Why consider contrast-enhanced ultrasound (ce-US) in children?

Children are very specific; particularly in terms of radiation sensitivity. They not only have a tenfold higher sensitivity towards radiation, but also a longer expected lifespan where potentially radiation induced tumours may manifest^(1–7). Therefore radiation protection is of outmost importance. At present – with standard imaging algorithms – many conditions are diagnosed by imaging which using ionising radiation (x-ray); particularly those with relatively high radiation burden such as fluoroscopy or CT should be replaced by other non-ionising imaging methods if feasible and available – following the ALARA-Principle^{(4, 6, 8)}.

Ultrasound contrast agents have been introduced decades ago; the first generations of these stable agents that were able to pass the capillary bed were approved for paediatric use in some countries. During this time first experiences have been gathered with their potential paediatric applications and the benefit in terms of radiation protection. Particularly the assessment of vesicoureteric reflux (VUR) by contrast enhanced voiding urosonography (ce-VUS) has been a widespread application replacing and reducing the need for fluoroscopic voiding cysto-urethrography (VCUG)^(9–13). It is well documented that ce-VUS has a comparable or even higher sensitivity towards VUR and that no relevant side effects have been observed with this intra-luminal application. The other potentially interesting application is intravenous administration of ultrasound contrast agents which will allow for improved depictions of vessels and assessment of “perfusion” pattern similar to contrast-enhanced CT or contrast-enhanced MRT, particularly valuable for liver lesion detection and characterisation^(14–17).

However, with the advent of second generation contrast agents which are even more stable and yield a better contrast response, first generation ultrasound contrast agents have been taken off the market – but these new agents are not registered for paediatric use. Nevertheless, exploiting the improved features of modern ultrasound with modern contrast visualisation techniques such as pulse inversion, contrast imaging or low MI techniques (based on specific resonance phenomena and respective response of the ultrasound contrast bubbles to the ultrasound beam), quality and reliability of ce-US with all his optional applications has even improved. In adults, intravenous ce-US (commonly named CEUS) has become an expected method for assessment of focal lesions in abdominal parenchymal organs, either in oncology or inflammation as well as in trauma; similar reports exist in numerous other body areas and organs, and respective guidelines and recommendations have been issued^{(16, 17)}.

But in children the more liberal use of ce-US is presently hindered by the lack of approval for paediatric use. Nevertheless, ongoing research has shown its huge potential – both in intra-luminal (particularly intravesical) and intravenous applications. Ce-VUS has become an accepted method for VUR detection – even intrarenal reflux can be demonstrated (fig. 1). And using a perineal approach assessment of the urethra is no longer an obstacle^(18–22) (fig. 2). Intravenous ce-US has been shown to be very valuable for lesion detection in paediatric parenchymal organs, e.g., after trauma or in inflammatory and oncologic conditions^(23–30). And exploiting the dynamic abilities of ultrasound imaging, observation of enhancement pattern enables a better lesion characterisation similar to what is known from contrast enhanced CT or MRT, without any radiation burden (fig. 3). Thus not only restrictions of conventional nonenhanced ultrasound can be overcome but also contrastenhanced irradiating imaging techniques can be avoided as ultrasonography can easily observe dynamics without increasing any burden from imaging, whereas fluoroscopy and CT are always limited to the shortest possible radiation dose and acquisition / fluoroscopy time to keep radiation at the lowest possible level. Furthermore – when compared to fluoroscopy – ultrasonography not only depicts the qualities of the contrast-filled structure but also demonstrates non-filled structures (e.g. nonrefluxing dilated ureters or pelvi-calyceal systems) and reveals information on structure, size and parenchymal pathology of these areas (e.g. the renal parenchyma, not assessable by fluoroscopic VCUG) (fig. 4). Combining all features of ultrasound – particularly with the support of modern high resolution imaging, dynamic observation of function (e.g. during voiding, peristalsis…), multiplanar information (e.g. using 3D- and 4DUS)⁽³¹⁾, and the additional information from contrast filling or parenchymal enhancement – offers a unique possibility of comprehensive, reliable and decisive imaging diagnosis which can most often be achieved even without sedation (which is often needed for CT or MR in small children and infants). Considering this and the lack of radiation burden, ce-US must be remembered as an important option in the orchestra of alternate imaging modalities that may help to reduce the need for irradiating imaging. This holds true particularly in the present situation, where most of the relevant drugs used for treating severely sick children in the intensive care unit, at the neonatal intensive care, in oncology or paediatric cardiology have not been tested for children and are not registered for use in paediatrics.

Fig. 1.

Ce-VUS for detection of VUR. Serial images demonstrate the contrast reflux into the distal ureter in a oblique section (A) – where a second ureter also seems to be present and refluxing (equalling low pressure VUR of mild degree during filling), one contrast filled mid ureter portion (B), and the dynamic contrast reflux into the renal collecting system (C), with increasing dilatation during voiding (D) indicating additional dilating high grade and high pressure VUR. Also note the duplication of the collecting system in C and D

Fig. 2.

Ce-VUS – urethra assessment during voiding using a perineal approach. At the end of ce-VUS, the bladder is emptied and the urethra is visualised from a perineal approach. Dual image technique: left – contrast dedicated image, right – orienting grey scale b-mode image

Fig. 3.

Intravenous ce-US (CEUS) of the liver in a treated and already shrunken, partially calicafied liver haemangiendothelioma (A) with no central but little peripheral enhancement in early phases (B, dual image technique), but some residual peripheral slightly nodular enhancement on late scans (C, between + … + ). Additionally for demonstration of CEUS images and effects: normal and homogenuous enhancement of spleen (D) and gas bubbles in the liver (similar to portal pneumatosis) as known to happen with ce-US, when bowel is withing the insonated field (E) after the ce-US investigation

Fig. 4.

US demonstrates also non-contrasted structures, e.g. non-refluxing megaureter (U) behind the contrast filled urinary bladder in a axial view (A), or the regionally dysplastic renal parenchyma in the respective hydronephrotic kidney without any refluxed contrast in the dilated collecting system – proving absence of VUR (longitudinal section) (B)

In conclusion – when considering the general situation and scenario as well as the benefits from ce-US – this option should be pursued not only by using ultrasound contrast agents after obtaining and informed consent as done with many other important paediatric drugs and agents, but also by pressurizing the drug licensing agencies and the providing pharmaceutical companies to eventually provide and approve these agents for use in children.

And finally, whoever takes on this rewarding technique, one must be prepared to handle potential (though very rare) severe adverse reactions (encountered with intravenous applications) by adequate standardized measures (as routinely done with any other contrast agent applications in fluoroscopy, CT or MRI)^(32–36). Eventually not only economics will benefit from this altered approach by reducing the number of more expensive CT and MR investigation, but particularly the children – as one will become able to provide reliable diagnoses of many conditions without irradiating imaging, reducing the need for sedation or at least helping to individually tailor those examinations that may become necessary as a complementary step. Keeping all this in mind, many scientific organisations such as the EFSUMB or the ECS, ICUS, ESUR and the ESPR are promoting the use of ce-US during childhood also giving some advice towards indications, results and procedural details^{(18, 19, 37, 38)}. With this help, some understanding from the hospital administration, and a combined effort to find some way of reimbursement for the costs of the contrast agent, the paediatric ultrasound community should take on this rewarding task to bring ce-US to routine paediatric sonographic diagnosis.