Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward

Caleb Ing, M.D., M.S.; David O. Warner, M.D.; Lena S. Sun, M.D.; Randall P. Flick, M.D., M.P.H.; Andrew J. Davidson, M.B.B.S., M.D., F.A.N.Z.C.A., F.A.H.M.S.; Laszlo Vutskits, M.D., Ph.D.; Mary Ellen McCann, M.D.; James O'Leary, M.D.; David C. Bellinger, Ph.D., M.Sc.; Virginia Rauh, Sc.D.; Beverley A. Orser, M.D., Ph.D., F.R.C.P.C.; Santhanam Suresh, M.D.; Dean B. Andropoulos, M.D., M.H.C.M.

Disclosures

Anesthesiology. 2022;136(3):500-512.

Abstract and Introduction

Abstract

Anesthetic agents disrupt neurodevelopment in animal models, but evidence in humans is mixed. The morphologic and behavioral changes observed across many species predicted that deficits should be seen in humans, but identifying a phenotype of injury in children has been challenging. It is increasingly clear that in children, a brief or single early anesthetic exposure is not associated with deficits in a range of neurodevelopmental outcomes including broad measures of intelligence. Deficits in other domains including behavior, however, are more consistently reported in humans and also reflect findings from nonhuman primates. The possibility that behavioral deficits are a phenotype, as well as the entire concept of anesthetic neurotoxicity in children, remains a source of intense debate. The purpose of this report is to describe consensus and disagreement among experts, summarize preclinical and clinical evidence, suggest pathways for future clinical research, and compare studies of anesthetic agents to other suspected neurotoxins.

Introduction

Questions regarding the safety of general anesthetic drugs in children emerged nearly 20 yr ago with the finding of neuronal apoptosis and functional deficits in rodents after exposure to these medications.^[1] Over the course of the subsequent two decades, exposure to anesthetic agents during brain maturation has been found to consistently disrupt neurodevelopment in animal models.^[2] In response, in December 2016, the U.S. Food and Drug Administration (Silver Spring, Maryland) issued a Drug Safety Communication regarding all commonly used anesthetics that bind to γ-aminobutyric acid and N-methyl-D-aspartate receptors.^[3] The Food and Drug Administration warning that "repeated or lengthy use of general anesthetic and sedation drugs during surgeries or procedures in children younger than 3 yr old or in pregnant women during their third trimester may affect the development of children's brains" was largely based on preclinical animal models and the limited clinical data available at the time.^[4] While preclinical data are convincing, the interpretation of the human data has been more complex, with some studies reporting an increased incidence of neurodevelopmental deficits in young children exposed to anesthetics and other studies finding no such differences.

Given the mixed results of the studies in children, the fundamental questions of the safety of commonly used anesthetics and whether this line of research inquiry should continue remains a source of intense debate. The purpose of this report is to provide expert consensus opinion regarding the state of the current preclinical and clinical evidence, the remaining questions, suggestions for future research, and comparisons to the evolution of research of other suspected neurotoxins, with the ultimate goal of ensuring that the millions of children who undergo procedures requiring anesthetic agents do so safely.^[5–7]

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Table 1. Advantages and Disadvantages of Potential Research Approaches
Approach	Advantages	Disadvantages
Further randomized controlled trials	Randomized controlled trials are the gold standard for proving causal effect of anesthetic exposure.	Randomized controlled trials are expensive and time consuming. Children cannot be randomized to no anesthetic, and what constitutes a "safe" anesthetic is unclear. A phenotype of injury and the ideal outcomes to evaluate are unclear. The optimal, feasible study design is not obvious.
Observational studies and causal theory	Randomized controlled trials may not be feasible in all situations. Causal theory is commonly applied to other areas such as environmental toxicity.	Observational studies are limited by the inability to distinguish effects of anesthesia from surgery and other perioperative factors, as well as issues with confounding by indication Application of causal theory relies on well-designed observational studies.
Intermediate outcomes and biomarkers	Injury could be identified at an earlier stage. Objective pre- and postexposure testing could be performed. Endophenotypes could be identified. Translation between animal models and humans could be improved.	No consistent biomarkers have been identified. Any identified biomarker would need to be correlated to a long-term clinical outcome of interest. Intermediate outcomes and biomarkers would not be able to distinguish the effects of anesthesia from surgery and other perioperative factors.
Prenatal exposures	Children may be more vulnerable to prenatal exposures. Less confounding by indication in the child as exposure is typically due to a condition in the mother rather than underlying conditions in the child.	The effects of anesthesia from uterine perfusion, inflammation, and other fetal stressors cannot be distinguished. A randomized controlled trial is unlikely to be able to randomize a mother to general anesthesia or spinal anesthesia.
Nonhuman primate studies	This is the animal model that is most similar to humans. This model can be used to evaluate questions that cannot be studied in humans.	Translation between humans and animal models is challenging. The one study that evaluated the same outcome in humans and nonhuman primates found differences in nonhuman primates but not children, although nonhuman primates had significantly longer exposures.

Authors and Disclosures

Caleb Ing, M.D., M.S., David O. Warner, M.D., Lena S. Sun, M.D., Randall P. Flick, M.D., M.P.H., Andrew J. Davidson, M.B.B.S., M.D., F.A.N.Z.C.A., F.A.H.M.S., Laszlo Vutskits, M.D., Ph.D., Mary Ellen McCann, M.D., James O'Leary, M.D., David C. Bellinger, Ph.D., M.Sc., Virginia Rauh, Sc.D., Beverley A. Orser, M.D., Ph.D., F.R.C.P.C., Santhanam Suresh, M.D. and Dean B. Andropoulos, M.D., M.H.C.M.

Departments of Anesthesiology (C.I., L.S.S.) and Pediatrics (L.S.S.), Columbia University Vagelos College of Physicians and Surgeons, New York, New York; the Department of Anesthesiology (C.I.) and the Heilbrunn Department of Population and Family Health (V.R.), Mailman School of Public Health, Columbia University, New York, New York; the e Department of Anesthesiology, Pharmacology, Intensive Care, and Emergency Medicine, University Hospitals of Geneva, Geneva, Switzerland L.V.); the Department of Anesthesiology, Critical Care and Pain Medicine (M.E.M.) and the Departments of Neurology and Psychiatry (D.C.B.), Harvard Medical School, Boston, Massachusetts; the Departments of Anesthesiology, Critical Care and Pain Medicine (M.E.M.) and Neurology and Psychiatry (D.C.B.), Boston Children's Hospital, Boston, Massachusetts; the Department of Anesthesiology, Bon Secours Hospital, Cork, Ireland (J.O.); the Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts (D.C.B.); the Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada (B.A.O.); the Departments of Anesthesiology and Pediatrics, Northwestern University, Chicago, Illinois (S.S.); and the Departments of Anesthesiology and Pediatrics, Texas Children's Hospital, Houston, Texas (D.B.A.).

Address correspondence to
Dr. Ing: Columbia University Vagelos College of Physicians and Surgeons and Mailman School of Public Health, 622 West 168th Street, BHN 4–440, New York, New York 10032. ci2119@cumc.columbia.edu. Anesthesiology's articles are made freely accessible to all readers on www.anesthesiology.org, for personal use only, 6 months from the cover date of the issue.

Competing Interests
This group of authors was assembled by SmartTots (San Francisco, California), a public-private partnership between the U.S. Food and Drug Administration (Silver Spring, Maryland) and the International Anesthesia Research Society (San Francisco, California) formed in 2009 to evaluate the possibility of adverse consequences of general anesthesia in young patients. No authors received any renumeration for their involvement in this article. However, any funding of the authors by SmartTots directly or indirectly or by either the Food and Drug Administration or the International Anesthesia Research Society is disclosed. While the International Anesthesia Research Society and Food and Drug Administration have shared interests and activities, they have no financial relationship, and each group is responsible for its own activities and resources. The International Anesthesia Research Society, however, does receive a National Institutes of Health (Bethesda, Maryland) grant from the Food and Drug Administration for specific research and administrative activities in support of SmartTots. Dr. Ing received a 1-yr SmartTots research grant in 2012 for the project "Anesthetic Exposure Duration and Effects on Cognitive Language Ability." Dr. Warner and Dr. Flick received funding from the Food and Drug Administration between 2008 and 2011 (Food and Drug Administration SOL-08-SAFEKIDs CLIN 005–Project 5–Assessment of Long-term Cognitive Development following General Anesthesia as an Infant). Dr. Sun received funding from SmartTots between 2013 and 2016 to support the Pediatric Anesthesia and NeuroDevelopment Assessment (PANDA) Study and a conference grant to support the 2016 PANDA Symposium (New York, New York) and was the Medical Director of SmartTots from 2017 to 2018. She also received funding from the Food and Drug Administration between 2008 and 2011 (Food and Drug Administration SOL-08-SAFEKIDS Clin 004–Project 4) for the PANDA study from 2020 to 2022 (Food and Drug Administration 5U01 FD005936-05, subaward 417811G/UR FAO GR511088) for participation in the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership, and from 2019 to 2023 (Food and Drug Administration contract 75F40119C10101 for BAA EETWP#31) for the project Neurodevelopmental Outcomes in Infants Receiving Opioid-Replacement Pharmacotherapy for Neonatal Opioid Withdrawal Syndrome. Dr. Sun and Dr. Davidson are also co–editor-in-chiefs of the Anesthesiology section of UpToDate, Riverwoods, Illinois. Dr. McCann received funding from the Food and Drug Administration between 2008 and 2011 (Food and Drug Administration SOL-08-SAFEKIDS Clin 002–Project 2) for the General Anesthesia or Awake–Regional Anesthesia in Infancy (GAS) trial. Dr. Orser and Dr. Suresh serve on the Steering Committee for SmartTots without compensation or reimbursement. International Anesthesia Research Society policy specifically prohibits any payments to Trustees for work related to SmartTots. In addition, they serve as members of the International Anesthesia Research Society Board of Trustees and International Anesthesia Research Society Officers. As trustees, they receive reimbursement for travel expenses on behalf of International Anesthesia Research Society and honoraria for meetings on travel days. As officers, they receive a small stipend in addition to travel reimbursement. Dr. Andropoulos also serves on the Steering Committee for SmartTots without compensation or reimbursement, but his institution receives a partial salary reimbursement for his service as Medical Officer under the Food and Drug Administration grant. Dr. Davidson is an Executive Editor of ANESTHESIOLOGY, and Dr. Vutskits is an Editor of ANESTHESIOLOGY. Dr. Orser is also co-director of the Perioperative Brain Health Center (Toronto, Ontario, Canada; http://www.perioperativebrainhealth.com); is a named inventor on a Canadian patent (2,852,978) and two U.S. patents (9,517,265 and 10,981,954) describing new methods for preventing and treating delirium and persistent neurocognitive deficits after anesthesia and surgery; and also collaborates on clinical studies supported by in-kind software donations from Cogstate Ltd. (New Haven, Connecticut). The other authors declare no competing interests.