Pediatric Research and Scholarship: Another Gordian Knot?

Abstract

Peter J. Davis, MD Appearing in this issue of the journal are four clinical papers on the use of dexmedetomidine in children (1–4). Previous studies of the use of this drug in children have dealt with sedation in the intensive care unit (5), prevention of postoperative agitation associated with sevoflurane anesthesia (6,7), and sedation for noninvasive procedures (8–12). These articles also illustrate a number of subtle concerns that are relevant to drug development in children and the ethical principles that guide research in human subjects as proposed by the National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, and summarized in the Belmont Report. In a randomized study of 30 pediatric cardiac surgical patients anesthetized with isoflurane and undergoing cardiopulmonary bypass (CPB), Mukhtar et al. (1) evaluated the effects of a continuous dexmedetomidine infusion on patients’ underlying hemodynamics and neuroendocrine system compared with patients receiving a saline control infusion. The authors infused dexmedetomidine after anesthetic induction until the termination of CPB. Dexmedetomidine attenuated the increase in the neuroendocrine markers of stress caused by sternotomy and CPB. In addition, dexmedetomidine provided better intraoperative hemodynamic stability in children with congenital heart disease. The report focused on hemodynamic outcome and did not address how this drug affected tracheal extubation time, recovery, length of hospital stay, or long-term outcome. Thus, the reader is left to ponder whether the reduction in the cortisol and norepinephrine, markers of neuroendocrine response, affect outcome. Moreover, we do not know how to titrate dexmedetomidine or if the optimum dose was administered. Are there dexmedetomidine doserelated adverse effects in this population? Should the dose be altered at the start of CPB? What is the effect of the fluctuation in the patient’s temperature (37° to 25° and return) on plasma levels achieved using a standard infusion rate? Why was dexmedetomidine not continued until the end of surgery? Why did the dexmedetomidine infusion not allow for less anesthetic administration, as had been shown in an adult study (13)? Did dexmedetomidine improve hemodynamic stability after bypass? Although this study measured biochemical endpoints to assess stress response, can we infer that the effect of this drug will be as salutary as the effect of opioids in the mortality of children having surgery for congenital heart disease? These questions were not answered because the study was not funded, limiting the number of subjects and the resources available to the investigators. Had this study been funded by the pharmaceutical manufacturer, the authors could have enrolled more patients, perhaps included other study centers, assayed blood for dexmedetomidine concentrations, developed pharmacokinetic models of dexmedetomidine in this population, and performed a pharmacodynamic concentration-versus-response analysis. In a study of 60 children undergoing magnetic resonance imaging, From the Department of Anesthesiology, Wake Forest University School of Medicine, Winston-Salem, North Carolina; Department of Anesthesia, Stanford University, Stanford, California; Department of Anesthesiology, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Accepted for publication March 22, 2006. Address correspondence and reprint requests to Peter J. Davis, MD, Professor of Anesthesia and Pediatrics Anesthesiologistin-Chief, University of Pittsburgh School of Medicine, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213. Address e-mail to davispj@anes.upmc.edu. Copyright © 2006 International Anesthesia Research Society DOI: 10.1213/01.ANE.0000220033.34889.CE