Authors Reply:

We read with interest the letter of Dr. Keith Barrington about major ethical issues concerning our paper ((1). Maybe it was not totally clear in the population section of the paper how the subjects of the study were selected. In 1992 we started an approved study to establish normal values for dobutamine stress echocardiography in children. The stress dobutamine echocardiography was also used to study functional cardiac reserve and cardiac dysfunction in patients suspected of anthracycline cardiotoxicity (2), and the test is now used in our hospital in clinical practice. At that time it occurred to us that the stress-velocity data were different from what could be expected. We decided to use the aforementioned data gathered during the course of the first study (2) together with new data obtained in nonsedated newborns at rest for the purpose of this paper, meaning that not a single subject underwent a dobutamine stress echocardiography for the sake of elucidating the nature of the stress-velocity relationship only!

The other remarks of Dr. Barrington are important because they illustrate the ethical difficulties one encounters in pediatric research. A recent paper focused on specific ethical issues of pediatric research (3). One of the most important remarks was that children have the right to the best care possible including research to ensure that they have equal and safe access to existing and new drugs (and diagnostic procedures). The authors underline that “one of the greatest stumbling blocks to the implementation of appropriate pediatric drug research is a confusion around the therapeutic or nontherapeutic distinction.” Therapeutical research is used for research involving subjects with a specific disorder and with the potential for some benefit to the subject and nontherapeutic research is conducted with volunteers for the acquisition of generalizable knowledge. The authors state that many levels of research defy the classification and that research projects should not be labeled as therapeutic or nontherapeutic, but understood as “research” in the first place, meaning to be undertaken for the acquisition of new knowledge. The evaluation of the ethical integrity of each research project should only be focused on the ratio of risk and benefit and not on its therapeutic investigative intent. The aim of pediatric research could be defined as a potential benefit to the participating child or to children in general. Accepting, as we do, that dobutamine stress echocardiography has a potential benefit to children and that to evaluate the response of patients with heart disease, normal values in healthy controls are necessary, one is confronted with the question whether this information can be obtained from healthy children at minimal risk. Minimal risk is understood to mean that the probability and the magnitude of harm and discomfort anticipated in the research are not greater than those risks the child may encounter in daily life (3). We decided to use dobutamine at low doses not exceeding 5 μg/kg/min in carefully selected and monitored healthy individuals (2). Since dobutamine has no chronotropic effect below a dose of 5.5 μg/kg/min and because we could not find evidence of other important side effects at low doses (4, 5), we consider the infusion of this low dose of dobutamine in a well-monitored healthy individual a minimal risk. In adults with coronary heart disease, the frequency of serious events in all reported dobutamine studies, with high doses up to 40 μg/kg/min, is comparable to that reported for exercise testing (6).

We agree that parents of siblings of cancer patients might consent to the procedure out of a sense of gratitude, but we took great care not to put any stress on them, and the parents only consented to the test after being well informed by the cardiologist, who was not involved in the cancer treatment (no dependent relationship). Other children were also involved in the study, and it took us a few years to collect sufficient data in healthy controls because we took great care not to influence the volunteers or their parents. Moreover we asked the children, even the youngest, if they really consented to participate in this study involving insertion of a venous catheter and administration of a drug that would influence the working of their heart. We can inform you that parents and children do not make this type of decision without deep reflection, and it seems that in most circumstances parents are the best advocates of their children's rights.

We chose to respond to Dr. Barrington's letter because we agree that the paper was not entirely clear in the explanation of the study's design. We think that we considered the ethical questions of the study thoroughly and that indeed we carefully weighed the risk for the individual child and the benefit of obtaining normal values for a diagnostic test in children.

D. De Wolf

H. Verhaaren

T. Sluysmans

D. Matthys