Recent scholarly publications have raised the question whether repeated exposure to general anesthesia is harmful to the developing brain in infants and young children.  Millions of children have surgery under general anesthesia each year.

Is repeated exposure to general anesthesia safe for the developing brain of your child? Let’s look at the evidence.

In 2011, a retrospective Mayo Clinic study looked at the incidence of learning disabilities (LD) in a cohort of children born in Olmsted County, Minnesota, from 1976 to 1982.  Among the 8,548 children analyzed, 350 of the children received general anesthesia before the age of 2.  A single exposure to general anesthesia was not associated with an increase in LD, but children who had two or more anesthetics were at increased risk for LD.  The study concluded that repeated exposure to anesthesia and surgery before the age of 2 was a significant independent risk factor for the later development of LDs.  The authors could not exclude the possibility that multiple exposures to anesthesia and surgery at an early age adversely affected human neurodevelopment with lasting consequences. (Flick RP et al, Pediatrics. 2011 Nov;128(5):e1053-61. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery)

The same group of Mayo Clinic researchers looked at the incidence of attention-deficit/hyperactivity disorder (ADHD) in children born from 1976 to 1982 in Rochester, Minnesota.  Among the 5,357 children analyzed, 341 ADHD cases were identified.  For children with no exposure anesthesia before the age of 2 years, the cumulative incidence of ADHD at age 19 years was 7.3%  Exposure to multiple procedures requiring general anesthesia was associated with an increased cumulative incidence of ADHD of 17.9%. The authors concluded that children repeatedly exposed to procedures requiring general anesthesia before age 2 years were at increased risk for the later development of ADHD. (Sprung J, Flick RP et al, Mayo Clin Proc. 2012 Feb;87(2):120-9. Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia)

Anesthesia scientists decided to study this problem in mice.  In March 2013, researchers at Harvard and other hospitals exposed 6- and 60-day-old mice to various anesthetic regimens. The authors then determined the effects of the anesthesia on learning and memory function, and on the levels of proinflammatory chemicals such as cytokine interleukin-6 in the animals’ brains. The authors showed that anesthesia with 3% sevoflurane for 2 hours daily for 3 days induced cognitive impairment (i.e. unusually poor mental function) and neuroinflammation (i.e. elevated levels of brain inflammatory chemicals such as interleukin-6) in young but not in adult mice. Anesthesia with 3% sevoflurane for 2 hours daily for 1 day or 9% desflurane for 2 hours daily for 3 days caused neither cognitive impairment nor neuroinflammation. Treatment with the non-steroidal anti-inflammatory (NSAID) drug ketorolac caused improvement in the sevoflurane-induced cognitive impairment. The authors concluded that anesthesia-induced cognitive impairment may depend on age, the specific anesthetic agent, and the number of exposures. The findings also suggested that cellular inflammation in the brain may be the basis for the problem of anesthesia-induced cognitive impairment, and that potential prevention and treatment strategies with NSAIDs may ultimately lead to safer anesthesia care and better postoperative outcomes for children. (Shen X, Dong Y,et al, Anesthesiology. 2013 Mar;118(3):502-515.  Selective Anesthesia-induced Neuroinflammation in Developing Mouse Brain and Cognitive Impairment)

The same Harvard research group assessed the effects of sevoflurane on brain function in pregnant mice, and on learning and memory in fetal and offspring mice. Pregnant mice were treated with 2.5% sevoflurane for 2 hours and 4.1% sevoflurane for 6 hours. Brain tissues of both fetal and offspring mice were harvested and immunohistochemistry tests were done to assess interleukin-6 and other brain inflammatory levels.  Learning and memory function in the offspring mice was determined by using a water maze. The results showed that sevoflurane anesthesia in pregnant mice induced brain inflammation, evidenced by increased interleukin-6 levels in fetal and offspring mice.  Sevoflurane anesthesia also impaired learning and memory in offspring mice. The authors concluded that sevoflurane may induce detrimental effects in fetal and offspring mice, and that these findings should promote more studies to determine the neurotoxicity of anesthesia in the developing brain.

What does all this mean to you if your children need anesthesia and surgery?  Although further studies and further data will be forthcoming, the current information suggests that:  1) if your child has one exposure to anesthesia, this may constitute no increased risk to their developing brain, and 2) repeated surgery and anesthetic exposure to sevoflurane may be harmful to the development of the brain of children under the age of 2 years.  It would seem a wise choice to delay surgery until your child is older if at all possible.

What does all this mean to anesthesiologists?  We’ll be watching the literature for new publications on this topic, but in the meantime it seems prudent to avoid exposing newborns and young children to repeated anesthetics with sevoflurane.  Currently, sevoflurane is the anesthetic of choice when we put children to sleep with a mask induction, because sevoflurane smells pleasant and sevoflurane works fast.  Children become unconscious within a minute or two.  After a child is asleep, it may be advisable to switch from sevoflurane to the alternative gas anesthetic desflurane, since the Harvard study on mice showed anesthesia with 9% desflurane for 2 hours daily for 3 days caused neither cognitive impairment nor neuroinflammation.  A second alternative is to switch from sevoflurane to intravenous anesthetics alone, e.g. to utilize propofol and remifentanil infusions instead of sevoflurane.

The concept of pediatric anesthesia harming the developing brain was reviewed in the lay press in Time magazine in 2009 (Eben Harrell, Anesthesia: Could Early Use Affect the Brain Later, Time, Nov 3, 2009).  The four articles I summarized above represent the most recent and detailed advances on this topic.  Stay tuned.  The issue of anesthetic risk to the developing brain will be closely scrutinized for years to come.