Volume 28, ISSUE 2

Update on Neurotoxicity of Anesthetics in Children

Lee C. Woodson, MD Anesthesia Patient Safety Editor

In 2015 the consensus statement of the FDA, SmartTots, and the American Academy of Pediatrics (http://smarttots.org/about/consensus-statement/) was revised to convey a heightened level of concern regarding the potential for agents that increase GABAA receptor activity (volatile anesthetics, propofol, and benzodiazepines) or block NMDA receptors (ketamine and nitrous oxide) to produce neurotoxicity. Continued concern is based on accumulating substantial preclinical evidence of neurotoxicity of these drugs in young experimental animals.

In response to parent’s questions, the SmartTots consensus statement advises healthcare providers to highlight the uncertainty of extrapolating observations in animals to children and recommends that we explain that “no specific medications or technique can be chosen that is safer than any other.”[1]

Recent studies, both animal and clinical, provide encouraging evidence of the safety of general anesthesia for pediatric patients. The GAS trial is a multinational prospective study comparing the effects of awake regional anesthesia with general anesthesia for inguinal hernia repair. The study’s primary outcome measure is neurodevelopmental assessment at 5 years of age. Results of the 2 year assessment (a secondary outcome measure) recently published in Lancet found no evidence of adverse effects after exposure to approximately 1 hour of sevoflurane anesthesia as an infant.[2] This remains a complex topic and this study does not address prolonged or multiple anesthetics or more vulnerable subgroups but is the strongest evidence to date that a single exposure to general anesthesia does not produce significant neurotoxicity.

Extrapolation of effects in experimental animals to clinical applications is difficult. Studies in newborn rodents consistently show neurotoxicity of anesthetics but it is difficult to monitor small animals during exposure and the studies are associated with a significant rate of mortality. Of more concern was the demonstration of adverse effects of ketamine in subhuman primates.[3] The clinical relevance of this study is likely low, since the doses studied were much greater (20mg/kg IM followed by a 24 hour infusion at 20-50 mg/kg/hr) than typically used in humans. Until recently this was the only study in nonhuman primates that studied neurodevelopmental effects of anesthetics. In 2015, Zhou and others reported that infant monkeys anesthetized with sevoflurane for 5 hours did not experience observable adverse neurodevelopmental effects 7 months later.[4]

A Swedish epidemiological study found no decrease in school performance at age 16 years in children who had one surgery at either 0-6 months, 7-12 months, or 13-24 months of age. In contrast, gender did have an effect (males 9.7% lower) as did month of birth (children born in December had school marks 5.31% lower than the overall mean.)[5]

These more recent studies provide “talking points” to reassure concerned parents. Currently it appears that a single brief anesthetic exposure is safe. Harmful effects associated with prolonged or multiple anesthetics remain theoretical and unknown but, if real, appear subtle since solid evidence is difficult to produce. These theoretical risks must be weighed against harm due to delays or avoidance of urgent needs.

I appreciate comments and can provide additional references on request to: lwoodson@utmb.edu.

  1. Rappaport BA, Suresh S, Hertz S, Evers AS, Orser BA.: Anesthetic neurotoxicity–clinical implications of animal models. N Engl J Med. 2015 Feb 26;372(9):796-7
  2. Davidson AJ 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 Jan 16;387(10015):228.
  3. 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 Mar-Apr;33(2):220-30.
  4. Zhou L, Wang Z, Zhou H, Liu T, Lu F, Wang S, Li J, Peng S, Zuo Z. Neonatal exposure to sevoflurane may not cause learning and memory deficits and behavioral abnormality in the childhood of Cynomolgus monkeys.
    Scientific Reports 2015 Jun 5;5:11145.
  5. Glatz P, Sandin RH, Pedersen NI, Bonamy AE, Eriksson LI, Granath FN. Academic performance after anesthesia and surgery during childhood: a large-scale nation-wide study. Anesth Analg 2015; 120: S289.

This editorial was reviewed by Dr. Wayne Snodgrass, Professor, Pediatrics, Head of Clinical Pharmacology-Toxicology Unit and Medical Director of Texas Poison Center, University of Texas Medical Branch, Galveston, TX.

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