Risks associated with anesthesia have declined dramatically over the past decades. Mortality rates, which were once as high as 1 in 2,500, now stand at about 1 in 13,000. Young children and infants, however, are more vulnerable to adverse events due to the nature of their physiology. One study, the 2014-2015 Anesthesia Practice in Children Observational Trial (APRICOT), found a 30-day in-hospital mortality rate of 1 in 1,000, examining 31,127 anesthetic procedures from 261 hospitals in Europe, independent of anesthesia type. In recognition of the particular risks associated with pediatric surgery, organizations like the Society for Pediatric Anesthesia and Wake Up Safe have made important breakthroughs in developing safety resources and conducting quality improvement research on anesthesia exposure in children (1).

While short-term outcomes and safety of surgery, particularly among infants, are improving with these efforts, the long-term neurological impact of anesthesia on children is a mounting topic of concern. There is a growing body of evidence demonstrating that, in animals, a wide range of anesthetics — isoflurane, sevoflurane, propofol, phenobarbital/thiopental, ketamine, and others — are related to neurotoxicity, affecting the developing brain in vitro and/or causing subtle but long-term neurobehavioural changes in vivo. Though the majority of functional outcome studies have been performed in rats and mice, they have documented learning, memory, attention, and motor function abnormalities (2). Notably, ketamine and other N-methyl-d-aspartate (NMDA) receptor antagonists have been shown to induce neurodegeneration in the developing brain of rodents in a dose-dependent manner (3). This is particularly the case if exposure occurs during periods of heightened synaptogenesis (post-natal day 7 in rodents), especially with high doses or with a combination of anesthetic agents. Studies also suggest that anesthetics can inhibit neurogenesis and impact development of the dendritic spine architecture (2).

In response to these findings, scientists have recently spearheaded large-scale randomized controlled trials to examine the effects and safety of anesthesia exposure on children. The GAS trial, which studied neurodevelopmental outcomes after general anesthesia or awake-regional anesthesia in infancy, found that slightly less than one hour of general anesthesia in early infancy was not associated with altered neurodevelopmental outcomes at age 5 in 242 infants who received general anesthesia at hospitals worldwide, compared to 205 infants who received awake-regional anesthesia for the same urological surgeries (4). The PANDA (Pediatric Anesthesia and NeuroDevelopment Assessment) study, published in 2016, similarly found that among 105 sibling pairs, a single anesthesia exposure (20-240 minutes) before 36 months of age was not associated with statistically significant differences in IQ scores at follow-up (when the children were 8-15 years old). The researchers noted, however, that “[f]urther study of repeated exposure, prolonged exposure, and vulnerable subgroups is needed” (5).

Interestingly, studies have found that anesthesia exposure at slightly later points in development (after two years) may be associated with very modestly elevated neurodevelopmental deficits in children. A population-based cohort study from Canada found an odds ratio of 1.05 (95% confidence interval: 1.01 to 1.10) for increased risks of early developmental vulnerability in children exposed between two to four years of age but not in children less than two years old. A retrospective cohort study found that both single and multiple exposures in children between two and four years were associated with slight neurological deficits, particularly in communication and language/cognition — however, the authors write that confounding factors are likely to have influenced these results (7).

Neurotoxicity associated with anesthesia is receiving greater national attention, with public-private partnerships like Strategies for Mitigating Anesthesia-Related Neuro-Toxicity in Tots (SmartTots) elevating the profile of the issue through its support of pediatric anesthesia research. In 2016, the U.S. Food and Drug Administration (FDA) released a warning stating that children under the age of three may be at an increased risk of learning, memory, or behavioral problems when they undergo anesthesia for more than three hours or are exposed to repeated anesthetics. Still, current guidelines recommend pursuing surgical treatments for life-threatening conditions (congenital heart defects, esophageal atresia, urological surgeries, and more), without alteration to standard anesthesia practice given that no agent has been shown to be safer than others (1). For elective and non-urgent procedures, parents should consult their child’s physicians to weight the benefits and risks of delaying treatment.

References 

1. Lorinc AN, Walters CB, Lovejoy HK, Crockett CJ, Reddy SK. Hot topics in safety for pediatric anesthesia. Children (Basel). 2020;7(11):242.
2. Sun L. Early childhood general anaesthesia exposure and neurocognitive development. Br J Anaesth. 2010;105 Suppl 1:i61-8.
3. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesth Analg. 2007;104(3):509-520.
4. McCann ME, de Graaff JC, Dorris L, et al. Neurodevelopmental outcome at 5 years of age after general anaesthesia or awake-regional anaesthesia in infancy (GAS): an international, multicentre, randomised, controlled equivalence trial. Lancet. 2019;393(10172):664-677.
5. Sun LS, Li G, Miller TLK, et al. Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA. 2016;315(21):2312-2320.
6. O’Leary JD, Janus M, Duku E, et al. A population-based study evaluating the association between surgery in early life and child development at primary school entry. Anesthesiology. 2016;125(2):272-279.
7. Graham MR, Brownell M, Chateau DG, Dragan RD, Burchill C, Fransoo RR. Neurodevelopmental assessment in kindergarten in children exposed to general anesthesia before the age of 4 years: A retrospective matched cohort study. Anesthesiology. 2016;125(4):667-677.
8. Safety Announcement. FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. FDA. https://www.fda.gov/media/101937/download