Skip to main content

Main menu

  • Home
  • COVID-19
    • Articles & podcasts
    • Blog posts
    • Collection
    • News
  • Content
    • Current issue
    • Past issues
    • Early releases
    • Collections
    • Sections
    • Blog
    • Infographics & illustrations
    • Podcasts
    • Classified ads
  • Authors
    • Overview for authors
    • Submission guidelines
    • Submit a manuscript
    • Forms
    • Editorial process
    • Editorial policies
    • Peer review process
    • Publication fees
    • Reprint requests
  • CMA Members
    • Overview for members
    • Earn CPD Credits
    • Print copies of CMAJ
    • Career Ad Discount
  • Subscribers
    • General information
    • View prices
  • Alerts
    • Email alerts
    • RSS
  • JAMC
    • À propos
    • Numéro en cours
    • Archives
    • Sections
    • Abonnement
    • Alertes
    • Trousse média 2021
  • CMAJ JOURNALS
    • CMAJ Open
    • CJS
    • JAMC
    • JPN

User menu

Search

  • Advanced search
CMAJ
  • CMAJ JOURNALS
    • CMAJ Open
    • CJS
    • JAMC
    • JPN
CMAJ

Advanced Search

  • Home
  • COVID-19
    • Articles & podcasts
    • Blog posts
    • Collection
    • News
  • Content
    • Current issue
    • Past issues
    • Early releases
    • Collections
    • Sections
    • Blog
    • Infographics & illustrations
    • Podcasts
    • Classified ads
  • Authors
    • Overview for authors
    • Submission guidelines
    • Submit a manuscript
    • Forms
    • Editorial process
    • Editorial policies
    • Peer review process
    • Publication fees
    • Reprint requests
  • CMA Members
    • Overview for members
    • Earn CPD Credits
    • Print copies of CMAJ
    • Career Ad Discount
  • Subscribers
    • General information
    • View prices
  • Alerts
    • Email alerts
    • RSS
  • JAMC
    • À propos
    • Numéro en cours
    • Archives
    • Sections
    • Abonnement
    • Alertes
    • Trousse média 2021
  • Visit CMAJ on Facebook
  • Follow CMAJ on Twitter
  • Follow CMAJ on Pinterest
  • Follow CMAJ on Youtube
  • Follow CMAJ on Instagram
Commentary

Anesthetic neurotoxicity and the developing brain

Anthony M.-H. Ho, Melinda L. Fleming and Glenio B. Mizubuti
CMAJ August 14, 2017 189 (32) E1028-E1029; DOI: https://doi.org/10.1503/cmaj.170313
Anthony M.-H. Ho
Department of Anesthesiology and Perioperative Medicine, Queen’s University, Kingston, Ont.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Melinda L. Fleming
Department of Anesthesiology and Perioperative Medicine, Queen’s University, Kingston, Ont.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Glenio B. Mizubuti
Department of Anesthesiology and Perioperative Medicine, Queen’s University, Kingston, Ont.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: gleniomizubuti@hotmail.com
  • Article
  • Figures & Tables
  • Related Content
  • Responses
  • Metrics
  • PDF
Loading
KEY POINTS
  • In the human brain, synaptogenesis commences in the last trimester of pregnancy and is complete by the end of the third to fourth year of life. Lasting changes may theoretically occur when this process is disrupted by anesthetics and sedatives.

  • Research on animals, including primates, has shown extensive histologic neuronal injury and long-term neurocognitive deterioration after prolonged or multiple exposures to clinical anesthesia.

  • Many retrospective human studies have shown neurocognitive deficits in children with multiple exposures to anesthesia before three to four years of age.

  • High-level evidence suggests that an exposure to anesthesia for a few hours before three to four years of age causes no long-term harm. The effect of multiple or long exposures is not well elucidated.

  • No unnecessary procedures should be performed in children younger than three to four years of age; however, no necessary procedures should be delayed.

On Dec. 14, 2016, the US Food and Drug Administration warned that anesthetics and sedatives used in children younger than three years of age, or in pregnant women in their third trimester, who were undergoing general anesthesia for more than three hours or used anesthetics repeatedly may affect pediatric or fetal brain development. Children’s hospitals across Canada are reportedly advising parents not to delay necessary procedures until their children turn three years old, according to a Mar. 2, 2017 report in The Globe and Mail. Clinicians must be prepared to allay parental concerns over this issue.

The brain undergoes major development in utero and during the first three to four years after birth; it could be vulnerable when exposed to modulators of neuronal activity. Numerous animal studies, several of which are summarized in Appendix 1 (available at www.cmaj.ca/lookup/suppl/doi:10.1503/cmaj.170313/-/DC1), have described neuronal apoptosis and neurocognitive deficits after exposure to anesthetics or sedatives. Many, but not all, studies using routinely collected data — for example, from the Ontario Electronic Medical Record Administrative Data Linked Database, Medicaid and birth registries — have found later neurobehavioural deficits in children who had prolonged or multiple exposures to general anesthesia before two to four years of age.

Fortunately, one brief general anesthetic may not increase the risk.1–3 Even if it does, there was only a tiny magnitude of difference between children who had received anesthesia previously and children who were anesthetic-naive (mean age 5.7 years) in the Early Development Instrument score, according to one study.4 Moreover, that vulnerability is incurred if the exposure came after 24 months of age, and not before.4 A Swedish study found a drop of less than 1% in intelligence quotient (IQ) and school grades, measured during adolescence, associated with exposure to anesthesia at age 37 to 48 months, but not before.5 Another study similarly found that exposure to anesthesia before the age of two years was not associated with lower Early Development Instrument performance, but exposure between ages two and four years was.6 In these three studies, 4–6 multiple exposures did not increase vulnerability. Another study showed that six-year-old Dutch children who had been exposed to anesthesia before the age of five years had a mean drop in IQ of 2.1.7

Babies born by cesarean delivery are no more likely to have a learning disability in their teen years than those delivered naturally.8 Interestingly, babies born by cesarean delivery under spinal or epidural anesthesia have been shown to have lower vulnerability than those delivered by cesarean under general anesthesia and those delivered naturally, possibly due to reduced stress.8

The effect on brain development of multiple or prolonged exposures to general anesthesia before the age of three years is the subject of more observational studies. These include the recently completed Mayo Anesthesia Study in Kids (MASK) retrospective-prospective study, which compared neurodevelopmental outcomes in children with no exposures to general anesthesia, those with one exposure, and those with multiple exposures as young children;9 the Recognition Memory Study, which addressed prolonged exposure to anesthesia in young children;9 and the University of California San Francisco Human Trial, which compared patients with late versus early and long versus short exposure to a volatile anesthetic and anesthesia-naive matched patients, on neuropsychological and comprehension scores at 8 to 11 years of age.9

However, retrospective observational studies are prone to bias. The impact of surgical illness and hospital admission on development in children can be profound. Otitis and tonsil or adenoid hypertrophy, common pediatric conditions that hinder hearing and sleep and often require anesthesia and surgery, may themselves affect cognitive development.10 Databases designed to look at other outcomes may be missing important information about anesthesia, surgery and life experience. Errors in disease coding are common.10 Records may not be accurate. Unmeasured confounders may be present despite apparently well-matched controls.

To settle this issue, data from robust, prospective, ideally experimental studies are needed. Because separating the impact of anesthesia and surgery in children is difficult, human randomized controlled trials (RCTs) must focus on comparing anesthetic techniques that are (thought to be) neurotoxic and non-neurotoxic. In the only RCT to date, 722 children younger than three years underwent inguinal herniorrhaphy with either general anesthesia with sevoflurane (median exposure 54 minutes) or awake spinal or caudal anesthesia.11 There was no difference in neurodevelopmental outcomes at two years; the five-year analysis will follow.11

In a retrospective-prospective study, children younger than three years who had had general anesthesia for between 20 and 240 minutes showed no differences in memory and learning, motor and processing speed, visuospatial function, attention, executive function language, or behaviour at age 8 to 15 years when matched against anesthesia-naive siblings.12 For longer surgical cases, sedation is required even if under regional anesthesia. The T-REX study is a planned RCT that will compare dexmedetomidine-remifentanil (both considered non-neurotoxic and used in combination to optimize intraoperative sedation without prolonging postoperative sedation) versus general anesthesia with sevoflurane after induction with sevoflurane and caudal block in infants for lower abdominal or limb surgery lasting more than two hours.9 Neurodevelopmental scores are the presumed primary outcome. For even longer cases, heavy sedation bordering on general anesthesia would be required and may be unsafe. It would be extremely difficult to run an RCT to study the effects of multiple exposures to general anesthesia in children. Future research on anesthetic neurotoxicity from long or multiple exposures to general anesthesia will therefore continue to rely on animal data and clinical studies that have uncontrolled and observational components. Examining the impact of early anesthesia or surgery on youth and young adults would require studies with long timelines.

The signals from animal and observational studies cannot be ignored. However, the observed clinical deficits have been subtle and anesthetic neurotoxicity in children remains unproven. As such, needed procedures must not be delayed because of such concerns. Poor cardiovascular, respiratory and metabolic homeostasis and pain or stress are themselves neurotoxic, and mitigating them must remain the main focus of perioperative management. Meanwhile, clinicians are using regional anesthesia, dexmedetomidine, opioids and muscle relaxants to reduce exposure to potentially more neurotoxic agents. Other potential neurotoxicity-mitigating techniques are being investigated.

Because there is often little choice but to use anesthetics and sedatives, we suggest raising the subject of potential neurotoxicity with parents and clinicians when procedures are wholly elective and can be delayed — an uncommon situation, as pediatric procedures are seldom undertaken lightly. If parents raise the subject, we suggest reassuring them that one brief exposure is likely to be inconsequential, that the effect of prolonged or multiple exposures is unknown, and that neuroplasticity and nurture will probably ensure no long-term sequelae.

Footnotes

  • Competing interests: None declared.

  • This article has been peer reviewed

References

  1. ↵
    1. DiMaggio C,
    2. Sun LS,
    3. Li G
    . Early childhood exposure to anesthesia and risk of developmental and behavioral disorders in a sibling birth cohort. Anesth Analg 2011;113:1143–51.
    OpenUrlCrossRefPubMed
    1. Wilder RT,
    2. Flick RP,
    3. Sprung J,
    4. et al
    . Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology 2009;110:796–804.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Sprung J,
    2. Flick RP,
    3. Katusic SK,
    4. et al
    . Attention-deficit/hyperactivity disorder after early exposure to procedures requiring general anesthesia. Mayo Clin Proc 2012;87:120–9.
    OpenUrlCrossRefPubMed
  3. ↵
    1. O’Leary JD,
    2. Janus M,
    3. Duku E,
    4. et al
    . A population-based study evaluating the association between surgery in early life and child development at primary school entry. Anesthesiology 2016;125:272–9.
    OpenUrl
  4. ↵
    1. Glatz P,
    2. Sandin RH,
    3. Pedersen NL,
    4. et al
    . Association of anesthesia and surgery during childhood with long-term academic performance. JAMA Pediatr 2017;171:e163470.
    OpenUrl
  5. ↵
    1. Graham MR,
    2. Brownell M,
    3. Chateau DG,
    4. et al
    . Neurodevelopmental assessment in kindergarten in children exposed to general anesthesia before the age of 4 years. A retrospective matched cohort study. Anesthesiology 2016;125:667–77.
    OpenUrl
  6. ↵
    1. de Heer IJ,
    2. Tiemeier H,
    3. Hoeks SE,
    4. et al
    . Intelligence quotient scores at the age of 6 years in children anaesthetised before the age of 5 years. Anaesthesia 2017;72:57–62.
    OpenUrl
  7. ↵
    1. Sprung J,
    2. Flick RP,
    3. Wilder RT,
    4. et al
    . Anesthesia for cesarean delivery and learning disabilities in a population-based birth cohort. Anesthesiology 2009;111:302–10.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Pinyavat T,
    2. Warner DO,
    3. Flick RP,
    4. et al
    . Summary of the update session on clinical neurotoxicity studies. J Neurosurg Anesthesiol 2016;28:356–60.
    OpenUrl
  9. ↵
    1. Flick RP,
    2. Nemergut ME,
    3. Christensen K,
    4. et al
    . Anesthetic-related neurotoxicity in the young and outcome measures. The devil is in the details. Anesthesiology 2014;120:1303–5.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Davidson AJ,
    2. Disma N,
    3. de Graaff JC,
    4. et al
    . 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;387:239–50.
    OpenUrlCrossRefPubMed
  11. ↵
    1. Sun LS,
    2. Li G,
    3. Miller TL,
    4. et al
    . Association between a single general anesthesia exposure before age 36 months and neurocognitive outcomes in later childhood. JAMA 2016;315:2312–20.
    OpenUrlCrossRefPubMed
PreviousNext
Back to top

In this issue

Canadian Medical Association Journal: 189 (32)
CMAJ
Vol. 189, Issue 32
14 Aug 2017
  • Table of Contents
  • Index by author

Article tools

Print
Download PDF
Article Alerts
To sign up for email alerts or to access your current email alerts, enter your email address below:
Email Article

Thank you for your interest in spreading the word on CMAJ.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Anesthetic neurotoxicity and the developing brain
(Your Name) has sent you a message from CMAJ
(Your Name) thought you would like to see the CMAJ web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Anesthetic neurotoxicity and the developing brain
Anthony M.-H. Ho, Melinda L. Fleming, Glenio B. Mizubuti
CMAJ Aug 2017, 189 (32) E1028-E1029; DOI: 10.1503/cmaj.170313

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
‍ Request Permissions
Share
Anesthetic neurotoxicity and the developing brain
Anthony M.-H. Ho, Melinda L. Fleming, Glenio B. Mizubuti
CMAJ Aug 2017, 189 (32) E1028-E1029; DOI: 10.1503/cmaj.170313
Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Footnotes
    • References
  • Figures & Tables
  • Related Content
  • Responses
  • Metrics
  • PDF

Related Articles

  • PubMed
  • Google Scholar

Cited By...

  • No citing articles found.
  • Google Scholar

More in this TOC Section

  • The case for relaxing no-visitor policies in hospitals during the ongoing COVID-19 pandemic
  • A “No More Waves” strategy for COVID-19 in Canada
  • Transforming race-based health research in Canada
Show more Commentary

Similar Articles

Content

  • Current issue
  • Past issues
  • Collections
  • Sections
  • Blog
  • Podcasts
  • Alerts
  • RSS
  • Early releases

Information for

  • Advertisers
  • Authors
  • Reviewers
  • CMA Members
  • Media
  • Reprint requests
  • Subscribers

About

  • General Information
  • Journal staff
  • Editorial Board
  • Governance Council
  • Journal Oversight
  • Careers
  • Contact
  • Copyright and Permissions

Copyright 2021, Joule Inc. or its licensors. All rights reserved. ISSN 1488-2329 (e) 0820-3946 (p)

All editorial matter in CMAJ represents the opinions of the authors and not necessarily those of the Canadian Medical Association or its subsidiaries.

To receive any of the resources on this site in an accessible format, please contact us at cmajgroup@cmaj.ca.

Powered by HighWire