The safety of anesthetics administered to infants and young children is a growing public health concern. With a number of rodent and primate studies indicating neurotoxic outcomes as the result of clinically relevant exposures in very young animals to anesthetic drugs (many of which are also used as sedatives, especially in the intensive care setting), the medical and scientific communities are joining forces to determine whether the same risks apply to humans. The result of this multidisciplinary collaboration is a public-private partnership between the International Anesthesia Research Society (IARS) and the United States Food and Drug Administration (FDA), Strategies for Mitigating Anesthesia-Related neuroToxicity in Tots (SmartTots).
In 2008, the FDA and the IARS began working together to create an administrative structure and scientific framework for SmartTots capable of identifying key research questions and overseeing investigations to ensure effective allocation of resources. In keeping with the recommendation by the FDA,1 we adopted a multidisciplinary approach involving broad and direct input from multiple stakeholders including professional societies and industry. Pharmaceutical companies, professional organizations, and more than 40 medical and scientific experts from around the world have since joined SmartTots.
On March 10, 2011, the FDA held a public Anesthetic and Life Support Drugs Advisory Committee meeting to discuss the current status of research investigating anesthesia-related neurotoxicity in pediatrics. During this meeting, the committee evaluated findings from recent studies conducted by the National Center for Toxicological Research and several academic centers, with a focus on the relevance of animal data to humans. The committee noted that although some progress had been made since the first Advisory Committee meeting on this issue in 2007, there were still not enough data, especially in humans, to draw any firm conclusions. With more than 6 million infants and children exposed to sedation and anesthesia in the United States on an annual basis,2 the implications of any recommendation regarding these agents are immense. Regardless of the strength of the animal data, altering clinical practice based on animal data alone would be a poor choice.3 The Advisory Committee concluded that before any practice recommendations could be considered, additional studies are needed.a
The SmartTots Scientific Advisory Board, a multidisciplinary team of researchers assigned to navigate our scientific direction (Table 1), immediately designed and implemented a research agenda focused on determining whether results from the animal studies could be translated to humans, the primary goal of our first request for applications released in August of this year.
We need to determine whether a signal suggesting anesthetics induce neurodegeneration in the developing human brain does in fact exist. To this end, we anticipate studies based on worst-case scenarios, focusing on volatile anesthetics administered during developmental periods of rapid brain growth in high-risk circumstances, such as prolonged sedation. Investigations will likely use in vitro and rodent models as strategic screening mechanisms before investigations are moved to higher, nonhuman primates. We anticipate that research supported by SmartTots will determine not only which anesthetics, if any, cause developmental neurotoxicity but also at which dose, duration, and frequency of exposure. We hope to define the most susceptible periods of vulnerability, and verify whether any short- or long-term neurocognitive, emotional, behavioral, or social outcomes result from exposure to anesthetic agents. Should frequently used drugs be deemed unsafe for use in young children, the goal is to identify and implement approaches for preventing and mitigating neurotoxic outcomes, which may include developing safer anesthetic regimens. As demonstrated in both rodents and primates, it is possible that some anesthetics will be found to be less toxic than others.4
Closing these research gaps will take years of research, major funding, and numerous collaborations. We anticipate that these studies may cost as much as $40 million, an expensive forecast during a time when funding is a major challenge. To ensure that we have the necessary funds to see this important safety initiative come to fruition, we have solicited the partnership of influential public figures to serve on our Executive Board to drive our fundraising efforts. Leading our Executive Board is Dr. Michael Roizen, Chair of the Cleveland Clinic Wellness Institute, New York Times best-selling author, household age and wellness expert, and a well known leader in anesthesiology. His longtime business partner, Dr. Mehmet Oz, cardiac surgeon and star of the hit television program TheDr.Oz Show, has also joined our executive team. Both Drs. Roizen and Oz are recurring guests on Good Morning America and coauthor a daily newspaper column syndicated nationwide.
During the IARS 2011 Annual Meeting, Dr. Roizen announced a $200,000 contribution made by the IARS to “jump start” funding for SmartTots. Dr. Roizen immediately complemented the IARS donation with a contribution of his own, an annual $50,000 challenge grant for the next 20 years, a $1 million pledge. This challenge grant is intended to match contributions made by “physicians and the general public.” SmartTots has since drawn interest from prominent philanthropists, pharmaceutical companies, and clinicians.
As you will read in this issue of Anesthesia & Analgesia, some of the brightest minds in our specialty are collaborating to help us answer the questions and evaluate the evidence. There is no way around the need for sophisticated, large-scale, long-term human studies, and these studies are going to be expensive. The confounding factors are many; human research needs to be very carefully thought out and conducted with the highest level of scientific expertise. Our broad-based group of experts on our Scientific Advisory Board, who will be driving the science, continue to set the research agenda, evaluate proposals, and guide the funding. We are optimistic that through SmartTots we will be able to determine the neurologic risks, if any, of exposure to sedative and anesthetic agents to our infants and children. If risks are real, then we will help set the agenda to develop safe techniques and new agents to provide the safest care and best outcomes. Perhaps most importantly, through this collaborative effort, we will be able to assure parents and children that necessary procedures and care can be provided with minimal risk of neurologic injury due to sedative and anesthetic agents.
On behalf of SmartTots, we'd like to invite you to join our quest to ensure the safety of every anesthetic administered to infants and young children. For more information about SmartTots and the research we support, visit us online at www.SmartTots.org.
Name: James G. Ramsay, MD.
Conflict of Interest: Co-Chair, SmartTots Steering Committee.
Name: Bob A. Rappaport, MD.
Conflict of Interest: Co-Chair, SmartTots Steering Committee.
a Minutes for the March 10, 2011 Meeting of the Anesthetic and Life Support Drugs Advisory Committee. Available at: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AnestheticAndLifeSupportDrugsAdvisoryCommittee/ucm238442.htm.Accessed July 29, 2011.
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2. DeFrances CJ, Cullen KA, Kozak LJ. National Hospital Discharge Survey: 2005 annual summary with detailed diagnosis and procedure data. Vital Health Stat 13. 2007; Dec (165):1–209
3. Stratmann G, Sall JW, May LD, Loepke AW, Lee MT. Beyond anesthetic properties: the effects of isoflurane on brain cell death, neurogenesis, and long-term neurocognitive function. Anesth Analg 2010;110:431–7
4. Paule MG, Li M, Allen RR, Liu F, Zou X, Hotchkiss C, Hanig JP, Patterson TA, Slikker W Jr, Wang C. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol 2011;33:220–30