The effect of general anesthesia on the developing brain is arguably the most widely discussed, highly publicized, and controversial patient safety issue that the pediatric anesthesia community has faced in the past two decades. The potential for adverse neurodevelopmental outcomes after anesthesia exposure has called into question the intrinsic safety of our primary anesthetic agents, leading to understandable concern for both parents and anesthesia professionals. In October 2016, the Anesthesia Patient Safety Foundation (APSF) Newsletter addressed these concerns in an article titled “The Effect of General Anesthesia on the Developing Brain: Appreciating Parent Concerns While Allaying Their Fears”.1 In today’s issue, we revisit the topic of anesthesia neurotoxicity, with a focus on three recent studies and their implications for the daily clinical practice of anesthesia professionals.
In 2016, the U.S. Food & Drug Administration (FDA) issued 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.”2 The new warning label was applied to nearly every anesthetic agent used in modern practice, including sevoflurane, isoflurane, desflurane, propofol, midazolam, and ketamine. When the FDA issued this warning, there was no definitive clinical evidence that showed anesthetic agents caused adverse neurodevelopmental outcomes. Rather, the warning was primarily driven by overwhelming data from animal studies across various species that demonstrated an association between anesthetic exposure and neurologic injury, such as widespread neuronal cell loss, oligodendrocyte loss, and impaired synaptogenesis during a period of rapid brain development.3–5 Animal studies also demonstrated a link between early exposure to anesthetics and impaired cognition, behavior, and learning.4,5
While concerning, the animal data cannot be easily translated to humans. The dose and duration of anesthetic exposure in animal models is considerably higher than what an infant or child is typically exposed to in the operating room. The animal models lack the precise physiologic monitoring, controlled ventilation, and resuscitative efforts routinely utilized in clinical practice. Additionally, each animal model has a different “window of vulnerability” during brain development, which is difficult to correlate with human brain development.
At the time of the FDA’s warning, the clinical data largely consisted of retrospective observational studies, comparing neurodevelopmental outcomes (e.g., cognition, behavior, learning disabilities) in individuals exposed to anesthesia at a young age to a matched, unexposed cohort. The results were variable and conflicting. Some studies showed no association between early anesthesia exposure and neurodevelopmental outcomes, suggesting that a single, brief exposure to anesthesia at a young age does not have negative effects on brain development.6–8 Other studies, however, suggested exposure to anesthesia may result in neurocognitive deficits, particularly in children exposed to multiple anesthetics at an early age.9–11 As the FDA acknowledged in their Drug Safety Communication, observational studies have many limitations and cannot prove causation.2 Controlling for confounders including birth weight, gestational age, parental age/education, socioeconomic status, income, and ethnicity proved to be very difficult in these studies.
In the last five years, three well-designed, landmark studies made efforts to minimize these limitations, and their collective findings suggest that a single, brief exposure to general anesthesia in children is likely safe:
- The Pediatric Anesthesia Neurodevelopment Assessment (PANDA) Study was a multicenter, retrospective, observational study comparing global cognitive function (IQ) of otherwise healthy children who were exposed to a single general anesthetic before age three to their unexposed sibling.12 By utilizing sibling-matching, the PANDA study minimized the effects of confounding variables such as genetic background, socioeconomic status, parental age/education, and family income. A total of 105 sibling pairs were included in the study, and IQ testing took place between 8–15 years of age. There was no significant difference in IQ scores between the groups. Additionally, there were no significant differences in secondary outcomes of neurocognitive function including memory/learning, motor/processing speed, visuospatial function, attention, executive function, language, and behavior.12
- The Mayo Anesthesia Safety in Kids (MASK) Study was a retrospective, observational study comparing general intelligence and neurodevelopmental outcomes in three groups of children—those never exposed to anesthesia, those exposed once before age three, and those exposed multiple times before age three.13 The authors utilized rigorous propensity-based matching of cohorts to minimize confounding variables, and administered a comprehensive battery of neuropsychological assessments. They found that anesthesia exposure—both single and multiple times—before age three was not associated with any deficits in general intelligence.13 Single exposures were not associated with deficits in other neuropsychological domains.13 However, multiple exposures were associated with a modest decrease in fine motor abilities and processing speeds, and parents of these children reported more difficulties with reading and behavior.13
- The general anaesthesia or awake-regional anaesthesia in infancy (GAS) study is the only randomized controlled trial on this topic to date. In this international, multicentered trial, otherwise healthy infants less than 60 weeks postmenstrual age (born at greater than 26 weeks’ gestation) undergoing inguinal hernia repair were randomized to receive either sevoflurane-based general anesthesia or awake-regional anesthesia.14 The primary outcome was intelligence quotient (Wechsler Preschool and Primary Scale of Intelligence Third Edition) at age five, and the secondary outcome was composite cognitive score (Bayley Scales of Infant and Toddler Development III) at age two.14 In 2016, the secondary outcome showed no evidence that sevoflurane anesthesia exposure of under one hour in infancy increased the risk of adverse neurodevelopmental outcome at age two compared to awake-regional anesthesia.15 In 2019, the primary outcome showed no difference in the intelligence quotient of children exposed to general anesthesia compared to awake-regional anesthesia.14 The FDA’s warning—and timing—was controversial, and took many anesthesia professionals by surprise.
The FDA met with an expert panel in 2007, 2011, and 2014 to advise them on the issue of anesthesia-induced neurotoxicity. Then, more than two years after the last expert advisory panel convened, the FDA issued the Drug Safety Communication warning about the potential risk of anesthesia neurotoxicity. Curiously, their warning came on the heels of reassuring results from the PANDA study12 and GAS secondary outcome.15 Usually FDA Drug Safety Communications are based on substantial clinical data,16 but in this case there was no definitive clinical evidence of neurotoxicity in humans. The FDA warning was based on a potential risk, rather than a known risk.
The intention of the FDA was to “better inform the public about this potential risk”,2 but their warning had downstream consequences. The FDA acknowledged that necessary surgery in children should proceed, but cautioned that “consideration should be given to delaying potentially elective surgery in young children where medically appropriate”.2 Many pediatric, surgical, and anesthesia professionals found this recommendation to be oversimplified and lacking in evidence-based guidance. Some medical experts even cautioned that the FDA warning could expose medical professionals to increased malpractice risk regardless of their decision to either proceed with anesthesia or delay the procedure.17 (Should myringotomy tubes be delayed knowing that hearing deficiencies secondary to recurrent otitis can lead to learning deficits? Should tonsillectomy for moderate sleep apnea be delayed, when sleep apnea itself can affect neurocognitive outcomes? If the child develops a learning disability later in life, will I be held liable for proceeding ahead? Will I be held liable for delaying?) After all, the risk-benefit discussion becomes more challenging when physicians are asked to consider an unsubstantiated risk. Just as attorneys would feel uneasy defending their clients under a presumption of “guilty until proven innocent,” anesthesia professionals were put in the challenging position of defending the appropriate use of anesthetic agents that were heavily stigmatized as neurotoxic after the FDA’s warning.
Discussions with parents regarding anesthesia-induced neurotoxicity are common. A survey of over 200 parents found that 60% report some degree of concern that general anesthesia will affect their child’s neurodevelopment.18 How are anesthesia professionals approaching these conversations? A study of pediatric teaching institutions in the US provided insight into the attitudes of anesthesia professionals and the process of informed consent nationwide.19 Of those surveyed, 91% discussed the topic “only if asked,” while 6% discussed it routinely, with the majority of those discussions occurring moments before surgery. In addition to direct conversation with the anesthesia professional, one third of respondents referred parents to the SmartTots Consensus Statement,20 and one third had specific departmental talking points. The majority of respondents did not discuss delaying “elective” surgery with parents, and chose not to offer a “safe age cutoff” to parents. Only 20% of respondents documented their discussion in the medical record, and few institutions specifically discussed the risk in the written consent.
Based on the available data, a single, brief exposure to general anesthesia in children under age three does not cause adverse neurodevelopmental outcomes. Anesthesia professionals and parents alike should be reassured by the findings of the PANDA, MASK, and GAS studies. Questions do remain, however, with regard to infants and children requiring multiple or prolonged anesthetics. In this vulnerable population, modest neurodevelopmental impairments may occur after anesthesia exposure,10,11,13 and additional research is necessary to better understand what clinical implications, if any, this may have on perioperative care. Researchers are also studying the dose-response curve of anesthetic agents on neurodevelopmental outcomes. The TREX trial is an ongoing randomized control trial comparing neurodevelopmental outcomes of standard-dose sevoflurane versus low-dose sevoflurane, with an expected completion date in 2022. Additionally, we may see the focus of research shift towards the conduct of an anesthetic, rather than the type and route of anesthetic. The role of intraoperative hypotension, transient hypoxia, metabolic derangements, glucose control, and temperature maintenance on neurodevelopmental outcomes are important questions that remain unanswered.
Anesthesia professionals who care for children should be prepared to address parental concerns, and should be familiar with the reassuring results of the PANDA, MASK, and GAS studies. Concerned parents should be directed to credible resources, such as the SmartTots website (https://www.smarttots.org), a partnership between the International Anesthesia Research Society and the FDA with informational material for parents and medical professionals.20 Caring for infants and children is a privilege, and anesthesia professionals should acknowledge the concerns of parents while allaying their fears related to the effects of general anesthesia on the developing brain.
- Janik LS. The effect of general anesthesia on the developing brain: appreciating parent concerns while allaying their fears. APSF Newsletter. 2016;31;38–39. https://www.apsf.org/article/the-effect-of-general-anesthesia-on-the-developing-brain-appreciating-parent-concerns-while-allaying-their-fears/ Accessed August 12, 2020.
- FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women, 2016. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm532356.htm Accessed May 8, 2020.
- Sanchez V, Feinstein SD, Lunardi N, et al. General anesthesia causes long-term impairment of mitochondrial morphogenesis and synaptic transmission in developing rat brain. Anesthesiology. 2011;115:992–1002.
- Jevtovic-Todorovic V, Hartman RE, Izumi Y, et al. Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J Neurosci. 2003;23:876–82.
- Paule MG, Li M, Allen RR, et al. Ketamine anesthesia during the first week of life can cause long-lasting cognitive deficits in rhesus monkeys. Neurotoxicol Teratol. 2011;33:220–30.
- Hansen TG, Pedersen JK, Henneberg SW, et al. Academic performance in adolescence after inguinal hernia repair in infancy: a nationwide cohort study. Anesthesiology. 2011;
- Hansen TG, Pedersen JK, Henneberg SW, et al. Educational outcome in adolescence following pyloric stenosis repair before 3 months of age: a nationwide cohort study. Pediatric Anesthesia. 2013;23 883–890.
- Bartels M, Althoff RR, Boomsma DI. Anesthesia and cognitive performance in children: no evidence for a causal relationship. Twin Res Hum Genet. 2009;12:246–253.
- Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130:476–485.
- Flick RP, Katusic SK, Colligan RC, et al. Cognitive and behavioral outcomes after early exposure to anesthesia and surgery. Pediatrics. 2001;128:1053–1061.
- Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110:796–804
- 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: 2312-2320.
- Warner DO, Zaccariello MJ, Katusic SK, et al. Neuropsychological and behavioral outcomes after exposure of young children to procedures requiring general anesthesia: The Mayo Anesthesia Safety in Kids (MASK) Study. Anesthesiology. 2018;129:89–105.
- McCann ME, de Graaff JC, Dorris L, et al. GAS Consortium: 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;393:664–677.
- Davidson AJ, Disma N, de Graaff JC, et al. and the GAS consortium. 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;387:239–250.
- Marcum ZA, Vande Griend JP, Linnebur SA. FDA Drug Safety Communications: a narrative review and clinical considerations for older adults. Am J Geriatr Pharmacother. 2012;10:264–627.
- McAbee GN, Donn SM. FDA warning on anesthesia calls attention to malpractice risks associated with medications, failure to timely refer. AAP News. September 27, 2017.
- Koh JH, Daniel P, Bong CL. Parental perception on the effects of early exposure to anaesthesia on neurodevelopment. Anaesthesia. 2019;74:51–56.
- Ward CG, Hines SJ, Maxwell LG, et al. Neurotoxicity, general anesthesia in young children, and a survey of current pediatric anesthesia practices at US teaching institutions. Pediatric Anesthesia. 2016;26:60–65.
- Consensus statement on the use of anesthetic and sedative drugs in infants and toddlers. SmartTots. October 2015