"Beyond the Abstract," Contrast-enhanced voiding urosonography with intravesical administration of a second-generation ultrasound contrast agent for diagnosis of vesicoureteral reflux, by Frederica Papadopoulou

BERKELEY, CA (UroToday.com) - Contrast-enhanced voiding urosonography (ce-VUS) is a highly sensitive and radiation-free diagnostic modality for vesicoureteral reflux imaging in children. The present study comprised of 1 010 children undergoing ce-VUS with the intravesical administration of SonoVue® is the largest prospective study to date to systematically evaluate the frequency, nature, and duration of possible adverse events related solely to the intravesical administration of a second generation US contrast agent. Our results showed that a total of 37 children, corresponding to 3.66% of the examined pediatric population, encountered some kind of post-procedural adverse event. The most frequent adverse event was dysuria (70.3%). Moreover, stratified data analysis revealed that the presence or absence of these adverse events was independent from any parameter related to a child’s age and gender, presence, grade or side of reflux, pelvicalyceal dilatation, bladder capacity, postvoid residual urine volume, and number of ce-VUS cycles performed.

Furthermore, similar adverse events were previously reported with the performance of the other imaging modalities used for reflux detection in children, namely VCUG and radionuclide studies. The authors concluded that these events could be attributed to the discomfort of the minimally invasive procedure of bladder catheterization itself as well as its psychological impact on the children, rather than the contrast agent or radionuclide used. Adverse events after ce-VUS, using the second generation US contrast agent, had not been reported in the previous studies. The fact that we actually reported adverse events may be due to the following three important facts: (1) the main and only objective of the study was focused on US contrast agent safety evaluation; (2) a very thorough, long-term post-procedural monitoring, encompassing a systemic detailed phone interview was carried out; (3) the study group was very large, having been comprised of 1 010 patients.

Recently, a review article by the Society for Pediatric Radiology and the International Contrast Ultrasound Committee was published that addressed safety issues from the intravesical and intravenous use of US contrast agents in children. Overall, the very low or absent adverse events reported so far support the appropriate use of contrast-enhanced ultrasonography as a safe and effective alternative imaging option for children. Moreover the World Federation of Ultrasound in Medicine and Biology (WFUMB) and the European Federation of Societies of Ultrasound in Medicine (EFSUMB) issued “Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS),” incorporating ce-VUS for the very first time in the 2008 version and later in the 2011 update as a safe, pediatric-specific application of US contrast agents. Furthermore the ESPR Uro-radiology Task Force and ESUR Paediatric Working Group included ce-VUS in the uro-imaging diagnostic algorithm as a reliable and safe imaging modality. These recommendations again demonstrate how ce-VUS in children has become embedded in the sonographic diagnostic options in the field of pediatric uro-radiology.

Our findings contribute substantially in this direction, documenting the safety from the intravesical use of this second US contrast agent. There are a number of major strengths regarding this safety study. As mentioned above, to date it is the largest pediatric population examined only with ce-VUS using SonoVue®, i.e., no concomitant performance with VCUG or DRC. The ce-VUS was carried out using “state-of-the-art” imaging modality with low MI and contrast harmonic imaging. This resulted in minimal US contrast agent destruction and improvement of its real-time detection. Moreover, the lowest dose of 0.5 ml SonoVue® per bladder filling was used to obtain adequate contrast duration, allowing for multiple ce-VUS cycles to be performed. The monitoring of adverse events was conducted in a meticulous manner. Among the limitations could be considered the fact that the design of the study allowed only for clinical adverse events to be detected. No attempt was made (and there were no means) to evaluate potential subclinical adverse events related to the possible interaction of the US contrast agent with the uroepithelium. It was also not possible to assess the potential effect of microbubble rupture -- despite low MI imaging -- and its possible consequences. Nevertheless, these subclinical effects were found to be negligible in research settings with the IV use of SonoVue®. With the dilution of the US contrast agent into the partially filled bladder, the overall larger bladder, ureteral, and renal pelvic volumes when compared to intravascular space volume, along with the applied low dose, low MI, and short scanning duration, it may be assumed that potential subclinical effects are much less likely compared to IV use.

One potential technical issue that may be cited as a limitation is the fact that the vital signs were not monitored electronically and continuously, but rather clinically and intermittently. Undoubtedly, the use of US contrast agents in infants and children requires specific considerations compared to an adult population. However, for children, taking into account the high diagnostic accuracy of ce-VUS, combined with the extremely low rate of adverse events (likely due to the catheterization and not the US contrast agent), along with the elimination of exposure to radiation and iodinated contrast agents, it seems clinically justifiable to support US contrast agents use, and specifically that of SonoVue®, for this specific indication.

Written by:
Frederica Papadopoulou as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Department of Radiology, Medical School of University of Ioannina, Ioannina, Greece
Pediatric Ultrasound Medical Center, Thessaloniki, Greece

Contrast-enhanced voiding urosonography with intravesical administration of a second-generation ultrasound contrast agent for diagnosis of vesicoureteral reflux: Prospective evaluation of contrast safety in 1,010 children - Abstract

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