Primum non nocere? Why Can’t We Use Second Generation Ultrasound Contrast Agents for the Examination of Children?

The first ultrasound examinations were performed at times when physical bases of CT (computed tomography) and MRI (magnetic resonance imaging) were formed. However, the first ultrasound contrast agents (UCAs), Echovist® and Albunex®, were registered for diagnostic purposes as late as the mid-1980 s [1], although the contrast media had long been used for CT and MRI on a routine basis at that time.

The history of UCAs starts with the end of the 1960 s, with the first attempts to visualize the aorta using a solution of physiological saline with multiple air bubbles [2]. The next stage was the registration of UCAs: Echovist® and Albunex®, which allowed for their echocardiographic application. At the beginning of the 1990 s, the first publications on Levovist® appeared. This preparation turned out to be useful not only in heart diagnostics, but also in the evaluation of focal lesions in the spleen and liver. In pediatric diagnostics, it was fully accepted for the purposes of assessing vesicoureteral reflux. Levovist® was finally registered in 1996.

After the year 2000, second-generation UCAs were launched on the market: Imagent®, Definity® (USA/Canada)/Luminity™ (EU), Optison™, SonoVue®. The first contrast agent is registered in the United States only. Remaining agents Definity® (under the name of: Luminity™), Optison™ and SonoVue® were registered in Europe. Apart from the SonoVue® contrast agent, the registration indications of all remaining second-generation UCAs include echocardiographic purposes only.

In the registration document for the SonoVue® contrast agent, marketed in the EU in the year 2001, there are also other applications mentioned, apart from echocardiography. These include the assessment of microflows and large vessel flows. In the first years after the introduction of SonoVue®, most of the publications focused on its potential for the detection and characterization of focal liver lesions. The results of these studies, showing a similar or even a higher sensitivity and specificity than CT or MRI, changed the diagnostic algorithms and marked a breakthrough in ultrasonography owing to second-generation UCAs.

The initial guidelines concerning clinical application of UCAs were developed in 2004 by a group of experts – EFSUMB (European Federation of Societies for Ultrasound in Medicine and Biology). There were eight pages with information on the registered second-generation UCAs and recommendations concerning their application in the detection and interpretation of hepatic focal lesions, as well as the evaluation of thermoablation procedures of hepatic tumors [3]. In 2008, the reedited version of the guidelines had 17 pages and included new recommendations regarding the application of UCAs: evaluation of focal lesions within kidneys, evaluation of the transplanted kidney, lesions within the pancreas, patients after blunt traumas of the abdominal cavity and transcranial ultrasonography [4]. Since 2008, there have been new articles in the literature, concerning the usefulness of the SonoVue® contrast agent for the diagnostics of muscle trauma, the degree of activity of the Crohn’s disease process, the differentiation of the focal lesions within breasts, the location of the focal lesions within adrenal glands, the evaluation of the lesions within the parotid glands, and others [5] [6] [7] [8] [9].

It should be emphasized that none of the UCAs (neither first nor second-generation) are registered for individuals under 18 years of age.

It is therefore interesting that according to guidelines regarding the clinical application of ultrasound contrast agents developed by the EFSUMB group of experts in 2008, UCAs (except Levovist®) cannot be used for diagnosing vesicoureteral reflux in children. However, this diagnostic method is presented during UCA training sessions organized by EFSUMB (Hanover – 2008).

Despite the fact that UCAs are not registered for individuals under 18, SonoVue® is applied in the pediatric population in some European centers.

There are also publications concerning the advantages of UCA application in children in emergency conditions, after blunt injuries to the abdominal cavity [10] [11] [12]. In the publication from 2008, Valentino presented studies conducted in 27 children (19 boys, 8 girls, mean age 8.9 years ± 2.8 [standard deviation]). In this group of patients, no adverse reaction was observed after the administration of SonoVue® [12].

Generally, revolutionary changes in ultrasound imaging that occurred due to ultrasound contrast agents, do not concern pediatric diagnostics.

Potential benefits, such as limited ionizing radiation thanks to a lower number of CT and standard cystourethrography scans, no need for sedation in the case of smaller children, reproducibility or lower costs of the examination compared to CT and MRI, are commonly known. It should be underscored that it is of utmost importance in the diagnostics of this group of patients to improve the sensitivity and specificity of the examination, which should allow for a more rapid and adequate diagnosis. The experiences with UCAs in adults, especially excellently documented examination of liver changes, could be easily applied to children [13] [14] [15] [16]. The possibility of bedside examinations is also important, especially in the ICU or in the case of children with hemato-oncological diseases. In cancer patients, second-generation UCAs would allow for the evaluation of the vasculature pattern within a tumor and monitoring of the response to initial chemotherapy introduced before a planned surgery. It seems that a more precise evaluation of the vascularization pattern of lymph nodes would be useful in the assessment of the primary and secondary lesions within the lymphatic system [17]. Moreover, it would also be possible to evaluate complications of anti-cancer treatment, i. e. residual lesions or evaluation of the central venous access in case of problems other than infectious complications.

Taking into consideration only this small but significant (from the point of view of pediatric diagnostics) group of potential advantages of the second-generation UCAs, we should try to answer the question: ”why do we refuse to provide children with better and more precise diagnostic procedures?”. We realize that this question tends to be rhetorical and controversial for the time being. However, the constant development of this diagnostic method in the adult patient population prompts this question. For the last few years, the authors of the article have been asking this question during ultrasound imaging conventions but they tend to receive the same answer: no registration of UCAs in individuals under 18.

This is confirmed by the SonoVue® information leaflet: Safety and efficacy have not been established in patients under 18, therefore SonoVue® is not intended for use in that group [18].

Theoretically, the reason could be the high costs of the clinical trials necessary to market the product and a problem with the reimbursement of the incurred costs. Most probably, such conditions determined the withdrawal of Levovist® from the markets of the majority of European countries. At present, this preparation is available in Europe in: Germany, France, Sweden, and Switzerland.

The next, and probably the most important, aspect of UCA use in pediatrics is the pharmacological safety of SonoVue®.

Despite the fact that this preparation was frequently examined for pharmacological safety in large population studies among adult patients, there have been no such studies in a child population yet.

The largest European studies conducted after the introduction of the SonoVue® product on the market included 23 188 patients who underwent evaluation of the abdominal cavity [19].

29 cases of adverse reaction to SonoVue® were recorded. 2 of them were rated as severe, while the remaining 27 were classified as ‘not posing threat to patient’s life’ [19]. The most important fact is that no deaths following adverse reactions were noticed. In the table presented below, taken from the above quoted study [19], the rate of adverse effects connected with the use of UCAs is lower than after the administration of the allegedly safe contrast media used in MRI ([Table 1]). The number of reported complications after SonoVue® administration is similar to the number connected with commonly used antibiotics or analgesics, estimated at 0.005 – 0.015 %, which was shown in a large population study carried out in the United States [20].

Table 1 The rate of adverse effects of various radiological contrast media from Piscaglia study 19. author/year sample size Ionic CM non-ionic CM Gadolinium-based CM for MRI Katayama et al. 1990 33,7647 0.22 % 0.04 % Cochran and Bomyea 2002 > 56,000 0.015 % Wolf et al. 1991 ≈15,000 0.25 % 0.1 % Palmer 1988 109,546 0.09 % 0.02 % Thomsen and Bush 1998 > 21,000 0.01 % Kirchin et al. 2001 2 540 0.2 % Kirchin et al. 2001 > 100,000 > 0.005 % Piscaglia 2006 23,188 SONOVUE 0.0086 %

Of course, the problem with UCA registration in children may be posed by reported deaths, which can have a potential connection with the use of second-generation UCAs and which were detected in the first 12 hours after agent administration.

Three fatal cases recorded after SonoVue® administration involved patients in a critical condition who underwent echocardiography. Ten fatal cases could be potentially connected with the administration of second-generation UCAs – Definity® and Optison™, which were recorded during 6 years of second-generation UCA use in the USA. Four of them occurred less than 30 minutes after UCA administration: one after a stress test, 2 in patients with severe heart failure and one in a ventilated patient with severe breathing difficulties, sepsis and an extensive pulmonary embolism [21]. The next 6 deaths occurred within 1 – 12 hours of UCA administration. The condition of all patients was very poor. Other medical procedures and intensive pharmacotherapy were applied simultaneously.

During the 6 years of UCA use, 2 million studies were performed. With 4 deaths that could potentially result from the application of UCAs, the risk of death is estimated at 1:500 000 cases. Just to compare, the fatality rate for transesophageal echocardiography is 1:10 000 [21] [22].

Despite that fact, the FDA (Food and Drug Administration) issued a recommendation not to use these agents in patients with cardiopulmonary instability, acute myocardial infarction and increasing heart failure, and introduced special warning stickers on those products – the so-called ‘black box warning’ [23]. After the FDA’s announcement, there were multiple comments questioning the legitimacy of that decision and showing the safety of UCAs on the basis of multiple previous studies conducted among patients with severe cardiopulmonary insufficiency [24] [25] [26] [27].

The authors obtained the following answers to numerous questions about registration and the potential clinical application of UCAs in patients under 18 years of age that have been raised during conventions and workshops on ultrasonography and contrast-enhanced ultrasonography: ”… there are very high bureaucracy standards to meet, which were established in the end to protect children’s welfare. For example, it is required that specially educated ethical committees are consulted, physicians educated in children psychology are performing the informed consent using age-related patient information for children and parents, etc. This problem has been realized by the European Medical Agency and they recently established an expert pediatric committee to take care of and facilitate procedures and conditions to obtain regulatory approval for drugs in children. The basis for clinical studies to obtain the pediatric indication is the development and approval of a pediatric investigation plan. The UCA producers are in continuous discussion with the EMA, to elaborate possibilities and conditions for line extension and removal of contraindications for their products. However, these discussions require time and the submission of extensive documents, which have to be compiled.”

At present, it is impossible to evaluate all potential benefits of the application of second-generation UCAs in pediatric populations. Hopefully rapid registration of these preparations in this group of patients is the main aim of the manufacturers. Physicians performing ultrasound examinations and many clinicians already support this idea. Based on the ‘Primum non nocere’ principle – let us allow the pediatric patients to benefit from the recent achievements of medicine.

M. Piskunowicz, Gdańsk, Poland, [e-mail]
W. Kosiak, Gdańsk, Poland, [e-mail]
N. Irga, Gdańsk. Poland, [e-mail]

Echovist® is a registered trademark of Bayer Schering Pharma AG.
Albunex® is a trademark of Mallinckrodt Inc.
Levovist® is registered trademark of the Bayer group, Germany
SonoVue® is a registered trademark of Bracco International B. V., Italy
Imagent® is a registered trademark of Alliance Medical, Austin, TX, USA
Luminity™ is a trademark of Bristol-Myers Squibb Medical Imaging, Inc.
Definity® is a registered trademark of Bristol-Myers Squibb Medical Imaging, Inc.
Optison™ is a trademark of GE Healthcare.

References

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1 Members of the EFSUMB Executive Bureau.

2 Chairperson of EFSUMB Committee for Medical Ultrasound Safety, [e-mail].