FDA Advisory on Sedation and Anesthesia Exposure in Children

By Joseph P. Cravero, MD
Research Committee

In mid-December 2016, the United States Food and Drug Administration published a Drug Safety Communication warning that “repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 years or in pregnant women during their third trimester may affect the development of children’s brains.” http://www.fda.gov/Drugs/DrugSafety
. In the same communication the FDA noted that human and animal studies looking at relatively short exposure to these medications in the infant or toddler age group is unlikely to have negative effects on behavior and learning. In fact, the single randomized, blinded, study in humans that has investigated this phenomenon was unable to show any neurological effects two years after general anesthesia in young newborns. http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(15)00608-X/abstract. The authors note that further research is needed to fully characterize how early life anesthetic exposure affects children’s brain development. 

As part of the effort to inform the public about this potential risk, the FDA is now requiring that a warning be added to the labels of general anesthetic and sedative medications.  (This is interesting since the general public is not (usually) reading the labels on the anesthetics and sedatives that are given to them.) The communication from the FDA goes on to state that the agency will continue to monitor data on patient outcomes and make further statements and recommendations based on the data that is supplied going forward. 

Sedation providers of all types need to continue to be aware of the issues involved in this latest missive from the FDA.  Anesthetic and sedative drugs are clearly required to in order to diagnose and treat conditions that could be very dangerous (even life threatening) to pediatric patients.  In addition, there is a well-developed literature that documents the long-term adverse effects of untreated painful experiences in animal models and humans. Recognizing these facts, the FDA does not advise against the use of sedatives/anesthetics but rather promotes the idea that health care professionals need to balance the benefits versus the risks when considering the timing and necessity of procedures in children.  When exposure to sedation/anesthesia can be delayed without jeopardizing the health of a child, that delay is recommended.  The FDA advises that when discussing sedation/anesthesia and obtaining consent for procedures, the potential adverse effects on brain development should also be discussed.   

Given the recommendation for more clear discussion of risks versus benefits, it is unfortunate that this FDA advisory message is not based on new information that has profoundly added to, or changed, the collected wisdom on this topic.  Rather, the FDA notes that over the last 15 years a large number of animal studies have documented the long-term effects on animals’ behavior and learning. (See references below)  They also note that there are human epidemiologic studies that appear to indicate that there may be detrimental effects in humans, particularly after repeated or prolonged exposure.  As before, it is recognized that the human data on this topic is not conclusive and the negative effects seen in children’s learning could be due to confounding variables such as underlying illnesses that led to the need for surgery.

The FDA has been following closely the potential adverse effects of general anesthetic/sedative drugs on brain development since the first animal study on this topic was published in 1999. There have been advisory committee meetings in 2007, 2011, and 2014.  In an effort to promote research in this area, the FDA formed a partnership with the International Anesthesia Research Society (IARS) called SmartTots (Strategies for Mitigating Anesthesia-Related neuroToxicity in Tots). The Society for Pediatric Sedation has participated in the discussion of this topic through the SmartTots initiative and remains committed to helping research and report on this matter. 

The take-home message from this FDA publication remains unchanged from previous advice on this topic.  There is really not enough evidence to recommend against the use of sedation/anesthesia in children.  On the other hand, until there is clarity on this topic, avoiding unnecessary exposure to these medications is clearly indicated.  Referring physicians should be made aware of this continued concern and should balance the risk of anesthetic exposure with other risks (such as radiation exposure).  Choices such as CT scan versus MRI scan for follow up studies in pediatric oncology patients should also take this warning into account.  Where tests or studies cannot be shown to convincingly influence care, they should likewise be avoided.  More than anything else, the added attention from the FDA enhances the need for the sedation physician to be a consultant and to help others who care for children understand the implications of sedation/anesthesia and make the best possible decisions for their patients.

References from the FDA Advisory:

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  2. Briner A, De Roo M, Dayer A, Muller D, Habre W, Vutskits L. Volatile anesthetics rapidly increase dendritic spine density in the rat medial prefrontal cortex during synaptogenesis. Anesthesiology 2010;112:546-56.

  3. Briner A, Nikonenko I, De Roo M, Dayer A, Muller D, Vutskits L. Developmental Stage-dependent persistent impact of propofol anesthesia on dendritic spines in the rat medial prefrontal cortex. Anesthesiology 2011;115:282-93.

  4. Creeley C, Dikranian K, Dissen G, Martin L, Olney J, Brambrink A. Propofol-induced apoptosis of neurones and oligodendrocytes in fetal and neonatal rhesus macaque brain. Br J Anaesth 2013;110 Suppl 1:i29-38.

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  27. Kalkman CJ, Peelen L, Moons KG, Veenhuizen M, Bruens M, Sinnema G, et al. Behavior and development in children and age at the time of first anesthetic exposure. Anesthesiology 2009;110:805-12.

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  32. Flick RP, Katusic SK, Colligan RC, Wilder RT, Voigt RG, Olson MD, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics 2011;128:e1053-61.

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  37. Sprung J, Flick RP, Katusic SK, Colligan RC, Barbaresi WJ, Bojanić K, et al. Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc 2012;87:120-9.

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  41. Davidson AJ, Disma N, de Graaff JC, Withington DE, Dorris L, Bell G, et al. Neurodevelopmental outcome at 2 years of age after general anaesthesia and awake-regional anaesthesia in infancy (GAS): an international multicentre, randomised controlled trial. Lancet 2016;387:239-50.

  42. Sun LS, Li G, Miller TL, Salorio C, Byrne MW, Bellinger DC, et al. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA 2016;315:2312-20.

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