SmartTots and FDA

American Society of Anesthesiologists Article

March 1, 2015

Volume 79, Number 3

Anesthetic-Related Neurotoxicity in Children – ASA Works in Close Cooperation With FDA and Others to Advance Research

Randall P. Flick, M.D., M.P.H., Chair

Committee on Pediatric Anesthesia

Caleb H. Ing, M.D., M.S.

With more than 1 million children younger than 5 years old in the United States receiving anesthesia for surgical procedures and thousands more for diagnostic procedures, the safety of anesthetics in young children is an important public health issue. Concerns about anesthesia affecting the developing brains of young children first emerged following findings of anesthetic agents inducing neuroapoptosis and subsequent behavioral deficits in pre-clinical animal model studies. The U.S. Food and Drug Administration (FDA) Anesthetic and Life Support Drugs Advisory Committee specifically convened a meeting to discuss the potential clinical significance of the results of these studies in April 2007. This was followed by sponsorship of the Safe Kids initiative by the FDA, which provided initial support for clinical research to address this issue.

Since 2007, a large number of pre-clinical studies have provided robust evidence of anesthetic neurotoxicity in the developing brains of rodents and non-human primates. The relationship between anesthetic exposure and neuroapoptosis with subsequent functional deficits in animals is now well established. However, determining whether these effects are present in children has been more problematic. Clinical studies of neurotoxicity in children face a number of challenges, including the lack of an obvious clinical phenotype, the inability to isolate anesthesia from surgery in healthy children and difficulties in evaluating cognition in early childhood. Despite this, clinical studies have looked at the association between different exposure types, including single and multiple anesthetic exposures for various surgical procedures, and also studied a range of different neuropsychological outcomes.

Overall, the results from these retrospective studies of observational data have been mixed, however, with some studies finding an association between anesthesia exposure and cognitive deficit while others found no such association.

In 2010, the International Anesthesia Research Society (IARS) partnered with the FDA to create a public-private partnership initiative called SmartTots to specifically conduct research to ensure anesthetic safety in children. The purpose of SmartTots is to mobilize stakeholders, including researchers, parents and caregivers, to raise money to fund research in three fundamental areas:

What is the spectrum of general anesthetic agents, sedatives, surgical procedures and/or opiates that causes developmental neurotoxicity? What are the doses, durations and frequencies of exposure? What are the most vulnerable periods of development?

  1. Are there short- and long-term neurocognitive, emotional, behavioral and/or social outcomes resulting from 2. exposure to anesthetic agents?

3. What approaches can be taken to prevent or mitigate developmental anesthetic neurotoxicity?

SmartTots has provided two separate rounds of funding to address these key questions with two inaugural grants awarded in 2012. One grant was awarded to Robert Block, M.D. and colleagues from the University of Iowa who had evaluated a cohort of children in Iowa by looking at academic performance after exposure to anesthesia. Their proposed funded study involved the use non-invasive imaging and cognitive testing to further evaluate the exposed children. The second grant was awarded to a group collaborating between Columbia University and the University of Western Australia evaluating a birth cohort from Perth, Australia. The proposed study involved comparing a variety of outcomes used in assessing children exposed to anesthesia, evaluating the association between duration of anesthetic exposure and deficit, and adjusting for comorbid illness. The common thread between the two inaugural projects was that the preliminary work was based on retrospective identification of exposure and analysis of previously collected outcomes assessments.

In the second round of funding in 2013, two further grants were awarded to Lena Sun, M.D. at Columbia University and Jeffrey W. Sall, M.D., Ph.D. at the University of California, San Francisco. In contrast to the two inaugural grants, these two projects were conceived as ambidirectional studies, retrospectively identifying children who were exposed to anesthesia at an early age, and then prospectively performing neurocognitive assessments. Dr. Sun is the principle investigator for the multicenter Pediatric Anesthesia and Neuro-Development Assessment (PANDA) Study. The PANDA Study aims to evaluate the effect of a single episode of anesthetic exposure for hernia surgery in healthy children prior to age 3 years and assesses a variety of cognitive outcomes at ages 8-15. Dr. Sall is specifically interested in measuring recognition memory deficits associated with anesthetic exposure, deficits he also found in rodent models. His project proposes to evaluate the effects of anesthetic exposure duration and age of exposure on recollection in children.

The problem with the published studies which have found cognitive differences between exposed and unexposed children is that these findings may be attributable to innate differences in children who need surgery, other perioperative or surgical insults, or additional confounders. The four SmartTots-funded studies were all designed to identify the association between cognitive deficit and various types of anesthetic exposure. The design of these studies, however, suggests they will unlikely establish causation between exposure and cognitive outcome. Thus the current status of evidence for anesthetic

neurotoxicity in children is best summarized by the SmartTots consensus statement: “In the absence of conclusive evidence, it would be unethical to withhold sedation and anesthesia when necessary.”

In order to address this uncertainty and determine the necessary direction of future scientific investigation, SmartTots and the FDA sponsored a meeting on June 20, 2014 in Arlington, Virginia. The goal was to identify a study or series of studies that would not only move the science forward but also resonate with and engage stakeholders. In addition to the fundamental research priorities of SmartTots, Bob A. Rappaport, M.D., Director of the Division of Anesthesia, Analgesia, and Addiction products at the FDA, emphasized the importance of establishing a causal link between anesthesia and adverse neurodevelopmental outcomes as well as the need to identify protective anesthetic strategies.

Methods to address these important clinical questions were discussed and two major categories of studies were proposed. The first involved the creation of a large-scale, prospective, observational study to assess subgroups of children exposed to anesthesia. The second proposed the creation of a prospective, randomized, controlled trial comparing standard anesthetic regimens with safer approaches. While the second approach would more effectively establish causality, data on “safe” anesthetic regimens was found to be lacking even in animal studies, and the need for preliminary data on alternate anesthetic regimens was recognized.

In November, data regarding the potential toxicity of anesthetic agents was presented to the FDA’s Science Board. The science board serves to directly inform the commissioner with regard to scientific issues of importance to the agency. ASA, the Society for Pediatric Anesthesia and American Academy of Pediatrics joined together to provide both written and verbal comments to the board encouraging urgent investment in research to clarify the risk of anesthetic exposure to young children. The results of the committee’s deliberations are pending.

While anesthetics have convincingly been found to cause neurotoxicity in young animals, much work remains in determining whether these agents cause a similar effect in children. The FDA and IARS, through their partnership in the SmartTots initiative, have taken an active role in moving the science forward in ensuring the safety of anesthetics in children. Since its inception, the funding priorities of SmartTots have advanced with the evolving science. While long-term neurodevelopmental differences between exposed and unexposed children have now been found in several studies, the reason for these differences is still unknown.

Based on their latest approach to investigating and funding studies of anesthetic neurotoxicity, SmartTots and the FDA have been increasingly determined to position the research to hone in on the question of whether the increased risk of cognitive deficits seen in some studies is truly a result of the anesthetic medications or due to another reason entirely. Ultimately, the answers to these questions are unlikely to be found unless a significant investment in research is made. Working with the IARS, ASA – along with SPA and AAP – continues to lobby for increased research funding.

Randall P. Flick, M.D., M.P.H. is Associate Professor of Anesthesiology and Pediatrics, and Director for Mayo Clinic Children’s Center, Mayo Clinic, Rochester, Minnesota.

Caleb H. Ing, M.D., M.S. is Assistant Professor of Anesthesiology, Division of Pediatric Anesthesia at Columbia University, Children’s Hospital of New York.


1. Rabbitts JA, Groenewald CB, Moriarty JP, Flick R. Epidemiology of ambulatory anesthesia for children in the United States: 2006 and 1996. Anesth Analg. 2010;111(4):1011-1015.

2. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg. 2007;104(3):509-520.