Annamaria Deganello

Contrast Enhanced Ultrasound (CEUS) Characterization of Grey-scale Sonographic Indeterminate Focal Liver Lesions in Pediatric Practice

PURPOSE To determine the usefulness of contrast-enhanced ultrasound (CEUS) in characterizing grey-scale sonographic indeterminate focal liver lesions (FLL) in pediatric practice. MATERIALS AND METHODS Local Ethics Board approval waiver was attained. Consent for CEUS examinations was acquired from parents. Forty-four children referred for CEUS assessment of grey-scale sonographic indeterminate FLL over a 5-year period underwent standard multiphase CEUS performed by experienced operators. A phospholipid microbubble agent was used and low mechanical index ultrasound imaging techniques employed. Interpretation by consensus of the CEUS examination was compared to consensus interpretation of other imaging and to histology. Follow-up imaging was used to confirm stability of benign abnormalities. Any contrast reactions were recorded. RESULTS The CEUS examination interpretation agreed with reference imaging in 29/34 (85.3 %) of cases. In discordant cases, reference imaging showed no abnormality (n = 5), with fatty change (n = 4) and regenerating nodules (n = 1) on CEUS and follow-up sonography. Where reference imaging was not performed (n = 10), histology (n = 7) or follow-up sonography (n = 3) confirmed the diagnosis. In one discordant case, all imaging modalities showed concordance identifying a malignant lesion; however histology demonstrated a benign hepatocellular adenoma. The specificity was 98.0 % (95 % CI; 86 - 100 %) and the negative predictive value was 100 %. No adverse effects to the contrast material were noted. CONCLUSION These findings demonstrate the usefulness of CEUS in characterizing indeterminate grey-scale sonography FLL in pediatric patients with the potential to reduce exposure to ionizing radiation.

Post-traumatic liver and splenic pseudoaneurysms in children: Diagnosis, management, and follow-up screening using contrast enhanced ultrasound (CEUS)

BACKGROUND Pseudoaneurysm (PA) formation following blunt and penetrating abdominal trauma is a recognized complication in solid organ injury, usually diagnosed by contrast-enhanced CT (CECT) imaging. Delayed rupture is a potentially life-threatening event, although its frequency is not known in pediatric trauma. Contrast enhanced ultrasound (CEUS) is a novel radiation-free alternative to CECT with the potential to identify PA. METHODS A retrospective review of consecutive cases of significant liver and splenic injuries admitted to single institution (tertiary and quaternary referrals) over more than a 12year period was performed. From 2011, CEUS was performed routinely postinjury (5-10days) using SonoVue™ as contrast. Initially, CECT and CEUS were performed in tandem to ensure accurate correlation. RESULTS From January 2002-December 2014, 101 (73M) children [median age was 14.2 (1.3-18)years] with liver and splenic injuries were admitted. Injuries included: liver [n=57, grade 3 (1-5)], splenic [n=35, grade 3 (1-5)], and combined liver/spleen [n=8, (1-4)]. Median Injury Severity Score (ISS) was 13 (2-72). The predominant mechanisms of injury were blunt trauma n=73 (72%) and penetrating trauma n=28 (28%). Seventeen children (17%) developed PA. Six children became symptomatic (35%), and five went on to have embolization [at 7 (3-11)days]. These were detected by CECT (n=4) and CEUS (n=2). Eleven children remained asymptomatic [detected by CECT (n=8) and CEUS (n=3) at median 5 (4-8)days]. One underwent embolization owing to evidence of interval bleeding. Sensitivity of CEUS at detection of PA was 83%, with specificity of 92% (PPV=71%, NPV=96%). There was no association between grade of injury and presence of PA in either liver or splenic trauma (P=0.4), nor was there an association between size of PA and symptoms (P=0.68). Children sustaining splenic PA were significantly younger than those with hepatic PA (P=0.03). Follow-up imaging confirmed resolution of PA in 16 cases. One child was lost to follow-up. CONCLUSIONS The incidence of PA is higher than previously reported in the pediatric literature (<5%). Postinjury imaging appears mandatory, and CEUS appears to be highly sensitive and specific for diagnosis and follow-up.

The EFSUMB Guidelines and Recommendations for the Clinical Practice of Contrast-Enhanced Ultrasound (CEUS) in Non-Hepatic Applications: Update 2017 (Long Version)

The updated version of the EFSUMB guidelines on the application of non-hepatic contrast-enhanced ultrasound (CEUS) deals with the use of microbubble ultrasound contrast outside the liver in the many established and emerging applications.

Retrospective Analysis of the Safety and Cost Implications of Pediatric Contrast-Enhanced Ultrasound at a Single Center

OBJECTIVE Because of concern over medical ionizing radiation exposure of children, contrast-enhanced ultrasound (CEUS) has generated interest as an inexpensive, ionizing radiation-free alternative to CT and MRI. CEUS has received approval for pediatric hepatic use but remains off-label for a range of other applications. The purposes of this study were to retrospectively analyze adverse incidents encountered in pediatric CEUS and to assess the financial benefits of reducing the number of CT and MRI examinations performed. MATERIALS AND METHODS All pediatric (patients 18 years and younger) CEUS examinations performed between January 2008 and December 2015 were reviewed. All immediate reactions deemed due to contrast examinations were documented in radiology reports. Electronic patient records were examined for adverse reactions within 24 hours not due to an underlying pathologic condition. With tariffs from the U.K. National Institute of Clinical Excellence analysis, CEUS utilization cost (

Paediatric contrast-enhanced ultrasound (CEUS): a technique that requires co-operation for rapid implementation into clinical practice.

94) was compared with the CT (

Cortical necrosis secondary to trauma in a child: contrast-enhanced ultrasound comparable to magnetic resonance imaging

168) and MRI (

Contrast-enhanced ultrasound (CEUS) appearances of an adrenal phaeochromocytoma in a child with Von Hippel-Lindau disease

274) costs of the conventional imaging pathway. RESULTS The records of 305 pediatric patients (187 boys, 118 girls; age range, 1 month-18 years) undergoing CEUS were reviewed. Most of the studies were for characterizing liver lesions (147/305 [48.2%]) and trauma (113/305 [37.1%]); the others were for renal, vascular, and intracavitary assessment (45/305 [14.8%]). No immediate adverse reactions occurred. Delayed adverse reactions occurred in two patients (2/305 [0.7%]). These reactions were transient hypertension and transient tachycardia. Neither was symptomatic, and both were deemed not due to the underlying disorder. The potential cost savings of CEUS were

Intravenous and Intracavitary Use of Contrast-Enhanced Ultrasound in the Evaluation and Management of Complicated Pediatric Pneumonia

74 per examination over CT and

Authors’ Reply to Letter: Role of Contrast-Enhanced Ultrasound (CEUS) in Paediatric Practice: An EFSUMB Position Statement

180 over MRI. CONCLUSION Pediatric CEUS is a safe and potentially cost-effective imaging modality. Using it allows reduction in the ionizing radiation associated with CT and in the gadolinium contrast administration, sedation, and anesthesia sometimes required for MRI.

Autoimmune Liver Disease in Children with Sickle Cell Disease

There are continuing efforts to reduce radiation exposure in children, and it is widely acknowledged by learned societies dealing with paediatric imaging, that ultrasound (US) and magnetic resonance (MR) imaging need to be used more often. Computed Tomography (CT) has an essential role but overuse and hence increased radiation exposure in children is a recognised problem. There have been a number of studies that point out the long-term detrimental effects of radiation in the young patient 1 2 , with the lifetime risk of a malignancy induced by the radiation of a single CT examination depending on age: 1/1000 at age 15 years and 2.5/1000 at age 1 year. This is not surprising as a single abdominal CT examination may involve a radiation dose of ≅30 mSv (± 12 years of background radiation). Campaigns are in progress to educate physicians of the potential deleterious long-term effects of CT induced radiation in patients, with a particularly concerted effort in progress from paediatric practitioners 3 . Ultimately, pressure from parents will ensure that radiation in children is kept at a minimal level needed for diagnostic requirements. CT examinations work best with a certain amount of body fat surrounding abdominal organs; most children lack this fat distribution, but US thrives on the absence of fat, making US much more suited to abdominal examinations in children. MR imaging is undoubtedly the imaging modality of choice in neuroimaging, but in the child’s abdomen MR imaging may struggle to achieve a diagnosis. This is coupled with the younger child requiring sedation, and the possible administration of a contrast agent, gadolinium, that may have devastating consequences 4 . What is not in doubt is the cost implications of using MR imaging; US remains the least expensive of imaging modalities. Furthermore US succeeds on all occasions as a child-friendly non-intimidating imaging technique. Contrast-enhanced ultrasound (CEUS) is now main-stream in adult imaging, and has proved itself in a number of clinical situations, as a practical, real-time, bed-side problem solving tool, with the European Federation of Societies in Ultrasound in Medicine and Biology (EFSUMB) leading the world in progress on this front and publishing widely accepted guidelines on evidence based CEUS deployment 5 6 . Paediatric imaging with CEUS is mentioned in these guidelines and the implications discussed 7 , with the topic of “off-label” adequately dealt with – there is no legal or regulatory board hindrance to using CEUS in children 8 . Indeed these legal and regulatory board implications in children have been a topic of discussion in the pages of many learned journals, all enthusiastic for the use of CEUS in children, all seemingly un-hampered by physician perceived regulatory and hospital hurdles and impediments 9 10 11 . It is at this point very important to raise two very valid issues with the use of microbubble contrast agents in children. Many drugs are not tested in children and are not licensed to be used to treat children; in one study 67 % of children admitted to five European hospitals were given unlicensed drugs 12 , many of these drugs with known side-effects in adult patients. Secondly, the microbubble contrast agent used in Europe, SonoVue (Bracco, SpA, Milan) has an excellent safety record in adults 13 and a recent survey of the use of paediatric CEUS in Europe recorded a very small number of minor reactions 14 . This agent has a recorded adverse event lower than that seen with iodinated contrast medium used in CT and equivalent to MR agents, widely accepted as essential to many imaging investigations. Historically regulatory procedures for licensing iodinated contrast agents in children followed national approval and was based on studies conducted in a non-controlled fashion, with small patient numbers yet with reported adverse events 15 16 ; there was no central European procedure for performing of clinical evaluation of a new contrast agent. Evaluation of gadolinium based contrast agents in children was performed later, with higher standards but still below of the expectations of today, again obtaining safety data from open-label or even retrospective studies 17 . Current regulatory requirements will imply huge cost necessities to perform prospective, well-controlled studies on microbubble contrast agents in children. Our experience to date in the paediatric patient includes the application of CEUS to interpreting indeterminate focal liver lesions in children with or without underlying chronic liver disease 18 and in the follow-up of blunt abdominal trauma 19 . Both these areas are well established in adult practice, and evidence from the two paediatric studies above confirms a similar usefulness of CEUS in children. Numerous case reports and case series continue to appear in the literature extolling the usefulness of the addition of CEUS to an US examination, with the desired diagnostic outcome achieved with little discomfort to the child, no exposure to radiation, sedation or the effects of iodinated contrast or gadolinium based contrast agents. The physicians involved in reporting what is often assumed as nothing other than a trivial “case-study” are to be congratulated for their desire to advance their clinical practice and directly add to the literature on the subject. By publishing their results a body of evidence builds up, and eventually what was previously a “taboo” area becomes mainstream and readily acceptable. There should be no further delay in introducing paediatric CEUS into routine clinical practice. We have no evidence that the microbubble agent is harmful to the child, but cautiously neither is there substantial evidence that it is safe. The only manner in which we can achieve a database of safety is to prospectively accumulate experience of the use of intra-venous CEUS. The only possibility of achieving this currently is in Europe and with the agent SonoVue (Bracco SpA, Milan). In the United States of America, licensing for adults is an issue, and the prospect of using microbubble contrast agents in paedaitric patients restricted to centers involved in research; it may be a while before any meaningful numbers can be accumulated. The amassing of experience in the Far East and with China in particular is a favorable prospect, but local regulations may be difficult to overcome. Currently, EFSUMB has an established record in pursuing the development of CEUS practice across Europe and to a certain extent across the globe. EFSUMB guidelines are probably the most respected source of knowledge on CEUS and have made the biggest impact on the expanding clinical use of CEUS. To develop a strategy for encouraging physicians involved with the imaging of children, to embrace CEUS into their clinical practice, national and international societies for the care and imaging of children need to be active and enthusiastic participants. Clearly there is a need to work together on this; there will be no assistance from the manufacturers of the microbubble agents as they are constrained by law to restrict their activities to licensed uses of their product. EFSUMB has now established a “registry” on their website which allows data input in a prospective manner and documents any adverse events. A meeting of learned societies to establish a strategy is needed, taking advantage of expertise available in different forums to achieve a rapid and useful outcome. The bottom line is that we owe it to our children to move away from harmful imaging techniques and establish CEUS as the “next-step” imaging modality after an inconclusive B-mode ultrasound examination. There is a risk that we may not get it right with CEUS as an alternative imaging method in children and it may not fulfil its promise – but we have to try and be seen to be trying. We believe that the future of imaging gently in children lies in US with the addition of CEUS a major step in reducing the use of ionizing radiation.