Spectrum, Applicability and Diagnostic Capacity of Contrast-Enhanced Ultrasound in Pediatric Patients and Young Adults after Intravenous Application – A Retrospective Trial

Abstract

Purpose: To investigate the spectrum, applicability and diagnostic capacity of intravenous contrast-enhanced ultrasound imaging (CEUS) in a pediatric population.

Materials and Methods: From 08/2005 to 11/2015, n = 40 pediatric patients and young adults from 0 – 26 years (Ø 11.4 ± 7.5) and 3.0 – 85.3 kg (Ø 40.8 ± 25.6) with n = 55 investigations received n = 79 IV applications of ultrasound contrast agent (UCA). UCA dose and side effects were documented. Scanned organs were the liver (n = 42), spleen (n = 9), kidney (n = 3), and testis (n = 1). Histology, surgery or reference imaging was compared to CEUS and clinical follow-up.

Results: The UCA dose < 20 kg was 0.4 ± 0.3 ml, (0.05 ± 0.02 ml/kg) and > 20 kg was 1.0 ± 0.4 ml (p< 0.0001) (0.02 ± 0.01 ml/kg, p< 0.0001). Adverse effects occurred in 2/79 applications (2.5 %). Agreement CEUS/gold standard resulted in 32/34 investigations. For liver diagnostics (gold standard: MRI, CT, histology, serology), n = 11 malignant and n = 15 benign focal liver lesions were included. The specificity was 100 % (95 % CI: 0.77 – 1.00), the sensitivity was 82 % (95 % CI: 0.48 – 0.98), the positive predictive value was 100 % (95 % CI: 0.69 – 1.00) and the negative predictive value was 88 % (95 % CI: 0.62 – 0.98, p< 0.0001). In n = 2 reference imaging misdiagnosed and CEUS was in accordance with clinical follow-up. All splenic/renal lesions were diagnosed correctly. In n = 1 an insufficient testicular perfusion was ruled out. The observation time was 30.4 ± 30.5 months.

Conclusion: CEUS is a well-tolerated and diagnostically equivalent modality in pediatric care, providing fundamental advantages compared to currently approved imaging modalities for these age groups.

Zusammenfassung

Ziel: Untersuchung von Spektrum, Anwendbarkeit und diagnostischen Möglichkeiten bei intravenöser Kontrastmittelsonografie in einem pädiatrischen Kollektiv.

Material und Methoden: Von 08/2005 bis 11/2015 erhielten n = 40 pädiatrische Patienten und junge Erwachsene von 0 – 26 Jahren (Ø 11,4 ± 7,5) mit 3,0 – 85,3 kg (Ø 40,8 ± 25,6) n = 55 Untersuchungen mit n = 79 i. v. Applikationen eines Ultraschallkontrastmittels (KM). KM-Dosis und Nebenwirkungen wurden dokumentiert. Untersucht wurden Leber (n = 42), Milz (n = 9), Niere (n = 3), und Hoden (n = 1). Histologie, Operation oder Referenzbildgebung wurde mit CEUS und dem klinischen Verlauf verglichen.

Ergebnisse: Die KM-Dosis lag für < 20 kg bei 0,4 ± 0,3 ml (0,05 ± 0,02 ml/kg) und für > 20 kg bei 1,0 ± 0,4 ml (p< 0,0001) (0,02 ± 0,01 ml/kg, p< 0,0001). Nebenwirkungen wurden in 2/79 Fällen (2,5 %) beschrieben. Übereinstimmung CEUS/Goldstandard resultierte in 32/34 Untersuchungen. Für Leberdiagnostik (Goldstandard: MRT, CT, Histologie, Serologie) wurden n = 11 maligne und n = 14 benigne fokale Läsionen eingeschlossen. Die Spezifität betrug 100 % (95 % CI: 0,77 – 1,00), die Sensitivität 82 % (95 % CI: 0,48 – 0,98), der positive prädiktive Wert 100 % (95 % CI: 0,69 – 1,00) und der negative prädiktive Wert 88 % (95 % CI: 0,62 – 0,98, p< 0,0001). In n = 2 lag die Referenzmethode falsch und CEUS zeigte eine Übereinstimmung mit dem klinischen Verlauf. Alle Milz-/Nierenläsionen wurden korrekt diagnostiziert, in n = 1 konnte eine unzureichende testikuläre Perfusion ausgeschlossen werden. Der Beobachtungszeitraum für den klinischen Verlauf waren 30,4 ± 30,5 Monate.

Schlussfolgerung: CEUS ist eine gut verträgliche und diagnostisch gleichwertige Modalität bei pädiatrischen Patienten, die fundamentale Vorteile im Gegensatz zu etablierten Methoden für die Altersklassen bietet.

Key words

CEUS - pediatric - off-label - contrast agents

Introduction

Due to its lack of radiation, constant availability and real-time imaging ability, ultrasound became the preferred first-line clinical diagnostic imaging tool. In the case of pediatric patients, it also establishes a close physician-patient relationship. These advantages have made it superior to magnetic resonance imaging and computed tomography in many different clinical scenarios.

In recent years, its diagnostic ability has greatly improved through the introduction of specific ultrasound contrast agents (UCA). They are mainly used in focal liver diagnostics [1] and were also applied for other abdominal applications, such as vascular or cardiac diagnostics [2] [3].

In the past decade, clinicians have gathered experience in adult patients and have proven the diagnostic accuracy of contrast-enhanced ultrasound (CEUS) [1] [4] [5] [6] [7], as well as its pharmacological safety [8], and cost efficiency in comparison to other conventional imaging modalities [9]. There are continuing efforts on the part of medical ultrasound societies to transfer this knowledge to our youngest patients.

However, specific tailored pediatric clinical trials and approval for IV usage in children are still lacking. Recognizing that there is a relevant demand for this technique, the general safety has already been shown in children receiving UCA “off-label” [10]. Sellars et al. conclude that there should be no delay in a rapid introduction of this modality in pediatric patients [11]. By achieving approval of this technique, a relevant portion of biopsies, long-duration scans, transportation, and monitoring of infants during longer hospitalization could be avoided.

We report a retrospective single-center study to investigate the diagnostic spectrum, applicability, and diagnostic capacity of intravenous contrast-enhanced ultrasound imaging with emphasis on pediatric abdominal diagnostics.

Materials and methods

No industry or grant support was provided for this study. All parents, guardians and/or patients signed informed consent for off-label use of UCA.

Study population

The hospital report database was searched to identify patients who underwent contrast-enhanced ultrasound in our department. The search was limited to examinations performed between January 1, 2006 and August 31, 2015. The keywords “CEUS”, “contrast agent” and “SonoVue” were used. This resulted in the identification of n = 169 database entries, corresponding to n = 169 ultrasound investigations. This database was harmonized with our internal documentation from the division of pediatric ultrasound with n = 40 cases and resulted in n = 55 final cases. n = 134 cases were excluded, n = 20 of these were duplicates, and in n = 45 cases CEUS was not performed but recommended. N = 6 patients (with n = 9 investigations) in follow-up with either pediatric oncologic diseases (leukemia, neuroblastoma) or metabolic diseases (cystic fibrosis) were included even though they were over 18 years of age. These young adults with typical pediatric diseases had not yet transitioned to adult medical care.

Two readers reviewed each electronic medical record. The following parameters were recorded for the analysis: patient sex, age at the time of imaging, weight (closest to the imaging date, at least < 2 weeks), imaged organ, maximum size of imaged lesion, volume of UCA administered, adverse reactions, clinical question, diagnosis, gold standard imaging comparison, pathology. CEUS was only applied in patients without known contraindications like clinically unstable or worsening congestive heart failure, right-left shunt, pulmonary hypertension, uncontrolled systemic hypertension, acute myocardial infarction or acute coronary syndrome, known allergic reaction or hypersensitivity to sulfur hexafluoride (SF₆) or SonoVue, respiratory failure/acute respiratory distress syndrome with signs or symptoms of carbon dioxide retention or hypoxemia and pregnancy. Patient characteristics are given in [Table 1].

Table 1 Patient and study characteristics.

category	u	mean±SD (range)
patients	n	40[1]
female	n	21
male	n	19
investigations	n	551
applications	n	79
mean age	y	11.4 ± 7.5 (0 – 26)
mean weight	kg	40.8 ± 25.6 (3.0 – 85.3)
mean lesion size	cm	3.8 ± 3.7

¹ n = 6 patients (n = 9 investigations) > 18years (pediatric oncologic diseases, cystic fibrosis).

Contrast-enhanced ultrasound imaging

All ultrasound examinations were performed using a contrast-specific low MI program and high-end ultrasound systems: Acuson Sequoia 512 (Acuson Corporation, Mountain View, CA, USA; curved array probe 4C1: 4MHz; linear probe 15L8w-S: 7 MHz), Siemens S 2000 (Siemens Medical Solution, Mountain View, CA, USA; curved array probe 6 C1HD: 1.5 MHz; linear probe /9L4: CPS 4 MHz), GE Logiq 9, and Logiq E9 (GE Healthcare, Milwaukee, WI, USA, curved array 4c: 4 MHz/ C1 – 6: 3 MHz, and linear probe M12 L/9L: 14 MHz/7 MHz). All imaging procedures were performed according to international guidelines [12]. All parents or guardians agreed to off-label use. Prior to each contrast-enhanced ultrasound, B-mode imaging was performed to assess the target area. Ultrasound contrast agent (UCA) (SonoVue^®, Bracco, Italy), which has been approved for regular use in adults since 2001, was reconstituted according to the manufacturer’s instructions. An intravenous bolus injection of UCA was administered following a maximum saline flush of 5 ml. During imaging representative videos and pictures were recorded and saved to the internal database or printed for archival storage.

Recording of adverse events

The principal investigator interviewed every parent, guardian or patient before and after the examination to assess for a history of allergic episodes and any adverse events (AE). Patients were observed for 30 minutes after application of the UCA. All reactions were classified as grade 1 to 5 according to the Common Terminology Criteria for Adverse Events (CTCAE) [13]. The grade refers to the clinical severity of an adverse event: grade 1: mild AE, grade 2: moderate AE, grade 3: severe AE, grade 4: life-threatening or disabling AE, grade 5: death related to AE. A detailed description for every organ system is published under: http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010 -06- 14_QuickReference_5x7.pdf.

Gold standard comparison

For every case the internal case documentation was reviewed for a comparable imaging modality. Reference imaging was based on computed tomography (CT), magnetic resonance imaging (MRI), histology, surgery, serology or a combination of more methods. Every result was compared separately to the ultrasound imaging report, e. g. one patient was included more than one time if CEUS was performed at different points of time.

Clinical follow-up

The medical record of each patient was reviewed to determine the last clinical visit and to evaluate the presence of any change in ultrasound or gold standard diagnosis.

Statistical analysis

GraphPad Prism 6.0 (GraphPad Software, LaJolla, CA) was used to perform statistical analysis. All tests were executed as indicated in the figures. Statistical analysis included calculation of medians, means, and standard deviations. P < 0.05 was considered statistically significant.

Results

Spectrum of imaging

A total of n = 21 female (11.0 ± 8.1 years) and n = 19 male patients (11.8 ± 6.7 years) were included. N = 6 patients (with n = 9 investigations) were > 18 years of age. CEUS exams included focal liver and liver perfusion diagnostics (n = 42), spleen (n = 9), kidney (n = 3) and testes (n = 1). Liver diagnostics included n = 41 focal lesions and n = 1 diagnostics for portal circulation. Spleen diagnostics included n = 5 infarctions, n = 1 torsion, n = 1 abscess, n = 1 hemangioma, and n = 1 inflammatory process. Kidney diagnostics included n = 1 angiomyolipoma, n = 1 imaging of perfusion and n = 1 inflammatory lesion. n = 1 CEUS imaging of testes visualized perfusion of the organ. An overview with all diagnoses is given in [Fig. 1].

Fig. 1 Spectrum of imaging. A total of n = 55 investigations were performed, including n = 42 liver, n = 9 spleen, n = 3 kidney, and n = 1 testis. The lower rings represent the portion of the whole with all final diagnoses in every organ system.

Tolerability and safety

Adverse effects were recognized in 2/79 applications (2.5 %), which manifested as nausea or a single wheal (CTCAE Grade 1 – 2 “immune system disorders”, mild to moderate: transient, responds promptly to symptomatic treatment) within less than 30 minutes. The latter was recognized in an oncologic patient with multiple known allergic sensitizations to substances other than the UCA. In both cases symptoms abated within < 10 minutes after immediate treatment with IV antihistamines. One patient (male, 16 years, preexisting condition: physical abuse) was admitted to the intensive care unit after unclear reaction to UCA application. He presented with fixed look, depressed breathing, and loss of ability to communicate and further developed extensive pain. Symptoms cleared after IV application of Lorazepam 2 × 1.5 mg und Piritramid 2 mg. Psychiatric evaluation diagnosed a dissociative disorder. This indicates that there is no causal relationship to the application of the UCA, so that it could not be rated as a serious adverse reaction (SAR). No more subjects had to be admitted to in-patient departments or needed further observation or monitoring.

The average UCA dose was 0.86 ± 0.44 ml and 0.03 ± 0.02 ml/kg (total n = 70 with documented weight). Age, weight, doses and weight-related doses in age groups according to the EMA (European Medicines Agency) and WHO (World Health Organization) are given in [Table 2]. The weight-adjusted dose for subjects < 20 kg was 0.05 ± 0.02 ml/kg (n = 19) and was significantly higher (P< 0.0001) compared to > 20 kg with a dose of 0.02 ± 0.01 ml/kg (n = 51). An overview is given in [Table 3]. A detailed presentation of all data points, both for absolute and weight-adjusted dosing, is given in [Fig. 2].

Table 2 Age-grouped dosing according to EMA and WHO.

age	n	weight (kg)	absolute Dose (ml)	p	weight- adjusted dose (ml/kg)	p
0 – 27 d	2	3.4 ± 0.2	0.20 ± 0.00	0.013	0.06 ± 0.00	0.0001
28 d – 23mo	9	6.1 ± 2.6	0.25 ± 0.06	< 0.0001	0.04 ± 0.04	< 0.0001
2 – 5y	5	15.0 ± 1.9	0.73 ± 0.18	ns	0.04 ± 0.01	0.0077
6 – 11y	10	38.7 ± 19.1	0.84 ± 0.29	ns	0.03 ± 0.03	ns
12 – 17y	20	56.9 ± 13.5	1.06 ± 0.34	ns	0.02 ± 0.01	ns
> 18y	9	65.6 ± 12.7	1.14 ± 0.41		0.02 ± 0.01
Total	55	40.8 ± 25.6	0.86 ± 0.44		0.03 ± 0.02

d = days, mo = months, y = years, ns = no significance, Mean ± SD. *one-way ANOVA with Bonferroni correction, multiple comparisons with > 18y.

Table 3 Weight-grouped dosing.

weight (kg)	n	absolute dose (ml)	p	n	weight- adjusted dose (ml/kg)	p
< 20	19	0.4 ± 0.3	< 0.0001	19	0.05 ± 0.02	< 0.0001
> 20	51	1.0 ± 0.4		51	0.02 ± 0.01
total	70	0.86 ± 0.44		70	0.03 ± 0.02

*two-sided unpaired t-test with equal SD.

Fig. 2 Dosing. A Visualization of age-grouped absolute dosing. Every symbol represents one data point; the bars represent the mean and standard deviation. “*” indicates significance. Test: ANOVA with Bonferroni correction. B Visualization of absolute dosing in groups of < 20 kg and > 20 kg. The boxplots indicate the mean with 5 to 95 percentile. “*” indicates significance. Test: t-test. C Visualization of age-grouped weight-adjusted dosing. Every symbol represents one data point; the bars represent the mean and standard deviation. “*” indicates significance. Test: ANOVA with Bonferroni correction. D Visualization of weight-adjusted dosing in groups of < 20 kg and > 20 kg. The boxplots indicate the mean with 5 to 95 percentile. “*” indicates significance. Test: t-test.

Diagnostic accuracy

Liver

Reference imaging was based on CT (n = 5), MRI (n = 21), MRI + CT + histology (n = 1), MRI+histology (n = 1), surgery+histology (n = 1), surgery (n = 2), histology (n = 2), serologic assessment (n = 1), and in n = 16 no gold standard was performed.

Agreement CEUS/reference was found in 32/34 investigations. For liver diagnostics combined gold standard (gold standard: MRI, CT or histology) resulted in n = 11 malignant and n = 15 benign focal liver lesions. The specificity was 100 % (95 % CI: 0.77 – 1.00), the sensitivity was 82 % (95 % CI: 0.48 – 0.98), the positive predictive value was 100 % (95 % CI: 0.69 – 1.00), and the negative predictive value was 88 % (95 % CI: 0.62 – 0.98) (P< 0.0001). Examples for benign and malignant focal liver lesions are given in [Fig. 3].

Fig. 3 Liver. A Series shows the arterial wash-in of UCA from 0 – 15 s, demonstrating the finding of a hemangioendothelioma. CEUS clearly shows the typical iris diaphragm sign. The lower tiles represent the corresponding MR images. It was captured in a 6-day-old boy. He received follow-up with B-mode and Doppler ultrasound imaging; the tumor showed spontaneous regression. The ring indicates the target lesion. B Series shows the arterial wash-in of UCA from 0 – 11 s, demonstrating the finding of a hepatoblastoma. CEUS shows the irregular vessel configuration of the tumor. The lower tiles represent the corresponding MR images. It was captured in an 11-day-old girl. She was treated according to hepatoblastoma protocol and histology confirmed imaging diagnosis. The ring indicates the target lesion.

In n = 2 cases reference imaging misclassified the lesion and CEUS was in accordance with clinical follow-up. 

Non-liver applications

In n = 6 investigations (= 100 %) a splenic infarction was detected, n = 5 proved by surgery/cross-sectional imaging, n = 1 (= 17 %) was clinically monitored. Two examples for splenic infraction/rupture imaging with CEUS and CT are given in [Fig. 4]. In 2/3 cases (inflammatory lesion and angiomyolipoma), MRI confirmed CEUS renal diagnostics. In the remaining case CEUS visualized renal perfusion. Examples, both for renal and testicular imaging, are given in [Fig. 5].

Fig. 4 Spleen. A Baseline B-mode, Doppler ultrasound, CEUS imaging features and CT-angiography (from left to right) of a splenic trauma in a 16-year-old boy. The ring indicates the splenic rupture and hematoma. The arrow is pointing at the free perisplenic fluid. B Baseline B-mode, Doppler ultrasound, CEUS imaging features and CT-angiography (from left to right) of a multiple splenic infarction caused by Wegener’s granulomatosis in a 15-year-old boy.

Fig. 5 Kidney and testes. A B-mode ultrasound, power Doppler ultrasound, and CEUS renal perfusion imaging (left to right) of a partly infarcted kidney in a 1-year-old girl. The arrows are pointing at singular contrasted vessel in the infarcted part of the kidney, which was not visualized by Doppler ultrasound. B Testicular imaging showing appropriate perfusion in a 14-year-old boy. Imaging was performed because of persisting testicular pain to rule out insufficient perfusion after surgery of an inguinal hernia. The arrows indicate the small testicular vessels.

Clinical follow-up

The mean clinical time for follow-up was 30.4 ± 30.5 months according to the individual patient documentation. No change in evidence, e. g. no difference between clinical follow-up and CEUS final diagnoses, was recognized. Until the end of the study, e. g. final data collection in November 2015, 4 patients died.

Discussion

Spectrum of imaging

Up to now, the performance of abdominal diagnostics using CT or MRI is superior to B-mode ultrasound imaging. In adults it is a very well established technique with widely accepted and evidence-based guidelines by the leading societies such as the European Federation of Societies in Ultrasound in Medicine and Biology (EFSUMB) [2] [3]. Up to now, almost all organs have been studied using this technique. However, research in children has been limited to only a few aspects, such as FLL diagnostics with or without underlying chronic liver disease [14] or abdominal traumata [15]. Further selected case reports are published, e. g. pheochromocytoma [16]. There is already clear evidence that CEUS might be helpful for many more indications in children such as in the case of inflammatory bowel disease [17].

According to the published literature, we found in our study that most clinical questions for CEUS arise from focal changes in the liver parenchyma (total cases for liver diagnostics n = 42: n = 41 for focal liver diagnostics, n = 1 for perfusion of portal vein), especially to differentiate malignant from benign focal lesions.

Trauma and splenic lesions are another important collective in our study (n = 7). Renal (n = 3) or testicular diseases (n = 1) are less frequent for CEUS diagnostics.

Tolerability and safety considerations

Ultrasound contrast agents (UCA) consist of gas-filled microbubbles, which strictly circulate intravascularly. The shell is formed by (phospho-)lipids and/or proteins that are metabolized in the liver. Its gas core is cleared through the pulmonary route with the exhalation air. 1 ml of application-ready UCA contains 8 µl SF₆ in microbubbles, which is equivalent to 45 µg SF₆. About 40 – 50 % of the injected dose is eliminated from the blood pool within the first minute and 80 – 90 % after 11 minutes. Therefore, an accumulation is very unlikely [18]. The main imaging effect is caused by microbubbles between 3 and 9 µm [19]. The recommended dose for SonoVue in adults is 0.02 – 0.03 ml/kg, even though it is still well tolerated at a dose 10 times higher (0.3 ml/kg) with an equivalent higher cumulative dose [18] [20]. Up to now, no specific recommendation for children has been reported. According to our data, the mean weight-adjusted dosing of SonoVue is 0.03 ± 0.02 ml/kg and the absolute dose is 0.9 ± 0.4 ml. Additionally, in our experience patients below 20 kg might need significantly higher weight-adjusted doses (0.05 ± 0.02 ml/kg). The very same cut-off could be shown at the age of 10 years. We hypothesize that high-frequency imaging probes and smaller diameters of intravenous catheters in children might destroy more bubbles, or the metabolism of the UCA, as known in many other medications, will be different.

Second, absolute doses below 0.3 ml might be ineffective and lead to unfavorable image quality with the imaging setup that was used. The dose of 0.2 ml in two infants (age: 2 months, diagnosis: hepatoblastoma, appropriate: 0.3 ml / 2 months, accessory liver tissue, 0.4 ml) showed inappropriate contrast enhancement. In two others (9 days, hemangioendothelioma / 11 days, hepatoblastoma) the contrast of 0.2 ml was sufficient. If this is due to different kinetics at this age, different scanning frequencies or mechanical properties (e. g. small diameter of IV) has to be determined in further studies.

We experienced safe absolute doses up to 0.3 ml in subjects below 10 kg and up to 0.5 – 1.0 ml in patients from 10 – 20 kg. These points have not yet been addressed and need further pharmacologic study, especially with regard to a correlation to different ultrasound imaging systems.

Dosing for testicular application could not be derived from our data and also needs further investigation with a greater number of subjects.

Side effects were observed in 2 applications (2/79, 2.5 %). One reaction was associated with nonspecific nausea and the other with the development of a single wheal in a patient with elevated allergic risk. Pre-emptively, antihistamines were administered intravenously (effect after 2 minutes) and all patients were able to leave the imaging site the same day or 30 minutes after imaging procedures. It is still unclear whether the UCA would have been also well tolerated without any additional medication. Corticosteroids or adrenalin did not have to be administered in any case nor did any resuscitation measures have to be performed, which underlines the excellent safety profile of the UCA that was used. In a study of 134 CEUS applications [21], comparable results were reported: no changes in hemodynamic status occurred, while n = 3 subjects (2.2 %) had transient side effects, n = 2 (1.5 %) with taste alteration, n = 1 (0.8 %) reported mild transient tinnitus and lightheadedness. Another study performed 167 examinations, which resulted in n = 1 (0.6 %) severe anaphylactic reaction but no other adverse events during or after intravenous administration of contrast were observed, e. g. no changes in heart rate and rhythm, blood pressure, oxygen saturation or respiratory rate [22]. A survey-based study by Riccabona [10] identified a total of 948 IV applications of SonoVue in children from 0 – 18 years in which n = 6 (0.6 %) minor adverse reactions occurred, including n = 3 subjects with altered taste (0.3 %), n = 2 with urticaria or rash (0.2 %), and n = 1 with hyperventilation (0.1 %). An overview of all studies is given in [Table 4]. In the case of adult patients, Piscaglia et al. reported a total of 23 188 investigations with no fatal event, but side effects in 29 cases yielding a rate of 0.0086 % [8]. In comparison, n = 13 334 gadolinium-based contrast media applications in children resulted in a frequency of allergic-like reactions as low as 0.04 % with mostly mild reactions [23]. Similar results were reported for n = 11 306 applications of nonionic iodinated contrast material which resulted in a frequency of allergic-like reactions of 0.18 % in pediatric patients [24]. In accordance with other studies, the inability of our youngest subjects to verbalize the occurrence of adverse side effects is a limitation and might lead to an underestimation of the true incidence of minor adverse reactions [21]. The comparison in numbers shows the current lack of solid data for UCA in children. Due to its fast liver and renal independent pulmonary clearing, its pharmacologic profile is superior to nonionic iodinated or gadolinium-based contrast media, especially in patients with a complicated medical history [18] [25].

Table 4 Reported side effects in pediatric studies.

study	n	effect	n (frequency)
Piskunowicz, 2015	167	severe anaphylactic reaction	n = 1 (0.6 %)
Coleman, 2014	134	taste alteration	n = 2 (1.5 %)
		tinnitus and lightheadedness	n = 1 (0.6 %)
Riccabona, 2012	948	taste alteration	n = 3 (0.3 %)
		urticaria	n = 2 (0.2 %)
		hyperventilation	n = 1 (0.1 %)

Diagnostic accuracy

Ultrasound imaging only displays a limited view of the whole anatomy. Therefore, its diagnostic accuracy is limited to this window. This point has been addressed extensively in adults, especially regarding focal liver lesion diagnostics [1] [4] [5] [6] [7]. CEUS is reported to have a sensitivity of > 90 % and sensitivity of > 90 %. In these cases, it is as precise as MRI or CT imaging. Jacob et al. could show that the CEUS examination interpretation in 44 children agreed with reference imaging in 29/34 (85.3 %) of the cases, resulting in a specificity of 98.0 % and a negative predictive value of 100 % [14]. These data are in good accordance with our findings.

We found agreement of CEUS with the reference diagnostics in 32/34 liver investigations. These data also support the finding that CEUS might reach the same diagnostic accuracy in children as shown in adult subjects.

Conclusion

B-mode ultrasound is one of the main techniques for abdominal imaging in pediatric patients. One drawback might still be its user dependency. Even if precautions have been taken to lower radiation exposure during CT scans, high cumulative doses of about 50 mGy might almost triple the risk of leukemia and 60 mGy might triple the risk of brain cancer in children [26]. Furthermore, MRI often requires sedation or anesthesia for appropriate results in young subjects. Depending on its imaging protocol, MRI might take up to 45 minutes of scanning time. CEUS has no need for these preparations and it is also easy and quick to perform with no need for special scanning rooms or personnel trained in radiology. This is why approval of UCA for ultrasound imaging is crucial and might be a major diagnostic step forward for our youngest patients. There are still legal issues with respect to the use of UCAs. However by NOT using them, we deny our youngest patients existing knowledge and medical progress [27]. The EFSUMB registry for the use of CEUS in pediatric practice can help to improve previous experiences (www.efsumb.org).

Our data are encouraging and we propose that controlled prospective trials in larger collectives for CEUS in pediatric patients are greatly needed to confirm the clinical relevance compared to cross-sectional imaging.

Addendum

After completion of this study another 14 off-label applications (n = 6 intravenous applications for focal liver diagnostics, including 2 patients < 1 year) of UCA were performed within 3 months. In this selected collective, an 11-year-old girl developed a severe adverse reaction (grade 3: arterial hypotonia, flush, emesis) after intravenous administration of the UCA and required short-term in-patient monitoring and treatment with steroids, antihistamines and fluids. This case illustrates again that all precautions should be taken before using CEUS in children.

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