Intravenous contrast-enhanced sonography in children and adolescents - a single center experience.

UNLABELLED: Compared to adult patients, ultrasonography in children and adolescents is much more common, due to lack of ionizing radiation, and its wide availability. With the introduction of contrast-media for use in ultrasonography, one major drawback of the method could be overcome. In Europe, SonoVue(®) is the only widely available agent, which due to improved stability makes it possible to image normal and diseased tissue perfusion and vascularization with high accuracy. Inability to hold the breath and voluntary body movement of the patient is less of an obstacle compared to color Doppler techniques and makes the method very attractive for use in children, which, depending on age, may not be very cooperative. Use of intravenous contrast-medium in minors is currently very limited for several reasons: availability, lack of recommendation in national and international guidelines, and lack of official licensing. The article will touch medical indications, technique, safety considerations, and perspective of intravenous use of contrast-media in children and adolescents, including data from a 6-year period in 37 patients.
PURPOSE: The purpose of the study was to collect data on ultrasonographic examinations, expanded by intravenous administration of the contrast agent SonoVue(®) in children and adolescents. Besides assessing diagnostic yield, data on adverse medication effects was collected.
MATERIALS AND METHODS: The study includes contrast-enhanced ultrasound examinations in 37 children at a single institution. Indications for the examinations were tumor lesions, infections, traumatic organ injuries, and parenchymal organ ischemia. Parents of the patients and adolescent patients were informed about the off-label use of the contrast agent. Thirty-nine examinations were performed, the average age of the patient was 11.1 years (range 1 to 17 years).
RESULTS: All of the examinations yielded additional diagnostic value, always expanding results from B mode and color coded sonography. Overall, most examinations were done to assess the liver (n=16), followed by the kidney in 10 cases. The different etiologies were encountered in the following order: tumor (n=22), infection (n=9), trauma (n=5), ischemia (n=4). Most examinations were performed to evaluate a hepatic lesion (n=12). There was one incident recorded that fit the criteria of a possible adverse effect. In an 8-year-old girl nausea was noted, that started 15 minutes after the end of the examination and resolved spontaneously. In none of the patients medical treatment for adverse effects was necessary.
CONCLUSION: Ultrasonography in children, enhanced by intravenous use of contrast medium is feasible and allows for further evaluating cystic and solid tumors, and organ perfusion. Given that proper medical equipment and correct ultrasound machine settings are used, it is a robust method without diagnostic failures. In this small-sized case series there were no severe adverse effects, however, off-label use in children needs to be addressed.

Introduction

Nowadays, ultrasonography is the primary imaging modality in infants and children in inflammatory, neoplastic, and traumatic disease of the abdomen. It is a well-established procedure with its clear advantages: wide availability and lack of radiation, and disadvantages: operator-dependency and difficult-to-ensure documentation of high quality. Picture archiving computer systems (PACS) improve the documentation issue to some degree. Still, well-trained sonographers – either doctors or technicians – lay the foundation for correct medical diagnoses.

Use of contrast-enhanced ultrasound (CEUS) with industrially manufactured substances (SHU 454, Echovist®) started around the year 1990(. Soon after the introduction of Echovist®, the second-generation echo enhancing agent SHU 508 A (Levovist®) came to market(. Due to its stability and its sensitive detection, several investigators could prove Levovist® to be a suitable alternative to X-ray imaging in investigating vesicoureterorenal reflux (VUR) in children(.

The third-generation agent BR1 (SonoVue®) was launched into market in 2001(. Again, it could be shown that in investigations for VUR, it can replace X-ray examinations(.

SonoVue® is now widely used in specialized medical centers and defines state-of-the-art sonography for diagnosing the adult patient population. Except for investigation of VUR, it has not been adopted to examine pediatric patients.

There are two reasons for that. Firstly, intravenous use of echo-enhancing agents is not approved by the national and international authorities. Secondly, this brings about lack of expertise in this new application in those routinely examining pediatric patients. Because of that, pediatric radiologists fall behind general radiologists and specialized clinicians.

Personal history

The author got in touch with CEUS imaging about 12 years ago, in the beginning mainly assessing focal liver and renal lesions in adult patients. To the authors’ knowledge, at that time there were very few people engaged in the method in Berlin, Germany – Prof. Wolfram Wermke, Department of Gastroenterology, Hepatology, and Endocrinology, University Hospital Charité, and Prof. Thomas Albrecht, Department for Radiology and Interventional Therapy, University Hospital Charité.

Own experience in pediatric patients was gained by carrying out a feasibility study in detecting and grading VUR(. Experience in intravenous use of the contrast medium SonoVue® was then transferred to examinations of pediatric patients.

A local perspective on the topic

In the federal state Thuringia, inhabiting 2.2 million people (about 280 000 below 18 years of age) most of the contrast-enhanced ultrasound examinations in patients less than 18 years are performed by pediatric radiologists. Most of the contrast-enhanced studies are performed to assess vesicoureterorenal reflux disease.

In the time period from May 2009 to February 2013 there were about 90 i.v. use contrast-enhanced ultrasound examinations performed in patients younger than 18 years, including 2 patients younger than 1 year (infants). All of the examinations were diagnostic. Only children with inconclusive non-enhanced B-mode (“fundamental”) and color-coded sonography examinations were considered eligible for contrast-enhanced examinations. No critically ill patients, no patients with congenital or acquired heart disease, known hypersensitivity to any substance, including pharmaceutic agents, and unknown pregnancy status were examined.

Prerequisites

All of the major vendors (General Electric, Philips, Siemens, Toshiba, Zonare) support CEUS in their midand high-end machines. It is noticeable, however, that support of ultrasound probes differs. Whereas low-frequency curved arrays are always supported, high-frequency linear probes may be unsupported. It is not advisable to do CEUS without dedicated vendor maintained presets.

Safety

SonoVue® is not licensed for intravenous use in patients younger than 18 years of age in any of the European countries. This situation will not change in the near future (personal communication with Bracco Imaging). Consequently, use in children will be off-label. This, however, does not preclude its use in children and adolescents.

Several precautions should be met:

There should be a clearly defined indication for the contrast-enhanced ultrasound. Alternative imaging methods (e.g. magnetic resonance imaging, MRI) have to be considered.

Risk stratification includes taking medical history, in particular knowledge of allergic reactions.

Informed consent must be obtained from at least one parent and the patient him-/herself when 16 years or older. Prior to consent thorough information on indication, alternative methods, and risks need to be gained. The off-label use of the medication needs to be clearly addressed.

Examination environment must fulfill certain safety criteria. Based on prior knowledge there is a risk of allergic reactions. This means that emergency equipment and staff must be always available.

Patient preparation

Patients are not required to be in a fasting state, however, examination after a heavy meal should be postponed (see below). A large-bore venous indwelling catheter serves for two purposes: firstly, contrast-medium administration and the saline flush can be performed, secondly, in case of treatment of an adverse event medication and infusion can be administered. Prior the examination, the catheter should be flushed in order to guarantee its patency. Monitoring of blood pressure, pulse rate, oxygen saturation, and ECG waves is an option. Our local policies do not include such a monitoring, however, prior knowledge makes monitoring advisable. As to the authors’ knowledge there are two cases (Gdansk, Poland; Halle/Saale, Germany) in which a severe adverse event occurred in children (personal communication) making intensive care necessary.

The examination

A contrast-enhanced ultrasound examination should always start with the fundamental B-mode sonography. Ideally, the region of interest is visible independent of the respiratory cycle of the patient. In-depth knowledge of the ultrasound machine helps to avoid incomplete documentation of the examination. Often, video loops can be stored either prospectively or retrospectively. Often, the length of the loop is limited to a certain amount of seconds. The settings can be changed in the machine's preference menu.

The mechanical index (MI) is an estimate of effects of the ultrasound waves on the tissue and the contrast medium bubbles. It differs between different ultrasound machines. Usually, it is set very low, below 0.1.

Currently, in Europe there is only one pharmaceutical company that sells echo-enhancing agents. SonoVue® (Bracco Imaging, Milan, Italy) has been used for many years now and shows a very good safety profile. The author uses it in a concentration of 0.1 ml solution per patient age in years. When necessary, a second injection with the same amount of contrast medium can be given, depending on the need for verification of results.

The freshly prepared contrast agent is given via a temporarily placed venous indwelling catheter or a Hickman® long-term venous catheter as a bolus injection, flushed with an appropriate amount of physiologic saline solution.

According to safety considerations issued by the manufacturer, patients should be kept under strict medical supervision for at least 30 minutes following the administration of SonoVue®. Before leaving the department of radiology all children should be checked for any abnormal physical signs and symptoms (erythema at site of injection, general erythema, flushing, warm skin, pruritus, urticaria, nausea, emesis, vertigo, dyspnea).

It is advisable to instruct parents to report any abnormal findings occurring within 24 hours after contrast medium application to the examiner.

Main indications for intravenous CEUS

Detection of flow/presence of vessels in space-occupying lesions, e.g. in non-simple (complicated) hepatic and renal cysts.

Lack of perfusion/vessels in infarction zones, abscesses and hemorrhages

Visualization of perfused (viable) tissue after tumor surgery in case of residual tumor tissue or tumor relapse.

Differentiation of the character of the lesions on the basis of their perfusion kinetics and vasculature pattern, especially in liver tumors.

Imaging of perfusion defects in case of parenchymal trauma.

Documentation of contrast-medium extravasation and abnormal vessel contours in case of vessel laceration, fistulae, and aneurysms.

The ultrasound examinations serve several purposes. Incidentally detected lesions in fundamental B-mode ultrasonography can be further characterized. Occult lesions in classic B-mode ultrasound can be demonstrated due to the higher sensitivity for perfusion defects. And finally, small and large vessels diseases can be characterized in much more detail than in power Doppler sonography alone.

At the University Hospital of Jena, there is one examiner specialized in intravenous CEUS in children. Tab. 1 shows indications for CEUS on a selected number of examined patients.

Tab. 1

Organs examined and pathologies in 39 examinations (in one patient both liver and spleen were examined)

Examined organs	Diagnoses
	Tumor	Infection	Injury	Ischemia
Liver	12	2	2
Kidney	2	3	1	4
Spleen	1	1	2
Pancreas	1
Adrenal	2
Lung		1
Lymph nodes	1
Ovary	1
Urinary bladder	2	1
Knee joint		1

The following four examples will demonstrate the additional diagnostic value of CEUS as compared to classic B-mode sonography.

Case 1

The 11.9-year-old girl was known to have a solitary complicated liver cyst. So far she was followed up with MRI examinations once a year. Classic B-mode sonography delineated a solitary, septated cystic lesion in the right lobe of the liver, measuring 82 mm. Power Doppler did not depict perfusion of the septa (fig. 1 A), although it was proven on MRI scans. CEUS not only confirmed one perfused septum, but showed a second one (fig. 1 B). The patient is followedup by annual ultrasound examinations, including CEUS.

Fig. 1

Case 1: The hepatic cyst is marked by the big arrows. The small arrows mark the septae. In power Doppler perfusion of the septae cannot be demonstrated (A). Strong enhancement of the septae proves perfusion (B)

Case 2

The 3.9-year-old girl was examined for abdominal pain. At B-mode sonography, a lesion measuring 14×21×42 mm which was hypoechoic, well outlined, solid, located in the 5th segment of the liver was found (fig. 2 A). In power Doppler sonography the lesion showed central perfusion, representing a central vessel (fig. 2 B). CEUS exhibited contrast flow dynamics typical of a hemangioma with pronounced peripheral enhancement in the arterial phase (fig. 2 C) followed by gradual centripetal filling (fig. 2 D). A follow-up B-mode ultrasound examination 18 months later (planned visits were repeatedly cancelled by the parents) showed the lesion stable as to size and echogenicity.

Fig. 2

Case 2: The arrows mark the focal liver lesion. The asterisk marks the gall bladder lumen. B-mode shows a slightly hyperechoic mass (A). In power Doppler mode there is a central perfusion (B). 27 sec after contrast-medium application there is strong enhancement in the periphery (C). 148 sec after contrast-medium application the lesion fills in and shows mostly homogenous enhancement (D)

In contrast to adult patients, hepatic hemangiomata in infants and children are not very often hyperechoic.

Case 3

The 17.1-year-old girl, suffering from chronic headaches had a general check-up examination of the abdomen. Transabdominal sonography revealed an incidental solitary hepatic mass of 42×41×33 mm, which was slightly hypoechoic and well circumscribed (fig. 3 A). CEUS showed a centrally located prominent vessel (fig. 3 B, video 1 – available on the website www.jultrason.pl), and a small scar (fig. 3 C, video 1 – available on the website www.jultrason.pl) and no late wash-out. Diagnosis of a focal nodular hyperplasia was made. The latest followup sonography 15 months after initial diagnosis showed the lesion stable as to size and echogenicity.

Fig. 3

Case 3: The big arrows mark a focal liver lesion. The small arrow marks the center of the lesion. The asterisks depict intrahepatic vessels. In B-mode sonography the lesion is isoechogenic to normal liver tissue, although there is a partial hyperechogenic rim (A). 61 sec after contrast-medium application the lesion shows a stronger enhancement compared to the surrounding liver tissue. The very center shows a medium-sized vessel (B). Besides the central vessel, there is a small area lacking perfusion, in keeping with a central scar (C). Video shows the central scar and typical vessel (video 1 – available on the website www.jultrason.pl)

Case 4

The 4.2-year-old boy complained about pain in the leg and was brought to the hospital in bad general condition. He lost 2 kg within the last 2 weeks. The initial abdominal sonography showed hepatomegaly, and multiple, hypoechoic, solid, lesions of different size in the liver. Some of them were poorly outlined and difficult to differentiate from normal parenchyma in standard B-mode exam, but were clearly visible in CEUS (fig. 4, video 2 – available on the website www.jultrason.pl). The lesions represented multiple metastases of neuroblastoma stage 4.

Fig. 4

Case 4: Dual display of contrast-enhanced mode (left side), and fundamental B-mode (right side). Arrows mark the outer margin of the lesion. The metastasis is not detectable in B-mode. In contrast-enhanced mode there is homogenous reduced perfusion in the late phase, in keeping with a metastasis (video 2 – available on the website www.jultrason.pl)

The patient received chemotherapy (NB2004 high risk protocol). He recently underwent stem cell transplantation (SCT).

In our series of 37 patients the author saw only one adverse event in one 8-year-old girl examined for renal infection. She complained about nausea ca. 15 minutes after i.v. administration of the contrast which continued for about 30 minutes. No medical treatment was necessary.

Discussion

Over the last decades, medical diagnostic sonography has advanced considerably, resulting in high-resolution images with little artifact overlay. Characterization of vascularization and assessment of perfusion is crucial in arriving at correct diagnoses in many disease entities. Color, and especially power Doppler coded sonography give information on that, however, lack sensitivity. Especially in (restless) toddlers and in body regions of interest close to moving organs (e.g. lungs and heart) Doppler techniques have limited diagnostic value in assessment of parenchymal perfusion due to motion artifacts. Therefore, contrast agents are necessary to overcome these drawbacks.

In the author's experience contrast-enhanced sonography in children, and adolescents is safe and of additional diagnostic value. Diagnostic certainty in various disease entities can be achieved and expanded. Except one case which resolved spontaneously, it is shown that intravenous use of SonoVue® is safe, even in preschool-children. Several papers present results of CEUS applications in pediatric patients. The largest study reported so far of intravenous contrast agents use in 51 children and adolescents showed an overall accuracy of CEUS of 95.2%. The study utilized Levovist® (SHU 508 A) as contrast agent. No adverse reactions were observed(.

Thorelius reports on the use of CEUS in blunt abdominal trauma in adults and in children(. Children are also the subject of CEUS exams in another paper describing SonoVue® application in mild liver and splenic trauma(. Valentino et al. examined 27 children with blunt abdominal trauma and compared CEUS with contrast-enhanced computed tomography. A high accuracy of sonography was found and no adverse effects were observed in i.v. use of SonoVue®(.

The use of SonoVue® in post-transplant patients was studied in 30 pediatric liver transplant recipients. The authors concluded that CEUS improved diagnostic confidence and reduced the need for a more invasive approach(.

The off-label use issue is indirectly addressed by the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines and Good Clinical Practice (GCP) recommendations by stating that “Caution should be considered for off label use of UCAs in tissues where damage to microvasculature could have serious clinical implications, such as in the eye, the brain and the neonate”(. The EFSUMB thereby does not per se exclude CEUS use in children. The 2008 update on guidelines and good clinical practice recommendations for contrast enhanced ultrasound in non-hepatic lesions includes some indications for intravenous CEUS in children which are: abdominal solid organs injury and spermatic cord torsion(.

The topic is very recently dealt with in detail in another EFSUMB document entitled the Update 2011 on nonhepatic applications by the correspondence between editor and advocates of the method(.

Another recent publication discusses intracavitary and intravenous use of CEUS in children in the United States and Europe. Members of the board of the Society for Pediatric Radiology (SPR) established a task force with the mission of spreading knowledge about CEUS in children(.

Whereas conventional B-mode ultrasound in children is performed by many (pediatric) radiologists, many pediatricians and some pediatric surgeons in Europe, information on the use of contrast-enhanced sonography in children became available recently(.

From the authors’ own knowledge there are some centers in Germany who perform CEUS for diagnosing VUR, however, there are only a couple of centers who do intravenous examinations.

It has to be taken into consideration that echo-enhancing agents so far are not approved by the authorities. For that reason their off-label use is rather uncommon to radiologists, however, is justifiable as long as parents and adolescent patients receive sufficient information and as long as informed consent is obtained. The availability of ultrasonography which is devoid of ionizing radiation and need of sedation or anesthesia must be emphasized to convince more radiologists and clinicians, and parents. Since radiologists are the ones who know about advantages and limitations of the various imaging methods, including use of contrast media, they are supposed to either become skilled in this method themselves or find ways to train sonographers. This topic is discussed in detail elsewhere(. As long as there is lack of statistically relevant data in children, results from adult's comparative studies need to be employed. These are very promising as shown by a large national multicenter trial(.

All major ultrasound machine manufacturing companies optimized their premium machines for CEUS recently, but mainly for scanning with low-frequency curved-array probes. While CEUS in children or superficial organs in adults require optimization of linear probes for CEUS, the industry needs to be convinced about the need for optimizing the technique across a broader range of ultrasound probes.