-bowel ultrasound is recommended as the first-line investigation because it requires relatively little preparation, is readily available and is generally well tolerated in young children. We present these recommendations, based on the current evidence for radiologic management in this group, and propose an imaging algorithm for investigating VEO-IBD.

Correction to: European Society of Paediatric Radiology abdominal imaging task force: statement on imaging in very early onset inflammatory bowel disease.

The above article was published online with incorrect author name. The right spelling should be Damjana Kljucevsek instead of Damjana Kjucevsek. The correct name is presented here.

Contrast-enhanced voiding urosonography (ceVUS) with the intravesical administration of the ultrasound contrast agent Optison™ for vesicoureteral reflux detection in children: a prospective clinical trial.

BACKGROUND: Contrast-enhanced voiding urosonography (ceVUS) is widely used outside the United States to diagnose vesicoureteral reflux (VUR) in children and is highly sensitive while avoiding exposure to ionizing radiation. At the onset of this study, two ultrasound (US) contrast agents were available in the United States. Pediatric safety data for intravenous administration was published for one, Optison™. OBJECTIVE: This study aimed to evaluate the diagnostic performance and safety of ceVUS using Optison™ and compare its diagnostic efficacy with voiding cystourethrogram (VCUG) for VUR detection and grading in children. MATERIALS AND METHODS: The United States Food and Drug Administration and institutional Investigational New Drug authorizations were obtained to conduct a prospective comparative study of ceVUS with Optison™ and VCUG. CeVUS was performed with intravesical administration of 0.2% Optison™/normal saline solution. A standard VCUG followed. Safety assessment included physical examination, and heart rate, pulse oximetry and adverse reactions monitoring before, during and immediately after the examinations. A follow-up questionnaire was completed by telephone 48-h after the studies. RESULTS: Sixty-two pelviureteric units were studied in 30 patients with a mean age of 3.5 years (range: 0.1-17 years) including 21 girls and 9 boys. No severe adverse events occurred. All patients had normal heart rate and blood oxygenation saturation prior to, during and after the studies. At the 48-h follow-up, one patient (3.3%) reported transient dysuria. Taking the VCUG as the reference standard, ceVUS had a sensitivity of 91.7% (95%; confidence interval [CI]: 61.5%-99.8%) and specificity of 98% (95%; CI: 89.4%-99.9%). The concordance between ceVUS and VCUG for VUR detection and grading was 84.3% and 81.8%, respectively. VUR grades were discrepant in 4/11 refluxing pelviureteric units, with VCUG upgrading VUR in 2. CONCLUSION: Detection of VUR with Optison™ ceVUS was comparable to VCUG without exposure to ionizing radiation. CeVUS with Optison™ is a well-tolerated diagnostic procedure with a favorable safety profile.