“Lake Wobegon, the little town that time forgot and the decades cannot improve, where all the women are strong, all the men are good-looking, and all the children are above average.” Garrison Keillor, A Prairie Home Companion
“You Yell ‘Shark,’ We’ve Got A Panic On Our Hands…” From the movie Jaws
David O Warner, Danqing Hu, Michael J Zaccariello, Darrell R Schroeder, Andrew C Hanson, Robert T Wilder, Juraj Sprung, Randall P Flick. Association Between Behavioral and Learning Outcomes and Single Exposures to Procedures Requiring General Anesthesia Before Age 3: Secondary Analysis of Data From Olmsted County, MN. Anesth Analg 2021 Jul 1;133(1):160-167 PMID: 32932391
Because of the enormous number of original papers and reviews that have been written on this subject, and to protect you from my (Myron’s) personal bias, I’ve asked Mary Ellen McCann and Mike Nemergut to guest edit this summary with me.
Concerns about long-term anesthetic-induced neurotoxicity have permeated the pediatric anesthesia community since landmark laboratory investigations reported neurodegeneration as well as behavioral deficits in juvenile animals exposed to general anesthetics and sedatives.(1,2) In 2016 the US FDA yelled “SHARK”, warning “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.” Not surprisingly, panic ensued among many anesthesiologists, surgeons, and, perhaps most importantly, the families we treat. Indeed, at least one major institution, Texas Children’s Hospital, this concern has altered practice and a discussion of the possibility of anesthetic neurotoxicity is had with families of young children as part of their informed consent prior to surgery.
While preclinical studies have consistently reported deleterious effects of anesthetics in developing animals, investigations in humans are far from clear. A quick summary of what we know clinically follows. The General Anesthesia versus Spinal Anesthesia (GAS) trial, a prospective randomized controlled equivalence trial, compared the neurocognitive outcomes of infants less than 60 weeks postmenstrual age who were exposed to either sevoflurane general anesthesia or bupivacaine regional anesthesia for inguinal hernia repair found no differences in neurocognitive outcomes between the 2 groups at 2 and 5 years of age.(3) Similarly, the Pediatric Anesthesia and Neuro Development Assessment (PANDA) study found no clinical evidence of anesthesia related injury.(4) On the other hand, the Mayo Anesthesia Safety in Kids (MASK) study, performed in Lake Wobegon, I mean Olmsted County, MN, found that multiple anesthetic exposures before age 3 were associated with a significant increase in the frequency of attention-deficit hyperactivity disorder (ADHD) and learning disabilities (LD) later in life.(5) In today’s paper by Warner et al., a secondary analysis of the MASK data was performed. The authors wondered if there was a dose response relationship? That is, would a single anesthetic exposure be associated with learning disabilities? The short answer is “NO” - they “did not find evidence that single exposures to procedures requiring general anesthesia before age 3 are associated with an increased risk of developing ADHD, LD, or the need for individualized educational plans in later life”.
OK, what does this mean? While the effect of multiple anesthetics on children remains unknown, there are increasing data that single anesthetics remain unassociated with adverse neurocognitive outcomes which should provide clinicians the ability to reassure parents in such circumstances. Again, quoting from Quint in the movie Jaws “You wealthy college boys don’t have the education enough to admit when you’re wrong.” For single anesthetics, we think it’s safe to go back in the water.
Myron Yaster, MD, Mary Ellen McCann, MD, and Michael Nemergut, MD
1. Jevtovic-Todorovic V, Hartman RE, Izumi Y, Benshoff ND, Dikranian K, Zorumski CF, Olney JW, Wozniak DF: Early exposure to common anesthetic agents causes widespread neurodegeneration in the developing rat brain and persistent learning deficits. J.Neurosci. 2003; 23: 876-882
2. Soriano SG, McCann ME: Is Anesthesia Bad for the Brain? Current Knowledge on the Impact of Anesthetics on the Developing Brain. Anesthesiol Clin 2020; 38: 477-492
3. McCann ME, de Graaff JC, Dorris L, Disma N, Withington D, Bell G, Grobler A, Stargatt R, Hunt RW, Sheppard SJ, Marmor J, Giribaldi G, Bellinger DC, Hartmann PL, Hardy P, Frawley G, Izzo F, von Ungern Sternberg BS, Lynn A, Wilton N, Mueller M, Polaner DM, Absalom AR, Szmuk P, Morton N, Berde C, Soriano S, Davidson AJ: 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
4. Sun LS, Li G, Miller TLK, Salorio C, Byrne MW, Bellinger DC, Ing C, Park R, Radcliffe J, Hays SR, DiMaggio CJ, Cooper TJ, Rauh V, Maxwell LG, Youn A, McGowan FX: Association Between a Single General Anesthesia Exposure Before Age 36 Months and Neurocognitive Outcomes in Later Childhood. JAMA 2016; 315: 2312-2320
5. Hu D, Flick RP, Zaccariello MJ, Colligan RC, Katusic SK, Schroeder DR, Hanson AC, Buenvenida SL, Gleich SJ, Wilder RT, Sprung J, Warner DO: Association between Exposure of Young Children to Procedures Requiring General Anesthesia and Learning and Behavioral Outcomes in a Population-based Birth Cohort. Anesthesiology 2017; 127: 227-240