20 Contrast-Enhanced Ultrasound (CEUS) in Pediatric Diseases

The most important advantage of CEUS in children is the potential of reducing the amount of ionizing radiation by reducing the frequency of CT and radiologic scanning. During their growth period, children have a higher radiation sensitivity.^{1 – 6} Repeated CT scanning during childhood was associated with a higher incidence of tumors in later life and therefore also with higher mortality.^{2 ,​ 7} Futhermore, ultrasound contrast agents (US-CA) are eliminated from the body hours after the examination without nephro-, cardio-, or hepatotoxicity, and without known organ deposition, which may be another advantage compared to the unknown effects of detectable gadolinium storage in the brain after repeated examinations despite normal renal function.^{8 ,​ 9}

Using US-CA in children is effective, safe, and well tolerated by parents.^{10 – 17}

The need for a rapid implementation of CEUS in pediatrics has been recognized as an important topic.^{13 ,​ 14 ,​ 18 ,​ 19} A pediatric register has been installed on the EFSUMB homepage in order to collect data for possible indications and safety aspects of its use in children.^{18 – 20}

There is a broad spectrum of indications for intravenous contrast-enhanced ultrasound (iv-CEUS) in children similar to those in adults: characterizing focal lesions in solid organs, perfusion disturbances, vessel patency, infectious complications, malignancy, active bleeding, and trauma.

Voiding urosonography (VUS) entails intravesical administration of US-CA for the diagnosis of vesicoureteral reflux (VUR).

20.2 Contrast-Enhanced Ultrasound (CEUS) in Children

At present, US-CA in children are most commonly used for the intracavitary pathway in VUS.²¹ For VUS, the most frequent indication in pediatrics is diagnosis or exclusion of VUR.^{21 – 23} The FDA approved SonoVue^® (in the US named Lumason^®) for VUR in 2016 in the US and the European authorities in 2017. Before this, the only US-CA approved for VUS was Levovist^®, which was no longer on the market.

In Europe, intravenous application of the second-generation US-CA in children and adolescents up to the age of 18 years is off-label for all indications.²⁴ Therefore, up to now, CEUS in children was used only in a few specialized centers using sulfur hexafluoride as gas (SonoVue^®, Bracco, Milano).

The same substance is called Lumason^® in the US, where it has been approved since 2016 for hepatic indications in children. Up to now, there are only a few studies published on CEUS in children.^{10 ,​ 12 ,​ 25}

20.2.1 Voiding Urosonography (VUS) Using Ultrasound Contrast Agents (US-CA)

VUS using US-CA is an alternative to the radiographic procedure for the detection of VUR.

After the regular B-mode US investigation of the kidneys and collecting urinary system with attention to ureteral or pelvic dilatation, VUS is performed. Warm and diluted US-CA (SonoVue^®) is inserted into the bladder by using a transurethral or a suprapubic bladder catheter under US control. Only a few drops of SonoVue^® together with warm physiologic saline solution plastic bags (no glass containers) are needed. In the US, Optison^® (GE Healthcare, Princeton, NJ) has also been evaluated for this indication.²⁶

Using continuous US scanning, possible VUR into the ureter, pelvis, or calices of the kidneys is observed during bladder filling. Both the kidneys and ureters are investigated by changing the sides. At the end, in males, the urethra is scanned via a perineal approach after removing the catheter and during voiding.

Primary indications for VUS are the initial investigation for the detection and grading of VUR and follow-up investigations after deflux therapy.

A disadvantage of VUS compared to the radiologic investigation is the different and possibly more difficult scanning of the urethra for detection of urethral valves with a perineal scanning approach.

Furthermore, the total investigation time using VUS may be longer due to the scanning of both the kidneys, and the US-CA is more expensive than the radiologic contrast agent. Cohortation of several patients for VUS on one day for logistical reasons can be useful.

The most important advantage of VUS is the missing radiation burden and the slightly higher detection rate of VUR by approximately 10%.^{21 – 23 ,​ 27 – 29}

20.2.2 Potential Indications for Intravenous Use of CEUS in Children

There is a broad spectrum of possible indications for iv-CEUS in children. An important advantage of the method is the real-time scanning with the possibility of a longer observation period of the dynamics and vessel architecture in the investigated lesions especially in the arterial phase.^{11 ,​ 30} As in the adult, the most commonly investigated organ is the liver for characterizing focal liver lesions or perfusion disturbances¹² (Franke, unpublished data from 600 single-center investigations in children).

An excellent indication for CEUS is trauma, where organ lacerations or active bleeding can be detected.^{31 – 37} The investigation itself and the interpretation of results in trauma are easy to learn. Compared to B-mode and Doppler scanning in trauma indications, CEUS has a much higher sensitivity for detection of organ laceration, rupture, or active bleeding.

Other possible indications are unclear focal organ lesions, perfusion disturbances (such as infarction), and differentiating complicated cysts.^{18 ,​ 38}

20.2.3 Indications for Contrast-Enhanced Ultrasound (CEUS) in Children

•Unclear focal lesions in parenchymal organs

•Perfusion disturbances: infarction, vessel patency, aneurysms

•Trauma

•Transplantation

•Tumors in children

•Oncologic follow-up

•Differentiation of complex cysts

•Active bleeding

•Intracavitary CEUS: abscesses, biliary system

•VUS

After solid organ or stem cell transplantation, vessel patency, thromboembolic or ischemic complications, infections, and posttransplant lymphoproliferative diseases (PTLD) are indications where CEUS is helpful.

CEUS investigations can also be performed using the intracavitary pathway, for example, for delineation of abscess cavities or for demonstration of the biliary system via biliary drains, fistulas in Crohn’s disease, for diagnosis or exclusion of urinary leakage after kidney transplantation (Fig. 20.1), or for urinary tract operation by using a transurethral or suprapubic catheter. For endocavitary use, only tiny amounts of US-CA are necessary (one to three drops of SonoVue^® with 100 mL physiologic sterile saline solution). Clinical examples and CEUS images in children are presented in this chapter (Fig. 20.1, Fig. 20.2, Fig. 20.3, Fig. 20.4, Fig. 20.5, Fig. 20.6, Fig. 20.7, Fig. 20.8).

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