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Research Articles

October 2021
June 2021

Research Progress of Pharmacological Intervention of Sevoflurane-induced Nerve Injury in the Developing Brain.

Gut microbiota mediates cognitive impairment in young mice after multiple neonatal exposures to sevoflurane.
Aging June 28, 2021

Neonatal administration of a subanaesthetic dose of JM-1232(-) in mice results in no behavioural deficits in adulthood.
Scientific Reports June 18, 2021

Repeated Neonatal Isoflurane Exposure is Associated with Higher Susceptibility to Chronic Variable Stress-induced Behavioural and Neuro-inflammatory Alterations.
Neuroscience June 15, 2021

Testosterone is Sufficient to Impart Susceptibility to Isoflurane Neurotoxicity in Female Neonatal Rats.
Journal of Neurosurgical Anesthesiology June 15, 2021

Histone Deacetylase 2-Mediated Epigenetic Regulation is Involved in the Early Isoflurane Exposure-Related Increase in Susceptibility to Anxiety-Like Behaviour Evoked by Chronic Variable Stress in Mice.
Neurochemical Research June 8, 2021

lncRNA Xist regulates sevoflurane-induced social and emotional impairment by modulating miR-98-5p/EDEM1 signaling axis in neonatal mice.
Molecular Therapy – Nucleic Acids June 4, 2021

Parental Decision-Making for Surgery and Anesthesia in Young Children.
Western Journal of Nursing Research June 4, 2021

A decade later, there are still major issues to be addressed in paediatric anaesthesia.
Current Opinion in Anaesthesiology June 2021

Effect of operative trauma and multiple propofol anesthesia on neurodevelopment and cognitive function in developmental rats.
Journal of Zhejiang University (Medical Sciences) June 2021

Maternal sevoflurane exposure induces temporary defects in interkinetic nuclear migration of radial glial progenitors in the fetal cerebral cortex through the Notch signalling pathway.
Cell Proliferation June 2021

May 2021

Evaluation of the Neuroprotective Effect of Pycnogenol in a Hypoxic-Ischemic Brain Injury Model in Newborn Rats.
American Journal of Perinatology May 27, 2021

Recent advances in understanding cognitive and behavioural alterations after early-in-life anaesthesia exposure and new mitigation/alternative strategies in preclinical studies.
Current Opinion in Anaesthesiology May 18, 2021

Why do We Use the Concepts of Adult Anesthesia Pharmacology in Developing Brains? Will It Have an Impact on Outcomes? Challenges in Neuromonitoring and Pharmacology in Pediatric Anesthesia.
J Clin Med May 18, 2021

RIPK1/RIPK3-Mediated Necroptosis is Involved in Sevoflurane-Induced Neonatal Neurotoxicity in the Rat Hippocampus.
Cellular and Molecular Neurobiology May 15, 2021

Maternal anesthesia with sevoflurane during the mid-gestation induces social interaction deficits in offspring C57BL/6 mice.
Biochemical and Biophysical Research Communications May 14, 2021

The effect of xenon on fetal neurodevelopment following maternal sevoflurane anesthesia and laparotomy in rabbits.
Neurotoxicology and Teratology May 5, 2021

Accounting for General Anesthesia: A Pre-Op Primer and Post-Op Factor.
Pediatric Annals May 1, 2021

Effect of dexmedetomidine on sevoflurane-induced neurodegeneration in neonatal rats.
British Journal of Anaesthesia May 2021

Effects of sevoflurane general anesthesia during early pregnancy on AIM2 expression in the hippocampus and parietal cortex of Sprague-Dawley offspring rats.
Experimental and Therapeutic Medicine May 2021

Longitudinal associations between exposure to anesthesia and neurocognitive functioning in pediatric medulloblastoma.
European Journal of Cancer May 2021

Preventing the Long-term Effects of General Anesthesia on the Developing Brain: How Translational Research can Contribute.
Neuroscience May 2021

April 2021

Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor and cognitive deficits.
Cell Biology and Toxicology April 29, 2021

The effect of sevoflurane anesthesia for dental procedure on neurocognition in children: a prospective, equivalence, controlled trial.
BMC Pediatrics April 16, 2021

Ferroptosis contributes to isoflurane-induced neurotoxicity and learning and memory impairment.
Cell Death Discovery April 7, 2021

Long Noncoding RNA SPRY4-IT1 Modulates Ketamine-Induced Neurotoxicity in Human Embryonic Stem Cell-Derived Neurons through EZH2.
Developmental Neuroscience April 7, 2021

Effects of general anaesthesia during pregnancy on neurocognitive development of the fetus: a systematic review and meta-analysis.
British Journal of Anaesthesia April 6, 2021

Intrapartum opioid analgesia and childhood neurodevelopmental outcomes among infants born preterm.
American Journal of Obstetrics & Gynecology MFM April 5, 2021

Anaesthesia, neural activity, and brain development: interneurones in the spotlight.
British Journal of Anaesthesia April 1, 2021

Ketamine inhibits neuronal differentiation by regulating brain-derived neurotrophic factor (BDNF) signaling
Toxicology in Vitro April 2021

MicroRNA-1297 suppressed the Akt/GSK3 β signaling pathway and stimulated neural apoptosis in an in vivo sevoflurane exposure model
Journal of International Medical Research April 2021

Repeated exposure to propofol in the neonatal period impairs hippocampal synaptic plasticity and the recognition function of rats in adulthood
Brain Research Bulletin April 2021

Anesthetic Exposure in Staged Versus Single-Stage Cleft Lip and Palate Repair: Can We Reduce Risk of Anesthesia-Induced Developmental Neurotoxicity?
Journal of Craniofacial Surgery March-April 2021

December 2020

Resveratrol ameliorates sevoflurane-induced cognitive impairment by activating the SIRT1/NF-κB pathway in neonatal mice
Journal of Nutritional Biochemistry December 31, 2020

Hypermethylation of EFEMP1 in the Hippocampus May Be Related to the Deficit in Spatial Memory of Rat Neonates Triggered by Repeated Administration of Propofol.
BioMed Research International December 19, 2020

Emerging Role of Long Noncoding RNAs in Perioperative Neurocognitive Disorders and Anesthetic-Induced Developmental Neurotoxicity
Anesthesia & Analgesia December 16, 2020

Hypotension and adverse neurodevelopmental outcomes among children with multiple exposures to general anesthesia: Subanalysis of the Mayo Anesthesia Safety in Kids (MASK) Study
Paediatric Anaesthesia December 15, 2020

Sevoflurane-induced neuronal apoptosis in neonatal mice is prevented with intranasal administration of insulin
American Journal of Translational Research December 15, 2020

Neurodevelopmental Outcomes after Premedication with Atropine/Propofol vs Atropine/Atracurium/Sufentanil for Neonatal Intubation: 2-Year Follow-Up of a Randomized Clinical Trial
The Journal of Pediatrics December 8, 2020

Sevoflurane Exposure Induces Neuronal Cell Parthanatos Initiated by DNA Damage in the Developing Brain via an Increase of Intracellular Reactive Oxygen Species
Frontiers in Cellular Neuroscience December 3, 2020

Neonatal exposure to ketamine disrupts developmental synapse unsilencing and predisposes adult mice for stressor-evoked anxiety
Neuropharmacology December 1, 2020

Prenatal sevoflurane exposure: Effects of iron metabolic dysfunction on offspring cognition and potential mechanism
International Journal of Developmental Neuroscience December 1, 2020

October 2020

Neuroprotection of the Developing Brain by Dexmedetomidine Is Mediated by Attenuating Single Propofol-induced Hippocampal Apoptosis and Synaptic Plasticity Deficits
Experimental Neurobiology October 31, 2020

Behavior and Regional Cortical BOLD Signal Fluctuations Are Altered in Adult Rabbits After Neonatal Volatile Anesthetic Exposure
Frontiers in Neuroscience October 23, 2020

Attention deficit hyperactivity disorder and educational level in adolescent and adult individuals after anesthesia and abdominal surgery during infancy
PLOS One October 21, 2020

miR-455-3p alleviates propofol-induced neurotoxicity by reducing EphA4 expression in developing neurons
Biomarkers October 18, 2020

An Overview on the Mechanisms of Neuroprotection and Neurotoxicity of Isoflurane and Sevoflurane in Experimental Studies
Brain Research Bulletin October 17, 2020

MicroRNA-204-5p mediates sevoflurane-induced cytotoxicity in HT22 cells by targeting brain-derived neurotrophic factor
Histology & Histopathology October 2, 2020

Androgenic Modulation of the Chloride Transporter NKCC1 Contributes to Age-dependent Isoflurane Neurotoxicity in Male Rats
Anesthesiology October 1, 2020

A Methyltransferase Inhibitor (Decitabine) Alleviates Intergenerational Effects of Paternal Neonatal Exposure to Anesthesia With Sevoflurane
Anesthesia & Analgesia October 2020

Effects of ketamine on neurogenesis, extracellular matrix homeostasis and proliferation in hypoxia-exposed HT22 murine hippocampal neurons.
Biomedical Reports October 2020

Sevoflurane leads to learning and memory dysfunction via breaking the balance of tPA/PAI-1.
Neurochemistry International October 2020

September 2020

Maternal sevoflurane exposure affects differentiation of hippocampal neural stem cells by regulating miR-410-3p and ATN1
Stem Cell Research & Therapy September 29, 2020

Anesthesia plus surgery in neonatal period impairs preference for social novelty in mice at the juvenile age.
Biochemical and Biophysical Research Communications September 24, 2020

Early childhood general anesthesia exposure associated with later developmental delay: A national population-based cohort study
PLOS One September 24, 2020

Protective role of protocatechuic acid in sevoflurane-induced neuron apoptosis, inflammation and oxidative stress in mice
Restorative Neurology and Neuroscience September 24, 2020

Conditions requiring hospitalisations, more than general anaesthesia itself, are associated with diagnosis of learning disorders in children
Anaesthesia Critical Care & Pain Medicine September 23, 2020

Effects of early postnatal sevoflurane exposure on oligodendrocyte maturation and myelination in cerebral white matter of the rat
Biomedicine & Pharmacotherapy September 18, 2020

Neonatal exposure to sevoflurane expands the window of vulnerability to adverse effects of subsequent exposure to sevoflurane and alters hippocampal morphology via decitabine-sensitive mechanisms
Neuroscience Letters September 14, 2020

Sevoflurane Post-Conditioning Ameliorates Neuronal Deficits and Axon Demyelination After Neonatal Hypoxic Ischemic Brain Injury: Role of Microglia/Macrophage
Cellular and Molecular Neurobiology September 2, 2020

Propofol inhibits the expression of Abelson nonreceptor tyrosine kinase without affecting learning or memory function in neonatal rats
Brain and Behavior September 1, 2020

Is Anesthesia Bad for the Brain? Current Knowledge on the Impact of Anesthetics on the Developing Brain.
Anesthesiology Clinics September 2020

Sevoflurane Induces Hippocampal Neuronal Apoptosis by Altering the Level of Neuropeptide Y in Neonatal Rats.
Neurochemical Research September 2020

Tau Contributes to Sevoflurane-induced Neurocognitive Impairment in Neonatal Mice
Anesthesiology September 2020

The protective effect of trilobatin against isoflurane-induced neurotoxicity in mouse hippocampal neuronal HT22 cells involves the Nrf2/ARE pathway
Toxicology September 2020

The Unspoken Question!
Anesthesia & Analgesia September 2020

Yes‑associated protein protects and rescues SH‑SY5Y cells from ketamine‑induced apoptosis
Molecular Medicine Reports September 2020

May 2020

Optimization of Ultrasound Backscatter Spectroscopy to Assess Neurotoxic Effects of Anesthesia in the Newborn Non-human Primate Brain
Ultrasound in Medicine and Biology May 29, 2020

Neonatal Exposure to Anesthesia Leads to Cognitive Deficits in Old Age: Prevention With Intranasal Administration of Insulin in Mice
Neurotoxicity Research May 26, 2020

Neonatal Ketamine Alters High-Frequency Oscillations and Synaptic Plasticity in the Subiculum But Does not Affect Sleep Macrostructure in Adolescent Rats
Frontiers in Systems Neuroscience May 26, 2020

Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics
World Journal of Psychiatry May 19, 2020

Upregulation of miR-215 attenuates propofol-induced apoptosis and oxidative stress in developing neurons by targeting LATS2.
Molecular Medicine May 6, 2020

Neurotoxicity of Sub-Anesthetic Doses of Sevoflurane and Dexmedetomidine Co-Administration in Neonatal Rats
NeuroToxicology May 5, 2020

Upregulation of miR-496 Rescues Propofol-Induced Neurotoxicity by Targeting Rho Associated Coiled-Coil Containing Protein Kinase 2 (ROCK2) in Prefrontal Cortical Neurons
Current Neurovascular Research May 5, 2020

Acetyl-l-carnitine Does Not Prevent Neurodegeneration in a Rodent Model of Prolonged Neonatal Anesthesia
Neurotoxicology and Teratology May 3, 2020

Standards for Preclinical Research and Publications in Developmental Anaesthetic Neurotoxicity: Expert Opinion Statement From the SmartTots Preclinical Working Group
British Journal of Anaesthesia May 2020


What is SmartTots?
SmartTots is a Public-Private Partnership (PPP) between the US Food and Drug Administration (FDA) and the International Anesthesia Research Society (IARS). The mission of this partnership is to coordinate and fund a research program with the goal of ensuring safe surgery for the millions of infants and young children who undergo anesthesia and/or sedation each year.
What is the National Center for Toxicological Research (NCTR)?
NCTR is an internationally recognized research center at the FDA that supports the goal of improving patient and consumer safety. NCTR, along with other centers at the FDA, conducts research to support the scientific basis for the FDA’s regulatory decisions and reduce risks associated with products regulated by the FDA. One of the ways that NCTR helps assess possible risks to human health is to perform animal research studies that investigate the potential for adverse effects and mechanisms of injury following exposure to potentially dangerous chemicals.
How did the concerns about the safety of anesthetic drugs for infants and young children arise?
The FDA’s National Center for Toxicological Research (NCTR), as well as investigators at several universities, conducted research to study the effects of anesthetics on the nervous systems of developing animals. This research demonstrated that exposure to some anesthetics and sedatives caused memory and learning difficulties and other harmful changes in the central nervous systems of some laboratory animals. Currently, inadequate data exist to prove or disprove whether similar effects occur in children. More information on the results of early animal studies is below.
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Consensus Statement

A growing body of evidence from animal studies and observational studies in humans suggests adverse effects on behavior, learning, and memory may result from exposure to anesthetics and sedation during periods of rapid brain development. In June 2014 the International Anesthesia Research Society and US Food and Drug Administration convened a group of experts in anesthesia, pediatric medicine, neuroscience, and patient safety to consider the evidence and what it means for health care providers and parents.  The SmartTots Consensus Statement on the Use of Anesthetic and Sedative Drugs in Infants, Toddlers, and Preschool Children is the result of many hours of deliberation by that diverse group of experts along with feedback from more than 20 stakeholder organizations.

Scientific Presentations

IARS 2015 Annual Meeting and International Science Symposium

Improving Health through Discovery and Education

Neurotoxicity of Anesthetics in the Developing Brain – A Translational Update

Key Summary Points

Neurotoxicity of Anesthetics in the Developing Brain
  1. The major excitatory neurotransmitter, glutamate, and the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), are generally associated with neuronal communication in the adult brain.
  2. In the developing brain, these transmitters play a central role in brain morphogenesis, including synapse formation, proliferation, migration, differentiation and survival of neurons.