Anesthesia/Analgesia/Sedation and Brain Health in Children: A Supplement of the Eighth PANDA Symposium
Myron Yaster MD and Lena S Sun MD, FAAP, DABA
Today’s PAAD discusses several articles published in the Journal of Neurosurgical Anesthesiology highlighting presentations from the eighth Pediatric Anesthesia and Neuro-Development Assessment (PANDA) Symposium held on March 9–10, 2024. As you all know, “safety concerns related to anesthesia first arose in 1999 following publication of a study that reported widespread apoptosis in the developing rat brain following exposure to ketamine.1 This prompted the US Food and Drug Administration (FDA) to establish a working group and rapid response team in 2000 and the addition of ketamine to the National Toxicology Program in 2001. In 2003, a study reported similar findings in rats treated with nitrous oxide, isoflurane, and midazolam.2 Subsequent studies published in 2006 and 2007 also found ketamine-induced apoptosis and neural degeneration, respectively, in nonhuman primates.3,4 These results ultimately led to a white paper discussing anesthetic risk in young children which was published in Anesthesia and Analgesia in 20075 and the creation of the Pediatric Anesthesia Neuro Development Assessment (PANDA) program, a public-private partnership (PPP) with the FDA to address these issues. I asked my good friend and colleague Dr. Lena Sun who is a leader of PANDA to assist. It is beyond the scope of the PAAD to review all of the articles in this supplement, so I chose 3 that I thought would be of most interest to our readership. The articles in this supplement are short (2-3 pages), not much longer than the PAADs, and are a terrific resource for those of you interested in this topic and want to take a deeper dive. Myron Yaster MD
Original article
Knapp A, Sun L, Sanhai W. The Pediatric Anesthesia Safety Initiative: A Public-Private Partnership for Children. J Neurosurg Anesthesiol. 2025 Jan 1;37(1):98-99. doi: 10.1097/ANA.0000000000000998. Epub 2024 Dec 2. PMID: 39882887.
Original article
Chen S, Haché M, Patel S, Ing C. Update on Clinical Research in Anesthetic Neurotoxicity. J Neurosurg Anesthesiol. 2025 Jan 1;37(1):95-97. doi: 10.1097/ANA.0000000000001002. Epub 2024 Dec 2. PMID: 39882886.
Original article
Eisler L, Knapp A, Griffiths KK, Houck CS, Nafiu OO. Neurodevelopmental Outcomes Following Early Childhood Anesthetic Exposure: Consideration of Perioperative Health Disparities. J Neurosurg Anesthesiol. 2025 Jan 1;37(1):138-140. doi: 10.1097/ANA.0000000000000995. Epub 2024 Dec 2. PMID: 39882899.
Anesthetic neurotoxicity: making sense of the clinical studies
Dr. Caleb Ing of Columbia University “discussed the challenges of interpreting more than 100 published clinical studies in a wide range of patient populations, incorporating different study designs, and utilizing many different outcome measures, interpreting this body of literature has been challenging.”6 Perhaps the 3 best-known studies evaluating children with single anesthesia exposures: “the PANDA7 and the Mayo Anesthesia Safety in Kids (MASK)8 studies, which were both observational studies, and the General Anesthesia or Awake-Regional Anaesthesia in Infancy (GAS) study,9 which was a randomized controlled trial. The primary outcome of all 3 studies was a measure of full-scale intelligence quotient (FSIQ). A variety of other secondary outcomes were also assessed. All studies evaluated the Child Behavior Checklist (CBCL) Total, Externalizing and Internalizing behavioral problems, and Behavior Rating Inventory of Executive Function scores in addition to FSIQ. After combining the data from these 3 studies, there was no observed difference in FSIQ between anesthetic-exposed and unexposed children. However, CBCL Total and Internalizing and Externalizing behavioral problems scores were significantly different. When evaluating the clinical relevance of these score differences, singly exposed children had a 47% increased risk of crossing a predefined threshold for clinical deficit in internalizing behavior problems, and a 68% increased risk of crossing a threshold for deficit in executive function problems.”6 A systematic meta analysis of all 108 clinical studies10 found that “the largest difference was in executive function with a standardized mean difference (SMD) in scores between exposed and unexposed children of 0.20 (95% CI, 0.09-0.32). To put this executive function score difference into context, a 0.20 SMD difference in FSIQ scores would be equivalent to a difference of 3 IQ points.”6
We think the evidence from human studies is pretty clear that single short exposures to general anesthetics are safe. But what about longer or multiple exposures? Chen et al highlight the ongoing research of Dr. Arslan-Carlon’s work with children with retinoblastoma who must undergo multiple general anesthetics in the treatment of their cancer. This ongoing study will contribute new data to hopefully answer this question.
“Social determinants of health are known to play a key role in the sequelae of pediatric illness, including long-term effects on the developing brain.11 For this reason, social identifiers such as race are commonly incorporated into risk-adjusted models examining the impact of early childhood exposure to anesthetic and/or sedative drugs on neurodevelopmental outcomes. ”12 Dr. Constance Houck and her panel suggested that to untangle differences in health care outcomes requires an awareness of the extent to which perioperative health care outcomes vary by racial and ethnic group. Race, ethnicity, socioeconomic demographics were not part of the design of the previously described clinical trials studying neurodevelopment outcomes following anesthetic exposure. “For example, it may be that part of the impact on neurocognitive or behavioral outcomes of race is being directly mediated by the increased likelihood of additional anesthetic exposures in minoritized races subject to a higher rate of reoperation surgeries or longer operative times. It would therefore also be informative to examine the relationship between race and adverse neurodevelopmental outcomes following early childhood anesthetic exposures, with the number or duration of procedures as a mediator.”12
What do you think? Does the potential for neuro detrimental outcomes affect how you provide (or don’t provide) anesthesia to your youngest patients? Send your comments to Myron who will post in a Friday reader response.
References
1. Ikonomidou C, Bosch F, Miksa M, et al. Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 1999;283(5398):70-74.
2. 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. JNeurosci 2003;23(3):876-882.
3. Slikker W, Jr., Zou X, Hotchkiss CE, et al. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. ToxicolSci 2007;98(1):145-158.
4. Knapp A, Sun L, Sanhai W. The Pediatric Anesthesia Safety Initiative: A Public-Private Partnership for Children. Journal of neurosurgical anesthesiology 2025;37(1):98-99. (In eng). DOI: 10.1097/ana.0000000000000998.
5. Mellon RD, Simone AF, Rappaport BA. Use of anesthetic agents in neonates and young children. Anesthesia and analgesia 2007;104(3):509-20. (In eng). DOI: 10.1213/01.ane.0000255729.96438.b0.
6. Chen S, Haché M, Patel S, Ing C. Update on Clinical Research in Anesthetic Neurotoxicity. Journal of neurosurgical anesthesiology 2025;37(1):95-97. (In eng). DOI: 10.1097/ana.0000000000001002.
7. 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. (In eng). DOI: 10.1001/jama.2016.6967.
8. 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(1):89-105. (In eng). DOI: 10.1097/aln.0000000000002232.
9. 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 (London, England) 2019;393(10172):664-677. (In eng). DOI: 10.1016/s0140-6736(18)32485-1.
10. Reighard C, Junaid S, Jackson WM, et al. Anesthetic Exposure During Childhood and Neurodevelopmental Outcomes: A Systematic Review and Meta-analysis. JAMA network open 2022;5(6):e2217427. (In eng). DOI: 10.1001/jamanetworkopen.2022.17427.
11. Brumbaugh JE, Vohr BR, Bell EF, et al. Early-Life Outcomes in Relation to Social Determinants of Health for Children Born Extremely Preterm. The Journal of pediatrics 2023;259:113443. (In eng). DOI: 10.1016/j.jpeds.2023.113443.
12. Eisler L, Knapp A, Griffiths KK, Houck CS, Nafiu OO. Neurodevelopmental Outcomes Following Early Childhood Anesthetic Exposure: Consideration of Perioperative Health Disparities. Journal of neurosurgical anesthesiology 2025;37(1):138-140. (In eng). DOI: 10.1097/ana.0000000000000995.