SmartTots Newsletter

Research News & Updates

Association Between Maternal Labour Epidural Analgesia and Autistic Traits in Offspring. Ming Ann Sim et al. October 2023.

Is there an association between maternal epidural anesthesia (MEA) and autism spectrum disorder (ASD)? For their prospective neurobehavioral observational cohort study, these authors recruit 704 mother/offspring pairs, and follow the babies for 7 years after birth. The mothers had normal vaginal deliveries and MEA during delivery. Findings from numerous tests, including those at the 7-year mark, show no significant association between MEA, the development of ASD, and autism traits in offspring. The clinical incidence of ASD was 2.32% and 1.76% in children with and without exposure to MEA, respectively.

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First Anesthesia Exposure Effects on Short-Term Neurocognitive Function Among 1- to 36-Month-Old Children: A Case-Control Pilot Study. Waitayawinyu et al. July 2023.

In their prospective case-control study, investigators studied short-term neurocognitive function after early anesthesia exposure. Subjects include 39 children ages 1-36 months hospitalized for non-cardiac surgery (AG-anesthesia group) and a control group (CG) of 20 healthy children. Findings show the AG with statistically and clinically lower baseline cognitive scores than the CG. The post-anesthesia composite cognitive scores for most of the AG were statistically higher than their baseline scores, but without clinical significance. Seven children in the AG had lower cognitive scores after anesthesia exposure.

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Unanswered Questions of Anesthesia Neurotoxicity in the Developing Brain. Ing & Vutskits. July 2023.

The authors discuss recent advances in developmental anesthesia neurotoxicity research, from both a preclinical and clinical perspective. They address these unanswered questions: 1) Does anesthesia cause neurotoxicity in humans? 2) What are the appropriate outcomes to evaluate? 3) Which subgroups of children are vulnerable? 4) What is the contribution of surgery and other perioperative factors to neurotoxicity? 5) Are there nontoxic general anesthetics? Scientists recognize an association between anesthesia exposure and deficits in certain cognitive domains, and not others, but still search for evidence that justifies anesthesia as the cause of neurotoxicity in children.

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Anesthesia, the Developing Brain, and Dexmedetomidine for Neuroprotection. Tsivitis et al. June 2023.

This literature review seeks to clarify the ability of dexmedetomidine (DEX) to mitigate anesthesia-induced developmental neurotoxicity. The authors address DEX vis-à-vis 1) findings in animal and human studies; 2) mechanisms of action and pharmacodynamics; 3) anesthesia-induced neuroapoptosis and neuroinflammation; and 4) neuroplasticity and synaptic architecture. Findings yield many studies in pediatric patients having low-risk, elective surgeries and “current evidence may not be strong enough to conclude that DEX is purely neuroprotective.” The field needs more research on DEX neuroprotection in high-risk patients having major surgeries.

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Dexmedetomidine Alleviates Propofol-Induced Neural Injury in Developing Rats. Weiren Xiao, Shouren Chen, Jinzhuan Chen, & Jianzhong Huang. August 2023.

What is the impact of dexmedetomidine (DEX) on propofol (PPF)-induced neuroapoptosis and subsequent cognitive problems in neonatal rats? Findings show DEX 1) reduces PPF-induced spatial learning and memory deficits and brain cell death; 2) modulates messenger RNA expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2 Associated X-protein (Bax); and 3) stops the PPF-induced increase in inflammatory factors in the brain. DEX mitigates PPF-induced neurotoxicity by activating the Akt/CREB/BDNF (Ak strain transforming/cAMP response element-binding protein/brain-derived neurotrophic factor) signaling pathway.

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Dexmedetomidine Suppresses Hippocampal Astrocyte Pyroptosis in Cerebral Hypoxic-Ischemic Neonatal Rats by Upregulating microRNA-148a-3p to Inactivate the STAT/JMJD3 Axis. Yi Zhong et al. August 2023.

What role does micro ribonucleic acid 148a-3p (148a-3p) play in the neuroprotective effect of dexmedetomidine (DEX) on cerebral hypoxic-ischemic (CHI) brain damage? Researchers expose neonatal mice to CHI conditions, a 148a-3p inhibitor, and DEX, then isolated hippocampal astrocytes for testing in an oxygen-glucose deprivation model. Findings show DEX exerts its protective effects by upregulating 148a-3p. Overexpression of 148a-3p inhibits astrocyte death, and deactivates the signal transducer and activator of transcription proteins/Jumonji domain-containing protein-3 (STAT/JMJD3) axis to alleviate cerebral damage in neonates with CH-ischemia.

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Sevoflurane Anaesthesia Induces Cognitive Impairment in Young Mice through Sequential Tau Phosphorylation. Feng Liang et al. August 2023.

What is the underlying mechanism of sevoflurane’s (SEVO) effect on tau phosphorylation (TP) and cognitive impairment (CI) in neonatal mice? Findings show an initial SEVO exposure induces calcium/calmodulin-dependent protein kinase type II subunit alpha (CaMKIIα) phosphorylation, leading to TP and tau detachment from microtubules. Subsequent SEVO exposures induce glycogen synthase kinase-3 beta (GSK3β) activation that phosphorylates detached or free tau, resulting in CI. There is also evidence of molecular interactions between tau, free tau, and CaMKIIα or GSK3β, and between tau and tubulin at a single-molecule level

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Editorial: Anesthetic Neurotoxicity in Developing Brains: Mechanisms, Biomarkers, and Therapeutic Targets. Yang Yu, Yonghao Yu, Yiying Zhang, & Huihui Miao. August 2023.

The editors highlight eight “intriguing” papers on age-dependent anesthetic effects in the developing brain, their mechanisms, and clinical applications. Important topics include 1) mechanisms underlying anesthesia-induced neurotoxicity and cognitive impairments in neonates; 2) the present state of clinical and basic research, and the challenges, in transferring information from animal investigations to clinical treatment; 3) clinical research components on the effects of prenatal anesthesia in neonates; 4) the impact of anesthesia monitoring devices in the perioperative period; and 5) applicable neuroprotective techniques and prospective therapeutic interventions.

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The Effects of General Anesthetics on Mitochondrial Structure and Function in the Developing Brain. Hogarth, Tarazi, & Maynes. July 2023.

Investigators describe available experimental data on the effects of general anesthesia (GA) on mitochondria (MT) in the developing nervous system. The discussion covers mitochondrial 1) structure, function, and modes of GA action; 2) morphology and energetics; 3) reactive oxygen species equilibrium; 4) quality control pathways; and 5) mediated regulated cell death pathways. Data from animal models may link GA exposure with MT damage, but limited experimental human data makes extrapolation to the clinical context challenging. It remains unclear as to whether anesthesia-induced MT changes, observed in experimental models, translate to developmental deficits later in life.

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Ketamine Counteracts Sevoflurane-Induced Depressive-Like Behavior and Synaptic Plasticity Impairments through the Adenosine A2A Receptor/ERK Pathway in Rats. Weiwei Yu et al. July 2023.

The authors explore the effects and mechanisms of ketamine (KT) against sevoflurane (SEVO)-induced depressive-like behavior in rats. Findings show 1) KT mediates extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation by downregulating adenosine A2A receptor (A2AR) expression; 2) phosphorylated ERK1/2 increases the production of synaptic-associated proteins, which enhance synaptic plasticity in the brain, and this 3) reduces SEVO-induced depressive-like behavior. These results provide a framework for reducing anesthesia-induced developmental neurotoxicity.

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miR-34a Targets SIRT1 to Reduce p53 Deacetylation and Promote Sevoflurane Inhalation Anesthesia-Induced Neuronal Autophagy and Apoptosis in Neonatal Mice. Xiang Xu, Caifeng Li, Junping Zou, & Liang Liu. July 2023.

What is the function of miR-34a (“34a,” micro ribonucleic acid 34a) and how does it interact with SIRT1 (sirtuin 1 gene) and p53 (tumor protein 53) in sevoflurane (SEVO)-induced neuronal apoptosis (cell death) and autophagy (cell renewal)? Findings in neonatal mice show SEVO 1) impairs learning, memory, and survival of hippocampal neurons; 2) increases expression of 34a; and 3) reduces SIRT1. 34a overexpression promotes SEVO-stimulated neuronal cell death and renewal by inhibiting SIRT1 expression and subsequent p53 deacetylation.

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A Spatial Memory Deficit in Male But Not Female Rats After Neonatal Diazepam Exposure: A New Model for Developmental Sedative Neurotoxicity. Chinn, Cummins, & Sall. June 2023.

What is the role of diazepam (DZ) on spatial and recognition memory in young adult rats after neonatal exposure? Investigators expose Postnatal Day (PND) 7 rats, males and females, to DZ or vehicle and follow with testing at PND 42. Findings show 1) DZ impairs performance in maze testing in males, but not in females; 2) no statistical differences between sexes for measures of recognition memory, anxiety, and locomotion activity; and 3) less aberrant arterial blood gas measures under DZ sedation when compared to isoflurane exposure. The spatial memory results for DZ are consistent with other volatile anesthetics suggesting a model in which the gamma-aminobutyric acid (GABA) system plays a critical role in determining susceptibility to behavioral deficits.

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Exposure to Halogenated Ethers Causes Neurodegeneration and Behavioural Changes in Young Healthy Experimental Animals: A Systematic Review and Meta Analyses. Hooijmans et al. May 2023.

Through a systematic review of 324 preclinical experimental animal studies, investigators seek to confirm the neurotoxic risk of halogenated ethers, including isoflurane (ISO), sevoflurane (SEVO), desflurane (DES), and enflurane, to the developing brain. Findings show SEVO and ISO, in particular, even after a single dose, cause neurodegeneration and behavioral changes, including learning/memory impairment and increased anxiety. These two agents plus DES significantly increase caspase-3 levels. Based on their results, the authors encourage restraint in using SEVO and ISO with vulnerable groups.

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Development of a Primate Model to Evaluate the Effects of Ketamine and Surgical Stress on the Neonatal Brain. Cheng Wang et al. April 2023.

Is ketamine (KT) neuroprotective or does it induce neuronal degeneration in the developing brain? Subjects included two groups of neonatal monkeys having thoracotomy surgery. Group A (N=4) received KT prior to and during surgery while Group B (N=4), the control, received “volumes” of normal saline. Findings in Group A, relative to Group B, show 1) elevated levels of inflammatory cytokines, monocyte chemoattractant protein 1, and macrophage inflammatory protein at 6 and 24 hours after surgery; and 2) significantly higher neuronal degeneration in the frontal cortex. KT effects were neither neuroprotective nor anti-inflammatory.

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Research News & Updates

Controversies in Anesthesia-Induced Developmental Neurotoxicity. Useinovic & Jevtovic-Todorovic. May 2023.

This review explores rapidly accumulating evidence in animal studies and in select, high-profile clinical trials that suggest early-life exposure to general anesthesia (GA) may alter cognitive and socio-affective development in the young. On the effects of neonatal exposure to GA, the authors address 1) mechanisms of action and neurotoxicity; 2) long-term behavioral outcomes; 3) timing of exposure; and 4) cumulative dosing. Highlights also include 5) the impact of underlying disease on long-term behavioral development; 6) prospective clinical evaluation of early-life sequelae; and 7) dilemmas on how to proceed given controversies in anesthesia-induced developmental neurotoxicity.

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Early Exposure to General Anaesthesia and Increasing Trends in Developmental Behavioural Impairments: Is There a Link? Jevtovic-Todorovic & Useinovic. May 2023.

This editorial discusses the accumulation of clinical findings suggesting a link between general anesthesia (GA) and behavioral deficits in human children. The authors find the issue worthy of further consideration as they focus, in particular, on the link between early anesthesia exposure and socio-affective deficits in Attention-Deficit-Hyperactivity-Disorder (ADHD) and Autism Spectrum Disorder (ASD). “Looking at currently available preclinical and clinical evidence, one wonders if the increase in ADHD and perhaps ASD over the past 20 years depends, at least in part, on the increased number of GA interventions in daily pediatric practice.”

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Multiple General Anesthesia in Children: A Systematic Review of Its Effect on Neurodevelopment. Colletti et al. May 2023.

In their database review, investigators explore the potential effects of multiple general anesthesia procedures (mGA) on neurodevelopmental outcomes (NDO) in children < 4 years. Ten acceptable out of 3,156 potential papers produced a total cohort of 264.7 unexposed and 11 exposed children who were assessed for NDO. Findings show a statistically significant difference in NDO between exposed and unexposed children in 9 out of 10 papers. Controlled studies of mGA for this cohort indicate there may be a greater risk of neurodevelopmental delay in children undergoing mGA.

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A Bibliometric Analysis of the Neurotoxicity of Anesthesia in the Developing Brain from 2002 to 2021. Ying Cao et al. April 2023.

What are publication trends on the topic of anesthesia-induced neurotoxicity in the developing brain? Investigators conducted a bibliographic analysis, a computer-assisted technique that identifies high-impact research articles by measuring the number of citations. Their literature search, from 2002-2021, identified 414 articles with a total of 10,419 citations from which the top 20 most commonly cited articles were selected for analysis. Findings show current clinical studies are mainly retrospective. Future analysis should prioritize prospective, multi-center, long-term monitoring studies.

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Neuroprotective Strategies in Anesthesia-Induced Neurotoxicity. Andropoulos. March 2023.

What neuroprotective strategies can reduce anesthesia-induced neurotoxicity and improve neurodevelopmental outcomes in infants and children? The authors discuss alternative anesthetics and elements of physiologic neuroprotection. A table presents the advantages/disadvantages of 15 neuroprotective strategies that can, plausibly, be introduced into clinical practice. Clinicians are encouraged to utilize techniques and drugs for which they are most proficient and to pursue proper training in additional neuroprotective strategies prior to emphasizing them.

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Clinical Investigations on Anesthesia-Induced Developmental Neurotoxicity: The Knowns, the Unknowns and Future Prospects. Vutskits & Davidson. March 2023.

The authors provide a comprehensive description of the current knowledge and unsolved challenges of clinical research on developmental anesthesia neurotoxicity (DAN). The discussion addresses 1) methodological considerations in human DAN research; 2) challenges in defining measurable outcome parameters; 3) anesthesia and psychiatric diseases; 4) impact of major surgery in neonates; and 5) remaining unknowns and future perspectives.

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Effects of Anesthesia Exposure on Postnatal Maturation of White Matter in Rhesus Monkeys. Tomlinson et al. July 2023.

How does anesthesia affect white matter maturation in the brains of baby monkeys? The authors analyzed magnetic resonance diffusion tensor imaging in 32 rhesus macaques, ages 2 weeks to 36 months. Findings showed significant age and anesthesia effects in most white matter tracts with major effects in tracts associated with low levels of anesthesia and limited episodes of exposure. Fractional anisotropy values were reduced across several white matter tracts, reflecting a delay in white matter maturation — a finding that elicits potential concern for even limited anesthesia exposure in human children.

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Neonatal Sevoflurane Exposure Induces Long-Term Changes in Dendritic Morphology in Juvenile Rats and Mice. Useinovic et al. June 2023.

What are long-term effects of neonatal anesthesia on subicular pyramidal neurons and on gene expression that regulates neuronal connectivity, learning and memory? Findings show a single dose of sevoflurane (SEVO) in neonatal rodents, when measured in juvenile phases, induces 1) lasting dysregulation of subicular messenger ribonucleic acid (mRNA) levels of cAMP responsive element modulator (Crem); cAMP responsive element-binding protein 1 (Creb1); and Protein phosphatase 3 catalytic subunit alpha (Ppp3ca). Early exposure to SEVO leads to persistent, anesthesia-induced genetic and morphological dysregulation, including rearrangement of subicular dendrites.

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Multiple Sevoflurane Exposures during Mid-Trimester Induce Neurotoxicity in the Developing Brain Initiated by 15LO2-Mediated Ferroptosis. Qian Jiang, Cong Wang, Qiushi Gao, Ziyi Wu, Ping Zhao. June 2023.

Investigators study the role and mechanisms of ferroptosis (FT), a form of iron-dependent brain cell death, in anesthesia-induced developmental neurotoxicity. Subjects included offspring of pregnant rats treated in the mid-trimester with sevoflurane (SEVO). Findings show that SEVO 1) raises malondialdehyde (MDA) and iron levels while inhibiting glutathione peroxidase 4 (GPX4) activity; 2) enhances 15-lipoxygenase2/phosphatidylethanolamine binding protein1 (15L02-PEBP1) interaction; and 3) activates ataxia telangiectasia mutated (ATM) and a downstream pathway.

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Ketamine Exerts Dual Effects on the Apoptosis of Primary Cultured Hippocampal Neurons from Fetal Rats in Vitro. Guo-Hua Wu et al. June 2023.

These researchers treated cultured hippocampal neurons from fetal rats with ketamine (KT) in a wide range of concentrations to explore KT’s neuroprotective and neurotoxic effects. Findings show low KT concentrations (10, 100, 1000 μM) support neuron survival and reduce cell death. High concentrations (2000, 2500, 3000 μM) reduce neuron survival and promoted cell death. When applied, an inhibitor of p38 mitogen-activated protein kinase (p38 MAPK) reduces high-concentration KT-induced neuron cell death — proving that KT’s neurotoxic effects relate to the activation of the p38 MAPK signaling pathway.

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Understanding Sedative Effects within the Context of Acute Neuroinflammation in the Developing Brain: Potential Induction of Delirium-Like Behaviors. Furman et al. June 2023.

How do benzodiazepines (BZs) and opioids (OPs) interact with inflammation in the developing brain? Researchers induced mild-moderate inflammation with lipopolysaccharide (LPS) in newly weaned rats on Postnatal Day 18 in combination with repeated OP + BZ sedation using morphine + midazolam (MorMdz). Findings showed 1) composite behavior scores significantly increase in LPS, MorMdz, and LPS/MorMdz groups; 2) expression of glial-associated neuro-inflammatory markers ionized calcium-binding adaptor molecule1 (Iba1) and glial fibrillary acidic protein (GFAP) are significantly higher after LPS vs LPS/MorMdz exposure; and 3) proinflammatory cytokines increase in LPS, but not in LPS/MorMdz-treated pups. The effects of multidrug sedation on homeostatic neuroimmune responses need to be considered along with neurodevelopmental effects.

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Endoplasmic Reticulum Stress-Activated Neuronal and Microglial Autophagy Contributes to Postoperative Cognitive Dysfunction in Neonatal Rats. Hui Zhang et al. June 2023.

What is the role of endoplasmic reticulum (ER) stress in regulating brain cell autophagy, a natural cell cleaning and renewal process? Investigators administered sevoflurane (SEVO) to Postnatal Day 7 rats with right carotid artery exposure; they tested learning and memory in adult rats and observed harvested brains cells. Findings show surgery and anesthesia increased the expression of 78 glucose-regulated protein-GRP78/BIP (kDa), an indicator of ER stress. The ER stress activator (tunicamycin) increases and the inhibitor (tauroursodeoxycholic acid) decreases autophagy markers. ER stress activates neuronal and microglial autophagy leading to learning and memory deficits later in life.

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Effects of Dexmedetomidine on Brain and Inflammatory Outcomes In Pediatric Cardiac Surgery: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Hashiya, Okubo, & Kato. June 2023.

What are the effects of dexmedetomidine (DEX) on the developing human brain and its inflammatory markers? Investigators conducted a systematic literature review followed by meta-analysis of 7 randomized clinical trials (RCTs) with 579 children <18 years having surgery for congenital heart defects. Findings show DEX associates with 1) reduced serum levels of Enolase, a neuron-specific marker, and Serum S-100β protein, a marker of brain injury; and 2) reduced levels of interleukin-6. In contrast, the results yield similar levels of tumor necrosis factor alpha and nuclear factor kappa-B in the DEX and control groups.

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Anaesthesia-Induced Changes in Genomic Expression Leading to Neurodegeneration. Alharbi et al. May 2023.

What are mechanisms of general anesthesia-induced alterations in late postnatal mice? This study presents the current science on early-life anesthesia exposure, including mediated alterations in genetic expression, with a focus on propofol, ketamine, and isoflurane. The authors explore the relationship between network effects and subsequent biochemical changes leading to long-term neurocognitive abnormalities. The literature provides strong evidence on the way specific anesthetic agents induce pathological events with associated transcriptional changes. The review fosters a greater understanding of exacerbated neuropathology and cognitive impairment due to acute and chronic anesthesia exposure.

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Longitudinal Effects of Ketamine on Cell Proliferation and Death in the CNS of Zebrafish. Santos, Valentim, Félix, Balça-Silva, & Pinto. May 2023.

What is the effect of ketamine (KT) on brain cellular function in zebrafish embryos? Investigators exposed embryos at the 1-4 somites stage to KT; they assessed the effects at 50 and 144 hours post fertilization (hpf) and at 7 months. Findings show KT in high concentrations (.8 mg/ml) induces alterations in autophagy and cellular proliferation of 144 hpf larvae with no significant KT-induced cellular aberrations in adult zebrafish. Dosing of KT in sub-anesthetic and anesthetic concentrations, despite transitory toxic effects in early zebrafish neurogenesis, may be safe in the long-term for the central nervous system.

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Early-life Propofol Exposure Does Not Affect Later-Life GABAergic Inhibition, Seizure Induction, or Social Behavior. Jinyang Liu, Daisy Lin, Alice Yau, James Cottrell & Ira Kass. May 2023.

What are the effects of early-life exposure to propofol (PPF) on adult excitatory and inhibitory behavior? Investigators exposed neonatal male mice to PPF for 2 hours followed by testing later in life. Adult findings show early exposure to PPF does not 1) significantly reduce paired pulse inhibition; 2) inhibit field excitatory postsynaptic potentials; 3) increase adult depression and anxiety; or 4) lead to social dysfunction. Neonatal PPF did not affect Gamma-aminobutyric acid (GABA) inhibition or enhance adult-induced seizures. However, similar experiments with sevoflurane and ketamine may induce unique long-term effects.

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Sevoflurane Exposure in Neonates Perturbs the Expression Patterns of Specific Genes That May Underly the Observed Learning and Memory Deficits. Jimenez-Tellez et al. May 2023.

Using neonatal rats, the authors study the long-term effects of commonly used pediatric anesthetic agents on genes associated with learning and memory. Findings show early exposure to sevoflurane (SEVO) results in subtle, but distinct memory deficits in adulthood. A Nanostring Study of 770 genes reveals differential changes in gene expression levels after exposure to SEVO and dexmedetomidine–particularly in genes that impact cellular viability, learning, and memory. The subtle, but long-term cognitive changes in adulthood may likely involve some disruption of specific gene expression patterns.

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Anesthetics Inhibit Phosphorylation of the Ribosomal Protein S6 in Mouse Cultured Cortical Cells and Developing Brain. Friese et al. May 2023.

Do anesthetic agents mediate synaptic changes, brain cell death, and long-lasting cognitive impairments through a common signaling pathway? Researchers exposed cultured cortical cells in vitro to various anesthetic agents (propofol, etomidate, dexmedetomidine); assessed protein levels in dozens of signaling molecules; and investigated expression of target proteins in the cortex of neonatal mice under sevoflurane. Findings show all anesthetic agents reduced phosphorylation of the ribosomal protein S6. This reduction with subsequent repression of the Mammalian target of rapamycin (mTOR) pathway may be a common signaling event that mediates the impact of general anesthesia on neural circuit development.

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Dexmedetomidine Alleviates Propofol-Induced Pyroptosis of Hippocampal Neurons through NLRP3 Inflammasome Pathway. Xin Wang & Zhenzhen Wan. May 2023.

How does dexmedetomidine (DEX) exert neuroprotection in propofol (PPF)-induced pyroptosis (PYR), a form of regulated cell death? Researchers assessed the viability of hippocampal neurons exposed to DEX pretreatment followed by PPF, each in differing concentrations. Findings show DEX pretreatment 1) stops PYR; 2) increases cell viability; 3) represses NLRP3 (NOD-like receptor family pyrin domain-containing 3 pathway) and the N-terminal fragment of gasdermin D-a gene (GSDMD-N); and 4) inhibits intracellular homeobox A5 gene (HOXA5) expression. DEX pretreatment suppresses NLRP3 expression by downregulating HOXA5 to inhibit PPF-induced neuronal cell death through PYR.

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Metformin Attenuates Sevoflurane-Induced Neurogenesis Damage and Cognitive Impairment: Involvement of the Nrf2/G6PD Pathway. Pei Fan et al. April 2023.

Does metformin (MET), a drug for diabetes, protect against sevoflurane (SEVO)-induced developmental neurotoxicity? Investigators pretreated neonatal rats and neural stem cells (NSCs) in vitro with MET prior to SEVO exposure and followed with testing on Postnatal Days 35-42. Findings show SEVO exposure 1) induces late cognitive deficits; 2) impairs neurogenesis; 3) reduces NSC viability/proliferation while increasing cell death; and 4) decreases protein expression of glucose-6-phosphate dehydrogenase pathway-related molecules (G6PD) in vitro. MET pretreatment stops SEVO-induced cognitive functional decline; it supports protein expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and G6PD.

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Protective Effect of Dexmedetomidine against Hyperoxia-Damaged Cerebellar Neurodevelopment in the Juvenile Rat. Puls, von Haefen, Bührer, & Endesfelder. April 2023.

Is dexmedetomidine (DEX) neuroprotective of brain cells exposed to hyperoxia (HX) — a state of excess oxygen — when compared to normoxia, a normal oxygen state? Investigators exposed neonatal mice to these conditions for 24 hours followed by neuronal assessments. Findings show HX 1) reduced the proportion of calcium binding protein 1 (Calb1) +- Purkinje neurons; 2) affected dendrite length; and 3) reduced the proliferation of Paired box protein (Pax6+-) granule progenitor cells. Oxidative stress reduced the expression of neurotrophins and neuronal transcription factors in cell proliferation, migration, and survival. DEX is neuroprotective of HX-injured Purkinje cells and, under normoxia, supports neuronal transcription without any toxic effects.

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Neobaicalein Prevents Isoflurane Anesthesia-Induced Cognitive Impairment in Neonatal Mice Via Regulating CREB1. Niming Wu, Hua Liu, Xiang Lv, Yu Sun, Hong Jiang. April 2023.

Can Neobaicalein (Neob), a plant-based compound with medicinal benefits, protect against isoflurane (ISO)-induced cognitive damage? Experiments with ISO-treated neonatal mice show that Neob 1) suppresses interleukin-1β, tumor necrosis factor-α, and interleukin-6 levels; and 2) significantly mitigates ISO-induced increases in Ionized calcium-Binding Adapter molecule-1 (IBA-1) -positive cell numbers in the hippocampus. Neob prevents cognitive impairment by suppressing ISO-induced brain cell death and inflammation, and increasing the activity of the cAMP Response Element Binding Protein (CREB1).

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Research News & Updates

TREX Trial Milestone – Enrollment is Complete!

The Toxicity Remifentanil DEXmedetomidine (TREX) trial investigators recently met a major milestone, the completion of enrollment of 450 trial subjects. The TREX trial began in 2017 and set out to study prolonged anesthetic exposure effects and address an important data gap – whether a dexmedetomidine-based anesthetic is associated with better neurodevelopmental outcomes. The study, partially funded by SmartTots, is a Phase III, randomized, active controlled, parallel group, blinded evaluator, multicenter, multinational, superiority trial comparing neurological outcome after standard sevoflurane anesthesia with dexmedetomidine/remifentanil, and low dose sevoflurane anesthesia in children less than 2 years of age undergoing anesthesia of 2 hours or longer. There are a total of 20 sites enrolling patients: 7 in Australia, 5 in the US and 8 in Italy with a variety of surgeries being studied at each site. The study subjects will return at age 3 years for a battery of neuropsychological testing, including general intelligence, language, fine and gross motor skills, behavioral testing and parent behavioral questionnaires. Once complete in the next 2-3 years, the TREX Trial will make an important contribution to the knowledge about the effects of anesthesia in infants and young children.

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IARS Annual Meeting 2023 Panel Session – Update on SmartTots Initiative and Funded Research

We hope that you were able to join us for the IARS 2023 Annual Meeting in Denver, CO. The meeting included a SmartTots-sponsored panel session entitled, “Update on SmartTots Initiative and Funded Research,” which highlighted the latest pediatric anesthetic neurotoxicity research. During this session, moderated by Dean Andropoulos, MD, MHCM, investigators and experts on this topic, Santhanam Suresh, MD, MBA, Jimcy Platholi, MS, PhD and Peter Szmuk, MD, delved into the latest discoveries from their funded research and how their findings will influence current knowledge, impact future studies, and potentially improve patient outcomes.

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Age-Stratified Propofol Dosage for Pediatric Procedural Sedation and Analgesia. van Dijk, Hendriks, van Eck-Smaling, van Wolfswinkel, & van Loon. March 2023.

For diagnostic procedures in children, do we need an age-stratified dosing schedule for propofol (PPF) induction and maintenance in Pediatric Procedural Sedation and Analgesia (PSA)? These authors conducted a retrospective cohort study with data on 6,438 hospital procedures to clarify whether PPF induction at mg·kg⁻¹ and maintenance at mg·kg⁻¹·h⁻¹ was age-dependent using a linear regression model. After adjustments for select variables, findings showed coefficients of -0.11 and -0.36 for age/years for PPF induction and maintenance dose, respectively. There is an inverse age-effect on PPF dose for both induction and maintenance in PSA. Infants and toddlers need a remarkably higher PPF dose than previously expected.

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Prenatal Anesthetic Exposure and Offspring Neurodevelopmental Outcomes-A Narrative Review. Nannan Zhou, Shuang Liang, Xinying Yue, Wangyuan Zou. March 2023.

In their review of animal and clinical studies, these authors summarized the effects of prenatal anesthesia exposure (PAE) during pregnancy on long-term neurodevelopmental outcomes in offspring. Animal studies show that in utero anesthesia exposure is neurotoxic to newborns based on histomorphological changes and cognitive deficits. Regional birth cohort studies detail time intervals between intrauterine exposure and the onset of developmental outcomes over time; investigators use databases, questionnaires and scales to screen for and diagnose neurodevelopmental disorders. These clinical research tools help to address confounding factors that may have a greater impact on neurodevelopment than prenatal anesthesia.

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Early Surgery in Very Preterm Infants is Associated with Brain Abnormalities on Term MRI: A Propensity Score Analysis. Kojima et al. March 2023.

Does surgery with general anesthesia (GA) associate with brain abnormalities and neurodevelopmental deficits in very preterm infants? In a prospective observational study of 392 infants ≤ 32 weeks gestation, investigators evaluated the independent effects of surgery on brain magnetic resonance imaging (MRI) results. Each infant completed the brain MRI at term, 341/392 (87%) completed neurodevelopmental testing at 2 years and 45 had surgery. Findings showed surgery is associated with worse MRI abnormalities, but with no developmental outcomes after propensity score matching. Global brain abnormality scores were associated with the Bayley III Cognitive and Motor Assessment composite scores. Exposure to surgery under GA poses a higher risk of brain abnormalities based on MRI results at term.

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Association Between Receipt of General Anesthesia During Childhood and Attention Deficit Hyperactive Disorder and Neurodevelopment. Joo Young Song et al. February 2023.

In their cohort study, investigators assessed the risk of attention deficit hyperactivity disorder (ADHD) and neurodevelopmental deficits in thousands of children with early exposure to general anesthesia (GA) with endotracheal intubation (ETI). The primary and secondary outcomes were ADHD diagnosis after 72 months and neurodevelopmental deficits, measured annually for 5 years, respectively. Findings showed 1) the incidence of ADHD in children with exposure v. no exposure at 42.6 and 27.7 per 10,000 person-years (PY), respectively; 2) a higher risk of ADHD, as reflected in a hazard ratio of 1.41, in the exposure cohort; and 3) a greater risk of ADHD for longer duration anesthesia with ETI and multiple exposures to GA.  

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Labor Epidural Analgesia and Risk of Autism Spectrum Disorders in Offspring: A Systematic Review and Meta-analysis. Ling-Ling Fang,1 Yuan-Yue Zhou 2, Hai-Yin Jiang 3, Yu-Dan Shi 4. February 2023.

What is the effect of maternal labor epidural anesthesia (LEA) on the risk of autism spectrum disorder (ASD) in offspring? Why are results of recent investigations inconsistent? Investigators completed a systematic literature review, performed a meta-analysis, conducted subgroup analyses and created estimates of relative risk. Results showed an association of LEA with higher risk of ASD in offspring after combining crude estimates from various studies. This association gradually diminishes but remains statistically significant. Unmeasured confounding factors partially explained the statistically significant association between LEA and ASD.  

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Perinatal Anesthesia Exposure and Autism Spectrum Disorders. Houck, Naus, Croen, & Sun. January 2023.

In their review and from a public health perspective, these authors explored the association between perinatal anesthesia exposure, particularly maternal epidural labor analgesia and autism spectrum disorder (ASD) in offspring. Different factors have been associated with ASD in the epidemiological literature, including the mother’s health, infectious and pharmacological etiologies, social factors and environmental exposures. However, data in this study showed no clear association between the use of epidural labor analgesia and the development of ASD.  

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Comparative Sedation with Sevoflurane and Thiopental in Children Undergoing MR Imaging. Kurt, Caliskan, & Gunes. November 2022.

What are the comparative effects of propofol (PPF) and thiopental (TPL), (a barbiturate banned in the US), on children having magnetic resonance imaging? Investigators in Turkey tested 1,222 pediatric patients in two groups: Group 1 at 2-18 years under PPF v. Group 2 at <2 years under TPL. Each child received sevoflurane via insufflation (blowing in of anesthesia) after PPF or TPL. When comparing both groups, Group 1 showed A) higher body weight and physical status scores; B) higher prevalence of epilepsy, cerebral palsy, [intellectual disability], speech deficits and autism; C) higher apnea and desaturation; and D) less neuromuscular growth [disability], hydrocephalus, metabolic disease, and bradycardia. The authors concluded that sevoflurane insufflation via facemask is safe in children after induction with PPF or TPL.

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Propofol-Induced Developmental Neurotoxicity: From Mechanisms to Therapeutic Strategies. Jing Zhang & Yu Li. March 2023.

What are the potential molecular mechanisms of propofol (PPF)-induced neurotoxicity in young children? This literature review summarized 1) preclinical models of PPF-induced neurotoxicity, including in vivo animal and in vitro cell models; 2) mechanisms of PPF-induced developmental neurotoxicity; and 3) therapeutic strategies. Mechanisms of PPF-induced neurotoxicity include abnormal autophagy, calcium overload, apoptosis, neuroinflammation, mitochondrial impairment, neurotropin disorder, synaptic dysplasia and dysregulation of noncoding ribonucleic acid molecules. The authors encourage clinicians to lower anesthesia doses and exposure times, where possible, for children who are vulnerable to nerve injury and to consider personalized PPF clinical application standards for unique pediatric conditions.

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Role of Posttranslational Modifications in Memory and Cognitive Impairments Caused by Neonatal Sevoflurane Exposure. Yongliang Jiang, Yue Zhou, Siwen Tan, Chongxi Xu, & Junpeng Ma. March 2023.

What are the mechanisms of sevoflurane (SEVO)-induced neurotoxicity in the developing brain? This review of preclinical studies described the effects of prolonged or recurrent exposure to SEVO on memory loss and cognitive impairment vis-à-vis post-translational modifications (PTMs). The authors discussed PTM dysregulation and therapeutic interventions in the context of histone acetylation, histone phosphorylation, histone methylation, post-translational modifications of nonhistone proteins and tau phosphorylation. As regulators of gene expression, protein activity and protein function, PTMs play a key role in mediating anesthesia-induced modifications in gene transcription and protein deficits affecting memory and cognition and warrant further study.

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Prolonged Exposure of Neonatal Mice to Sevoflurane Leads to Hyper-ramification in Microglia, Reduced Contacts between Microglia and Synapses, and Defects in Adult Behavior. Hong Li et al. March 2023.

What are immediate and long-term effects of prolonged neonatal sevoflurane (SEVO) (2.5% for 4 hours) on microglia (MG) in normal brain development? Investigators exposed Postnatal Day (PND) 7 mice to SEVO followed by brain tissue analysis for MG ultrastructure, depletion and repopulation on PNDs 14-21 and subsequent behavioral testing. Findings showed prolonged SEVO exposure 1) induces MG hyper-ramification with an increase in total branch length, arborization and branch complexity; and 2) reduces contacts between MG and synapses. In adulthood, anesthesia-induced changes in MG are associated with anxiety-like behaviors, but they lessen with repopulation of MG after depletion.

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Alfaxalone Alleviates Neurotoxicity and Cognitive Impairment Induced by Isoflurane Anesthesia in Offspring Rats. Xingkai Zhao et al. March 2023.

Does alfaxalone (ALF), a steroid anesthetic, alleviate the neurotoxic effects of maternal isoflurane (ISO) on rat offspring? Investigators assigned pregnant moms to four exposure groups: 1) controls only; 2) ISO + control; 3) ALF + control; and 4) ISO + ALF. On Gestation Day 15, fetal analysis shows that ALF significantly stops ISO-induced increases in expression of inflammatory cytokines and cell-death factors. At Postnatal Day 31, analysis in offspring finds expression levels of synaptophysin and hippocampal neuron numbers significantly lower for ISO + control v. ISO + ALF. Escape latency is significantly lower for ALF + control v. ISO + ALF. ALF can protect against ISO-induced neuroinflammation, embryonic cell death and cognitive impairment.

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Bicuculline and Bumetanide Attenuate Sevoflurane-Induced Impairment of Myelination and Cognition in Young Mice. Ningning Fu et al. March 2023.

Does sevoflurane (SEVO) impair neurological function, myelination and cognition via γ-aminobutyric acid A receptor (GABA_AR) and Na⁺-K⁺-2Cl^– cotransporter (NKCC1) in neonatal mice? These authors exposed neonates to SEVO, followed by brain tissue analysis, assays and behavioral tests. Findings show SEVO exposure 1) increases cortical neuron cell-death levels and decreases neurofilament protein levels; 2) inhibits proliferation, differentiation and migration of oligodendrocyte precursor cells; 3) reduces myelin sheath thickness; and 4) induces cognitive impairment. Bicuculline (a GABA_AR antagonist) and bumentanide (a NKCC1 antagonist) can protect against SEVO-induced neuronal injury, myelination impairment and cognitive dysfunction.

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Angelicin Alleviates Maternal Isoflurane Exposure-Induced Offspring Cognitive Defects Through the Carbonic Anhydrase 4/Aquaporin-4 Pathway. Jingying Liu, Meijuan Miao, & Fujiang Wei 3. March 2023.

What is the potential role for angelicin, a plant-based compound with anti-inflammatory properties, in isoflurane (ISO)-induced neurotoxicity with mouse embryos and neonatal offspring? Investigators exposed embryos on Embryonic Day 15 (E15) to ISO for 3 and 6 hours followed by in vitro and in vivo experiments. Findings show ISO-induces neurotoxicity on E18 with elevated cerebral inflammatory factors, blood-brain-barrier effects, and cognitive deficits in offspring. Treatment with angelicin significantly reduces these effects and partially reduces the ISO-induced increase in carbonic anhydrase 4 (CA 4) and aquaporin-4 (AQP4) expression in brain tissues. An AQP4 agonist confirms the role of AQP4 in the protective effect of angelicin.

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Effect of Sevoflurane Anesthesia to Neonatal Rat Hippocampus by RNA-seq. Jinhua Feng et al. March 2023.

Using an inhalation anesthesia model with neonatal rats, the authors explored the mechanisms of sevoflurane (SEVO)-induced neurotoxicity in multiple organs. Focal areas included the lungs, cerebral cortex, hippocampus and heart. Findings show that SEVO induces a significant up-regulation of siRNA-bckdhb (small interfering ribonucleic acid-branched chain keto acid dehydrogenase) in the hippocampus that, in turn, leads to hippocampal neuronal cell death. Pathway analysis clarifies several abundant pathways with DEGs (differentially related genes), including protein digestion and absorption and the PI3k-Akt (phosphatidylinositol-3 kinase or PI3 kinase/Ak strain transforming) signaling pathway.

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Research News & Updates

Opioids and Autism Spectrum Disorder: Liaisons Dangereuses? Vutskits. February 2023.

Do findings in the Sheng et al study on the association between repeated exposure to fentanyl in neonatal mice and autism-like behavior extrapolate to human children? The author of this commentary asserts that 1) Sheng’s experiments do not directly demonstrate that opioid exposure in early life induces autism spectrum disorder in humans; 2) the diagnosis of autism in humans requires subjective psychiatric symptoms not found in laboratory rodents; and 3) it remains unclear whether opioid exposure is an independent risk factor for developing autism spectrum disorder.

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Risk of Neurotoxicity with Multiple General Anaesthetics for Examination Under Anaesthesia in Paediatric Ophthalmology – A Cause for Concern? O’Connell, Stephenson, & Flitcroft. January 2023.

A 4-year retrospective analysis of electronic medical records examines the effect of a new, patient-centered, “active minimization” policy aimed at reducing multiple Examinations Under Anesthesia (EUAs) for pediatric ophthalmic procedures in a Dublin children’s hospital. Findings show EUAs in 32% of all surgical episodes in the first two years of the study and before policy implementation vs. 19% in the last two years of the study and after policy implementation. With emphasis on “training, technology, and patience,” active minimization strategies significantly reduce diagnostic EUA volume, lower patient risk and increase capacity for surgical interventions.

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Usefulness of Serum Neurofilament Light in the Assessment of Neurologic Outcome in the Pediatric Population: A Systematic Literature Review. Sariyar, van Pesch, Nassogne, Moniotte, & Momeni. January 2023.

Is serum neurofilament light (sNfL), as in sNfL chain protein, a prognostic biomarker for neuronal injury in children? In November of 2022, investigators searched large medical databases for prospective and retrospective studies that include sNfL sampling and evaluation of neurological outcomes in children ≤18 years old. Four manuscripts in neonatal encephalopathy, meeting the inclusion criteria, showed sNfL as a valuable biomarker of neuronal injury in the pediatric population. Subjects had significantly higher sNfL levels than healthy controls and high sNFL levels predicted adverse neurological outcomes.

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Single-nucleus Atlas of Sevoflurane-induced Hippocampal Cell-type- and Sex-specific Effects during Development in Mice. Shao-Yong Song et al. February 2023.

This single-nucleus RNA sequencing study explores sevoflurane (SEVO)-induced alterations in hippocampal (HP) cell clusters and sex-specific neurotoxic effects. Investigators exposed neonatal mice to SEVO with testing at Postnatal Day 37. Findings in males, and not females, showed SEVO-induces 1) changes in the dentate gyrus, oligodendrocytes and the proportion of neurons in one HP region; 2) changes in the number of significantly enriched ligand-receptor pairs in two HP regions and the trisynaptic circuit; and 3) causes toxic effects on granule cell neurogenesis, microglia differentiation and pyramidal diversity. In females, SEVO exposure alters oligodendrocyte differentiation.

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Sevoflurane Induces Neurotoxic Effects on Developing Neurons through the WNK1/NKCC1/Ca²⁺/Drp-1 Signalling Pathway. Ya-Fan Bai et al. February 2023.

What are the toxic mechanisms of sevoflurane (SEVO) via signaling pathway WNK Lysine Deficient Protein Kinase 1/Na-K-Cl cotransporter/calcium ion/Dynamin-related protein (WNK1/NKCC1/Ca²⁺ /Drp-1)? Findings show SEVO 1) decreases cell viability; 2) increases cell death; 3) causes intracellular overload; and 4) induces dephosphorylation of Drp-1 protein. Pretreatment with channel inhibitors can block the SEVO-induced increase in WNK1 kinase and NKCC1 protein concentration and reduce Drp-1 dephosphorylation. Reducing intracellular calcium influx may ameliorate SEVO-induced neurotoxicity.

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Long-term Sevoflurane Exposure Resulted in Temporary rather than Lasting Cognitive Impairment in Drosophila. Ziming Liu et al. February 2023.

How neurotoxic is one early and lengthy sevoflurane (SEVO) exposure? Investigators explore this question using the Drosophila melanogaster, a common fruit fly, exposed to 3% SEVO for 6 hours. Findings show SEVO induces an early, transient phase of brain cell death and cognitive impairment, but damage subsequently recedes and vanishes by late life. In this transient and deadly phase, levels increase in messenger ribonucleic acid (mRNA)-caspases, B-cell lymphoma proteins, reactive oxygen species (ROS) and adenosine triphosphate. mRNA levels of certain antioxidants that fluctuate with the rise and fall of ROS levels may offer neuroprotection.

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Effects of Cumulative Duration of Repeated Anaesthesia Exposure on Foetal Brain Development in the Ovine Model. Bleeser et al. January 2023.

In this randomized controlled preclinical study, investigators used sheep to explore the neurotoxic effects of maternal anesthesia during pregnancy on offspring. Twenty-four pregnant ewes randomly received no exposure, a single exposure, or repeated exposures to sevoflurane. Findings in ewe offspring in all sample groups showed 1) no differences in frontal cortex neuron density; 2) no significant differences in time needed to achieve the milestone of standing; 3) very limited differences in histological measures, including total cell density, cell proliferation, inflammation and synaptogenesis; and 4) no evidence of foetal neuronal injury or neurobehavioral impairments.

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Inhibition of ERK/CREB Signaling Contributes to Postoperative Learning and Memory Dysfunction in Neonatal Rats. Hui Wang et al. January 2023.

Investigators studied anesthesia-induced neurotoxic effects on learning and memory vis-à-vis inhibition of the extracellular signal-regulated kinase/cAMP response element-binding protein (ERK/CREB) pathway. Subjects included neonatal rats exposed to sevoflurane (SEVO) for right carotid artery surgery. Results suggested that surgery and anesthesia increases brain-derived natriuretic peptide (BNP) that in turn inhibit ERK/CREB signaling that in turn reduce glial cell-derived neurotrophic factor (GDNF). These effects lead to an imbalance in inflammatory response, a reduction in synaptic protein expression and development of postoperative cognitive dysfunction.

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Calpain-TRPC6 Signaling Pathway Contributes to Propofol-induced Developmental Neurotoxicity in Rats. Ying-Jun She et al. January 2023.

Is the calpain-transient receptor potential canonical 6 (c-TRPC6) pathway a target for propofol (PPF)-induced neurotoxicity? To explore, investigators injected neonatal rats with PPF or a fat emulsion followed by measures of neuronal injury, cognition and behavior. Findings showed prolonged exposure to PPF 1) induces neuronal injury, downregulation of TRPC6, and enhancement of calpain activity in the cerebral cortex, and 2) induces long-term behavioral disorders. Treatment with a TRPC6 agonist or a TRPC6 inhibitor confirmed the role of c-TRPC6 in PPF-induced neurotoxicity.

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Maternal Sevoflurane Exposure Induces Neurotoxicity in Offspring Rats via the CB1R/CDK5/p-tau Pathway. Yuxiao Wan, Ziyi Wu, Xingyue Li, & Ping Zhao.  January 2023.

What are the anesthesia-induced effects of maternal anesthesia vis-à-vis cannabinoid 1 receptor (CB1R) in offspring? Pregnant rats received pretreatment with saline, a selective antagonist of the CB1 receptor, or rimonabant followed by exposure to sevoflurane (SEVO) or air. Findings showed a single maternal exposure in mid-gestation to SEVO upregulates activity of cyclin-dependent kinase 5 and the level of phosphorylated tau via CB1R in offspring, along with a reduction in hippocampal neurons and dendritic spines. These neurotoxic effects are associated with neurobehavioral and cognitive deficits.

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mTORC1-Dependent and GSDMD-Mediated Pyroptosis in Developmental Sevoflurane Neurotoxicity. Wang Wen-Yuan et al. January 2023.

What are the mechanisms of sevoflurane (SEVO)-induced neurotoxicity vis-à-vis gasdermin (GSDMD—pores that drive cell death), pyroptosis (PYR—inflammatory cell death), and mammalian target of rapamycin (mTOR—a protein that controls cell survival). Findings showed 1) inhibition of GSDMD pore formation significantly reduces SEVO-induced neurotoxicity; 2) GSDMD inhibitors mitigate the release of damaging molecular patterns, plasma membrane rupture and dramatically improve SEVO-induced cognitive deficits; 3) overactivation of mTOR signaling appears in SEVO-induced PYR; and 4) suppression of mTOR activity restores PYR.

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Tandem Mass Tag-based Quantitative Proteomic Analysis of Effects of Multiple Sevoflurane Exposures on the Cerebral Cortex of Neonatal and Adult Mice. Jingyu Feng et al. December 2022.

What are age-dependent mechanisms of sevoflurane (SEVO)-induced neurotoxicity? Researchers administered SEVO plus oxygen to neonatal and adult mice followed by early and long-term assessments, including tandem mass tags pro-based quantitative proteomic analysis. Findings showed SEVO affects spatial learning, memory and dendritic spines in newborn, but not mature mice. Measurements in 6,247 proteins yielded 443 with age-dependent neurotoxic mechanisms after repeated SEVO exposures. In newborns, increasing levels of protein expression in three specific proteins and decreasing levels of protein expression in one additional protein, mediated SEVO-induced brain damage.

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Mechanistic Insight into Sevoflurane-associated Developmental Neurotoxicity. Mingyang Sun, Zhongcong Xie, Jiaqiang Zhang, & Yufang Leng. December 2022.

What are the mechanisms by which early sevoflurane (SEVO) exposure induces long-lasting undesirable effects on the brain? Investigators conducted an extensive review of preclinical and clinical literature, focusing on 1) neural cell death, 2) neural cell damage, 3) impaired assembly and plasticity of neural circuits, 4) tau phosphorylation, and 5) neuroendocrine effects. Findings showed many mechanisms by which SEVO induces developmental neurotoxicity. Investigators call for more investigation of tau phosphorylation, in particular, and greater use of new research methods, like single-cell-omics, proteomics, nanotechnology and ultrasound/photoacoustic imaging.

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Embryonic Exposure to Fentanyl Induces Behavioral Changes and Neurotoxicity in Zebrafish Larvae. Binjie Wang et al. December 2022.

Is maternal fentanyl (FTL) in pregnancy toxic to the fetus? To explore, investigators exposed zebrafish embryos to FTL for 5 days after fertilization followed by a 5-day recovery and assessments. Findings in larvae showed FTL at 1 and 5 mg/L induced elevated anxiety, decreased social preference and aggressiveness and behavioral sensitization with substantial alterations in neural activity, neuronal development and plasticity. FTL exposure during embryonic development is neurotoxic. Zebrafish are an important species in the research on the developmental effects of opioids in vertebrates.

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Z-DNA/RNA Binding Protein 1 Senses Mitochondrial DNA to Induce Receptor-Interacting Protein Kinase-3/Mixed Lineage Kinase Domain-Like-Driven Necroptosis in Developmental Sevoflurane Neurotoxicity. Wen-Yuan Wang et al. December 2022.

This study explores mechanisms of cell death in sevoflurane (SEVO)-induced neurotoxicity vis-à-vis Z-deoxyribonucleic acid/ribonucleic acid binding protein 1 (ZBP1), receptor-interacting protein kinase 3 (RIPK3), and mixed lineage kinase domain-like pseudokinase (MLKL) [ZBP1, RIPK3 and MLKL]. Findings showed 1) SEVO triggers neuronal cell death in a time-dependent way; 2) knockdown of RIPK3 ends MLKL-mediated neuronal cell death; 3) SEVO exposure leads to mitochondrial deoxyribonucleic acid (mtDNA) release into the inner cell; and 4) ZBP1 senses the mtDNA in the inner cell to induce RIPK3/MLKL-driven cell death.

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Ketamine impairs growth cone and synaptogenesis in human GABAergic projection neurons via GSK-3β and HDAC6 signaling. Xuan Li et al. November 2022.

What are the effects of ketamine (KT) on growth cones and synapses in developing GABAergic neurons? In vitro findings in neurons derived from human and embryonic stem cells showed KT exposure impairs growth cone formation, synaptogenesis, and dendritic development/maturation via KT-mediated activation of glycogen synthase kinase-3 (GSK-3) pathways. KT exposure also inhibited histone deacetylase 6 (HDAC6), a stabilizing protein for dendritic development and synapse maturation. KT’s neurotoxic pathway depends on GSK-3β and HDAC6 signaling. Microtube acetylation is a potential target for reducing KT’s toxic neuronal effects.

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Research News & Updates

Consequences of General Anesthesia in Infancy on Behavior and Brain Structure. Salaün et al. February 2023

What is the effect of a single early exposure v. no exposure to general anesthesia (GA) on behavior and brain anatomy? Investigators conduct two complementary studies, one using 6-8-week-old mice and a second in children ages 9-10 years. Findings show adult mice with early postnatal exposure to GA have chronic exacerbated fear behavior; there is an 11% reduction in gray matter. Human findings suggest lower emotional control after a single exposure; there is a 6.1% reduction in the posterior part of the right inferior frontal gyrus after a single exposure to GA.

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Comparer Pommes et Oranges: Perils of Translating Rodent Studies to Human Outcomes. Mary Ellen McCann & Sulpicio G. Soriano. February 2023

This editorial critiques the study by Salaün et al as it attempts to translate findings on the effects of anesthesia in neonatal rodents to children. There are many problems with this comparison: 1) investigators have no access to past anesthesia records in human subjects; 2) children and rodents receive different anesthetic agents; 3) the ages of children and rodents are incongruous; 4) the brain regions affected in children and rodents are anatomically different; 5) baseline cognitive and behavioral status for children missing from source data; 6) the comparison of deranged contextual fear conditioning in rodents to lower emotional control in children is “a leap of faith.”

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Association of sedation and anesthesia on cognitive outcomes in very premature infants: a retrospective observational study. Moser et al. December 2022

Investigators explore the association between early exposure to volatile anesthetics, those discussed in the 2016 United States Food and Drug Administration warning, and full-scale intelligence quotient (FSIQ). Subjects in this retrospective cohort study include 731 preterm infants born at < 29 weeks gestation, assessed at 36 months. Anesthetic/sedative exposure was associated with a decrease in FSIQ — imputed and complete case analyses show unadjusted associations at -7 and -6 FSIQ points v. adjusted associations at -3 and -4 FSIQ points. There is no association between opioid exposure and FSIQ.

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Anesthesia and neurodevelopment after 20 years: where are we now and where to next? Bailey & Whyte. December 2022

This editorial discusses recent government warnings on anesthesia in pregnant women and young children, the latest findings from clinical trials, unanswered questions about anesthesia and its association to neurotoxicity, and new directions in pediatric anesthesia neurotoxicity research. The authors praise Moser et al for their “unique contribution to the literature,” “exclusive focus on extremely premature infants,” and “rigor in adjusting for and measuring confounding variables.” Moser et al’s study “reminds us to continue to explore all avenues to apply primum non nocere (do no harm) to the very best of our individual and collective abilities.”

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Readability, Content, and Quality of Online Patient Education Materials on Anesthesia and Neurotoxicity in the Pediatric Population. Freed et al. December 2022

The authors evaluate patient education materials (PEMS) on pediatric anesthesia (27 examples) and neurotoxicity (8 examples) from websites of pediatric anesthesiology fellowship programs in the United States. Findings, based on the Patient Education Assessment Tool for Print and a test of reading level, yield generally poor results and a need for improvement. 100% of PEMS on neurotoxicity and only 13% on pediatric anesthesia mention the 2016 U.S. Food and Drug Administration safety warning. 60% of PEMS have “poor actionability” and 83% have “good understanding.” The mean readability score is greater than the recommended 6^th grade level.

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Justification Of Empiric Methodology to Determine Dexmedetomidine Dose for the TREX Study. Disma et al. November 2022

What is the appropriate target concentration for pediatric sedation with dexmedetomidine (DEX) in combination with remifentanil (RFT) and low dose sevoflurane? This study describes results from the Italian arm of the TREX (Trial Remifentanil Dexmedetomidine) Phase III clinical trial in children < 2 years having ≥ 2 hours of anesthesia. Findings show that 1) plasma concentrations of DEX are predictable based on the infant’s age and size; 2) the trial’s initial DEX concentration of 0.6 μg . L^-1 is inadequate; and 3) a higher loading dose of 1.0 μg . kg⁻¹ followed by a 1.0 μg . kg⁻¹.h⁻¹ infusion is adequate.

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Analgesia, Sedation, and Anesthesia for Neonates With Cardiac Disease. Smith-Parrish et al. November 2022

This article discusses the assessment and management of pain and discomfort in pediatric interventions involving anesthesia, analgesia, and other forms of sedation. The authors review doses and side effects of commonly used medications and provide recommendations for their use in newborns with heart disease. Procedures requiring deeper levels of sedation may call for airway and hemodynamic support. An early multimodal, multidisciplinary approach to the delivery of anesthesia/sedation is beneficial for safe patient management before, during, and after interventional procedures and surgery. These steps will help to reduce problems with sedation tolerance and postoperative delirium that can contribute to long-term cognitive dysfunction.

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Environmental enrichment holds promise as a novel treatment for anesthesia-induced neurocognitive disorders. Xiaohan Chang & Yue Tian. November 2022

In their review, the authors summarize recent research on environmental enrichment (EE), a novel and easy-to-implement rehabilitation treatment strategy to reduce anesthesia-induced neurotoxicity in the developing brain. In animal experiments, EE can include adding extra food, water, and play tools to foster and stimulate learning and memory. Findings show EE exerts its protective potential through different molecular mechanisms. Intervention mode, timing, and duration play critical roles in fostering EE’s neuroprotective effects.

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Anesthesia and developing brain: What have we learned from recent studies. Yixuan Niu, Jia Yan, & Hong Jiang. November 2022

In their review, the authors summarize progress in clinical and preclinical studies that provides new approaches and therapeutic targets for protecting the developing brain from anesthesia-induced neurotoxicity (AIN). Clinical studies in children often focus on the effects of single and multiple exposures to anesthesia. Current preclinical studies often look for mechanisms of AIN. Whether observed mechanisms on neurotoxicity in rodents translate to human subjects remains unclear. One alternative research approach is to combine single-cell sequencing technologies to screen for differential gene expression in non-human primates—because they are more genetically similar to humans than rodents–followed by in vivo validation in rodents.

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Neurotoxic Impact of Individual Anesthetic Agents on the Developing Brain. Ji & Karlik. November 2022

In their review, the authors address the ongoing controversy in identifying the risk of general anesthesia to the developing brain. The discussion includes a brief summative review of common volatile anesthetics and addresses the strengths and limitations of both preclinical and clinical research on anesthesia-induced neurotoxicity, highlighting important findings since the 2016/2017 Drug Safety Communications from the FDA. “At this time, data with animal models cannot entirely defend a potential association between the use of anesthetic agents and subsequent impact on neurocognitive development,” comment investigators. “It is becoming more evident that a brief single exposure to anesthesia, regardless of type, is not associated with any profound impairment in neurodevelopment and neurocognitive outcomes in children.”

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Spatial and temporal alterations of developing oligodendrocytes induced by repeated sevoflurane exposure in neonatal mice. Zhihao Zhang et al. December 2022

How does repeated exposure of young mice, on Postnatal Days (PNDs) 6-8, to sevoflurane (SEVO) affect their brains and behavior? Findings show that 1) general anesthesia (GA) induces the proliferation of oligodendrocyte (oligo/oligos) progenitor cells in the corpus callosum (CC) and hippocampus (HC) on PNDs 8-32; 2) mature oligos statistically reduce in the CC and HC after PND 32; 3) clemastine, an antihistamine, can significantly increase the number of mature oligos, promote myelination, and support cognition. Early exposure to SEVO affects oligo maturation and proliferation that contributes to GA-induced cognitive impairment.

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Neonatal ketamine exposure impairs infrapyramidal bundle pruning and causes lasting increase in excitatory synaptic transmission in hippocampal CA3 neurons. Cabrera et al. December 2022

Using mice, investigators explore the immediate and long-term effects of neonatal exposure to ketamine (KT) on stereotyped axonal pruning of the infrapyramidal bundle (IPB). How do impairments in the IPB, which normally supports healthy brain circuitry, alter synaptic transmission in hippocampal neurons? Findings show that neonatal KT exposure 1) interferes with normal neural circuit development and leads to a lasting increase in excitatory synaptic transmission; 2) increases the frequency/amplitude of miniature excitatory postsynaptic currents; and 3) leads to an extension of positive IPB fibers farther than normal into the stratum pyramidale of the hippocampus in juvenile mice.

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Neonatal Isoflurane Exposure in Rats Impairs Short-Term Memory, Cell Viability, and Glutamate Uptake in Slices of the Frontal Cerebral Cortex, But Not the Hippocampus, in Adulthood. de Oliveira et al. November 2022

What are the short and long-term effects of a single neonatal dose of isoflurane (ISO)? Investigators administer ISO to mice on Postnatal Day 7 followed by ex vivo analysis of cortical and hippocampal brain slices for cell viability and susceptibility to in vitro glutamate challenge, along with behavioral tests in adulthood. Findings show, a single neonatal exposure to ISO does not alter cell viability in cortical and hippocampal brain slices in infancy. When assessed in adulthood, a single neonatal ISO exposure 1) does selectively decrease cell viability and glutamate uptake in cortical slices; and 2) does induce short-term memory impairment in recognition tasks; but 3) does not alter hippocampal slice viability or glutamate uptake.

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Research progress on molecular mechanisms of general anesthetic-induced neurotoxicity and cognitive impairment in the developing brain. Jiaojiao Wang & Zhihui Liu. November 2022

This scientific review clarifies research findings, primarily in preclinical studies, on the underlying molecular mechanisms of general anesthesia (GA)-induced neurotoxicity and cognitive impairment in the developing brain after surgery. The authors discuss 1) studies on neurotoxicity in common anesthetics; 2) signaling pathways; 3) non-coding ribonucleic acid (RNA); 4) molecular protein; and 5) other potential mechanisms of neurotoxicity. Delving more deeply into available studies on molecular mechanisms may provide critical references for clinicians, as they seek new treatment strategies for pediatric anesthesia neurotoxicity and cognitive impairment caused by general anesthetics.

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Parvalbumin interneuron loss mediates repeated anesthesia-induced memory deficits in mice. Soriano Roque et al. November 2022

What are the underlying mechanisms of long-lasting anesthesia-induced cognitive impairment in neonatal and postnatal mice? Investigators find repeated exposure of postnatal mice to general anesthesia (GA) induces brain cell death and loss of parvalbumin (PVB)-positive inhibitory interneurons in the hippocampus (HC). Deletion of Mitochondrial Anchored Protein Ligase, a pro-death protein, helps to prevent the loss of PVB interneurons, reduce anesthesia-induced deficits in pyramidal cell inhibition, and rescue long-term memory. Partial depletion of PVB interneurons in neonates also creates long-lasting memory impairment.

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Egr2 contributes to age-dependent vulnerability to sevoflurane-induced cognitive deficits in mice. Ye-Ru Chen et al. November 2022

What are the molecular mechanisms underlying sevoflurane (SEVO)-induced neurotoxicity vis-à-vis the Early Growth Response-2 (Egr2) gene? Investigators administer SEVO for 2 hours/day for 3 days to young (Postnatal Day 6) and early adult (6-week old) mice. Findings show SEVO 1) induces significant long-term learning impairments of young mice; 2) significantly upregulates Egr2 in young mice and 3) stimulates distinct transcription responses in the Egr gene family in both young and early adult mice. Injection of Egr2 shRNA adeno virus alleviates SEVO-induced cognitive deficits and injection of Egr2 overexpression virus aggravates SEVO-induced learning impairments—in young mice only.

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Neonatal exposures to sevoflurane in rhesus monkeys alter synaptic ultrastructure in later life. Fehr, Janssen, Park & Baxter. November 2022

How does sevoflurane (SEVO) affect synaptic ultrastructure in the dorsolateral prefrontal cortex (dlPFC) and hippocampus (HC) without the confounding factors of surgery and illness? Investigators administer SEVO to neonatal monkeys and assess them 4 years later. Findings show 1) a reduction in the area of the largest synapse in the HC and dlPFC, predominantly in the perforated and nonperforated spinous synapses, respectively; and 2) subtle changes in mitochondrial morphology and localization in both regions. These ultrastructure changes in primates may inform future research on anesthesia-induced alterations in synaptic transmission and behavioral deficits.

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Ketamine modulates neural stem cell differentiation by regulating TRPC3 expression through the GSK3β/β-catenin pathway. Ying-Jun She et al. November 2022

What are the mechanisms of ketamine (KT) in neural stem cell (NSC) differentiation? Investigators extract NSCs from the hippocampi of neonatal rats and treat them with KT to induce NSC differentiation, followed by testing. Findings show KT 1) promotes neuronal differentiation of NSCs in a dose-dependent manner; 2) influences NSC differentiation by regulating transient receptor potential canonical 3 (TRPC3) expressions; and 3) represses TRPC3 expression with a significant increase and decrease in phosphorylated glycogen synthase kinase 3β (beta) and β-catenin protein expression, respectively. These actions promote differentiation of NSCs into neurons while inhibiting their differentiation into astrocytes.

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Repeated sevoflurane exposures inhibit neurogenesis by inducing the upregulation of glutamate transporter 1 in astrocytes. Fanli Kong et al. November 2022

What is the role of glutamate transporter 1 (GLT1) in the sevoflurane (SEVO)-induced decrease in neurogenesis? Investigators expose neonatal rat pups to 3% SEVO for 2 hours on 3 consecutive days, followed by study of brain cells and observations of rats in adulthood. Findings show multiple SEVO exposures induce a decrease in neurogenesis with a cascade of events, including neuron loss, calcium overload, and activation of messenger ribonucleic acid (mRNA) translation. The activation in mRNA translation causes upregulation of GLT1 that in turn induces the death of astrocytes. Inhibiting GLT1 ends SEVO-induced cognitive deficits in adult rats, thus clarifying the role of GLT1 in SEVO-induced cognitive impairment.

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Sevoflurane induces microRNA-18a to delay rat neurodevelopment via suppression of the RUNX1/Wnt/β-catenin axis. Yuge Jiang et al. October 2022

What are the underlying mechanisms of sevoflurane (SEVO) on neural stem cell (NSC) proliferation? Researchers treat neonatal rat hippocampal (HC) tissues with SEVO and isolate neural stem cells, followed by assessments of cell expression and assays of NSCs. Findings show 1) SEVO induces high expression of micro ribonucleic acid-18a (miRNA-18a) in HC tissues and NSCs; 2) miRNA-18a downregulates Runt Related Transcription Factor 1 (RUNX1) expression; and 3) RUNX1 promotes NSC proliferation by activating the Wingless-Related Integrated Site/Beta-Catenin signaling pathway.

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The propofol-induced mitochondrial damage in fetal rat hippocampal neurons via the AMPK/P53 signaling pathway. Fei Xiao et al. October 2022

Propofol (PPF) may be neurotoxic to the developing brain by inhibiting mitochondrial (MT) function—what is the mechanism behind this? The authors culture primary fetal rat neurons, incubate them in PPF for different lengths of time and in different concentrations, followed by analysis. Findings show PPF inhibits 5′ adenosine monophosphate-activated protein kinase (AMPK) activity in neurons; upregulates the expression of protein 53 (p53); and activates an MT-dependent brain pathway that may lead to neuronal cell death.

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Identification of Prefrontal Cortex and Amygdala Expressed Genes Associated With Sevoflurane Anesthesia on Non-human Primate. Yanyong Cheng, Siyu Liu, Lei Zhang, and Hong Jiang. July 2022

How do the roles of the amygdala (AMG) and the prefrontal cortex (PFC) differ in anesthesia-induced neurotoxicity? Using baby monkeys, investigators analyze transcriptional patterns in different brain regions to reveal their functions and differentially expressed gene sets after exposure to sevoflurane (SEVO). Findings show the functional annotations of the PFC, when compared to the transcriptional patterns of the AMG, are more enriched in glial cell related biological functions than in neuron and synapsis development after exposure to SEVO.

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Research News & Updates

The impact of early exposure to general anesthesia on visual and neurocognitive development. Wong-Kee-You, Loveridge-Easther, Mueller, Simon, & Good.  September 2022

How does early postnatal exposure to general anesthesia (GA) affect the visual system? Investigators summarize key mechanisms that may account for neurotoxic effects of GA on the developing brain and review existing literature on the effects of early anesthesia exposure on visual systems in both humans and animals including human neurocognitive development. The authors conclude by proposing directions for future research on unanswered questions regarding the impact of GA on visual development.

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Novel anesthetics in pediatric practice: is it time? N Useinovic & V Jevtovic-Todorovic. August 2022

A growing body of research in animals shows the association between anesthesia, when administered at the peak of brain development, and lasting behavioral impairments. In light of this, the authors suggest it may be time to consider new pediatric anesthetics. They review a number of promising ones, including 1) soft analogs of intravenous anesthetics; 2) remimazolam, a novel ester-analog; 3) two novel etomidate analogs; 4) quaternary lidocaine derivatives; 5) xenon as an anesthetic-sparing adjuvant; and 6) alphaxalone. The field will need well-designed preclinical studies to test whether these are, in fact, better than currently used pediatric anesthetics with no to lower neurotoxic risk.

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Long-term cognitive and behavioral outcomes following early exposure to general anesthetics. Ing & Bellinger. August 2022

This review summarizes results from clinical studies that evaluate behavioral outcomes in children exposed to surgery and anesthesia. Recent findings show that children with early exposure to both have limited to no difference in intelligence when compared to unexposed children. A few studies report more behavioral problems in children exposed to general anesthesia and an increase in the incidence in Attention-Deficit Hyperactivity Disorder, particularly with multiple exposures. Given the observational nature of most clinical studies, associations between anesthetic exposure and behavioral deficits cannot yet be directly attributed to the anesthetic medication. However, they can guide future research.

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100 Years of Pediatric Anesthesia With Anesthesia & Analgesia: Growing Together. Coleman & Waisel. August 2022

The authors discuss the pivotal roles of both Anesthesia & Analgesia (A&A) and the International Anesthesia Research Society (IARS) in the evolution of the pediatric anesthesiology subspecialty with emphasis on scholarship, clinical practice, and professionalization. A&A has been a distinguished resource on pediatric fundamentals in general anesthesia and on complex cases performed by pediatric anesthesiologists; it serves as a crucial forum for the subspecialty as it matures. IARS has addressed important questions in modern anesthesiology practice, as reflected in the founding of SmartTots to foster research on the neurodevelopmental effects of anesthesia in children.

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Associations between maternal exposure to surgery or pregnancy exposure to fluorinated anesthetics and children’s cognitive development and educational outcomes. Kravets, Klebanoff, & Keim. August 2022

What is the effect of a woman’s lifetime exposure to anesthesia and fluorinated anesthetics during pregnancy on her child’s cognitive abilities? Investigators explore this question using data from subjects in the Women’s US Collaborative Perinatal Project and records on offspring to age 7. Findings are inconsistent and may need further adjustment for confounding factors. Maternal surgery during childhood associates with offspring in special schools or not in school, but with slightly better cognitive ability across childhood, especially for male offspring. Maternal surgery in puberty associates with slightly lower IQ and poorer spelling in offspring. The child’s prenatal exposure to fluorinated anesthetics associates with slightly better spelling, but lower performance IQ, especially among boys.

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Is There an Association between the Use of Epidural Analgesia during Labor and the Development of Autism Spectrum Disorder in the Offspring? A Review of the Literature. Weronika Król et al. June 2022

This review explores the association between epidural anesthesia (ELA) during labor and the risk of autism. The authors describe the current state of knowledge on this topic based on their search through Scopus, PubMed, and EMBASE databases. The literature search yields 120 results with 6 acceptable cohort studies and, from these, concludes there is no significant association between ELA and autism. Investigators also discuss Qui et al, the only study to date to prove a significant association between ELA and autism, and its failure to adjust for important confounding factors.

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Utilization of neonatal sedation and anesthesia: an SPR survey. Misun Hwang et al. June 2022

How are pediatric anesthesiologists utilizing sedation and anesthesia in neonatal imaging (NI)? The authors summarize findings from 80 out of 1,226 potential respondents to a questionnaire among American and Canadian members of the Society for Pediatric Radiology. Findings show 70% of respondents are aware of departmental sedation policies and 89% are aware of neurotoxicity concerns raised in the literature. 93%, 85%, and 48% say sedation is used for interventional procedures, magnetic resonance imaging (MRI), and nuclear medicine, respectively. 63% report a success rate of >50% when using sedation for MRI. The use of sedation and anesthesia for NI varies widely across and within institutions. Greater awareness of the potential for anesthetic neurotoxicity and success of non-pharmacologic approaches in NI is crucial.

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S-ketamine administration in pregnant mice induces ADHD- and depression-like behaviors in offspring mice. Li-Min Zhang et al. September 2022

Can exposure of pregnant mice to S-ketamine (S-KT), a newly patented drug with anesthetic and anti-depressant effects in humans, induce attention-deficit hyperactivity disorder and depression-like behaviors in mouse offspring? Investigators administer low (15 mg), medium (30 mg), and high (60 mg) doses of S-KT to pregnant mice followed by testing of offspring at 21 days. Findings show a high dose of S-KT leads to miscarriage. The low and medium doses associate with behaviors in offspring that indicate impulsivity and memory dysfunction. The medium dose induces depression-like behaviors. S-KT associates with changes in astrocytic activation, synaptic function, and inhibitory presynaptic proteins in the offspring brain.

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Sevoflurane exposure during the second trimester induces neurotoxicity in offspring rats by hyperactivation of PARP-1. Cong Wang, Qian Jiang, & Ping Zhao. September 2022

Does maternal exposure to sevoflurane in the second trimester have neurotoxic effects on offspring? Investigators expose pregnant rats on Gestational Day 14 to sevoflurane (SEVO) or NO SEVO; 3-aminobenzamide (a PARP-1 [poly ADP ribose polymerase 1] inhibitor); or TC-2153 (a STEP61 [striatal-enriched phosphatase 61] inhibitor). Findings in offspring show 1) excessive PARP-1 activation and poly ADP-ribose polymer accumulation; 2) neurite growth problems; and 3) increased brain cell death. SEVO activates the STEP61/Pyk2 (proline-rich tyrosine kinase 2) pathway and increases levels of reactive oxygen species. The inhibitors significantly alleviate cell death, promote neurite growth, and reduce SEVO-induced spatial learning and memory impairment.

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Mild hypothermia fails to protect infant macaques from brain injury caused by prolonged exposure to Antiseizure drugs. Ikonomidou et al. September 2022

Does mild hypothermia protect infant nonhuman primates from phenobarbital (PB)- and midazolam (MZ)- induced neuro- and gliotoxicity? Investigators administer PB and MZ to neonatal rhesus monkeys over a 24-hour period of normothermia (temperature >36.5° C / 97.7° F) or mild hypothermia (temperature = 35° C / 95° F) followed by sacrifice at 36 hours and brain analysis. The researchers modeled the clinical situation/drug doses to those used in human infants and they found: 1) extensive damage to neurons and oligodendrocytes at 36 hours in both groups; 2) no protection against PB/MZ-induced neuro- and gliotoxicity for the mild hypothermia group; 3) neurotoxicity at plasma concentrations relevant to the treatment of human infants.

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Effects of toxic apolipoprotein E fragments on Tau phosphorylation and cognitive impairment in neonatal mice under sevoflurane anesthesia. Yang Yu et al. August 2022

This study explores the neuroprotection of full-length Apolipoprotein E (ApoE), a protein associated with cognitive impairment in adults, vs. ApoE fragments after sevoflurane (SEVO) exposure in young mice. Investigators measure SEVO-induced changes in messenger ribonucleic acid (mRNA), ApoE protein levels, phosphorylated Tau (p-tau), and cognitive function (CI). Findings show SEVO increases the expression or levels of ApoE mRNA, total ApoE, full length ApoE, ApoE fragments, p-Tau, and CI in young mice.  ApoE variant 2—not ApoE variant 3 or ApoE in knockout mice—shows a reduction in SEVO-induced p-Tau elevation and CI. Elevated ApoE fragments—not full-length ApoE—may be the underlying mechanism of age-dependent p-Tau and CI in young mice following SEVO exposure.

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Integrated Excitatory/Inhibitory Imbalance and Transcriptomic Analysis Reveals the Association between Dysregulated Synaptic Genes and Anesthetic-Induced Cognitive Dysfunction. Yasheng Yan et al. August 2022

What is the underlying mechanism of long-term cognitive deficits and behavioral problems following early exposure to anesthesia? The authors expose neonatal mice to propofol (PPF) on Postnatal Day 7 followed by analysis on Day 60 of synapse activity and expression levels for messenger ribonucleic acid molecules (mRNAs) in hippocampal tissues. Findings show early PPF exposure leads to abnormal expression of 317 mRNAs, including 23 synapse-related genes. Abnormal expression has implications for synaptic function, development, and plasticity; excitatory/inhibitory (E/I) balance; behavior; and cognitive impairment. Changes in E/I balance may be the mechanism for long-term PPF-induced impairments in learning and memory in mice. This finding may pave the way for development of therapeutic strategies against anesthetic neurodegeneration.

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MicroRNA-424-5p Alleviates Isoflurane Anesthesia-Induced Neurotoxicity in Human Embryonic Stem Cell-Derived Neurons by Targeting FASN. Xiaojiao Gu, Wei Yue, Mingyu Xiu, Quanyun Zhang, & Rufeng Xie. July 2022

What is the physiological role of micro ribonucleic acid (miRNA) 424-5p (424-5p), a noncoding gene, in isoflurane (ISO)-induced neuronal injury in human embryonic cell-derived neurons (hESC-derived neurons)? Findings show ISO induces neurotoxicity and a decrease in 424-5p production in hESC-derived neurons. The upregulation of 424-5p 1) represses ISO-induced neuronal cell death; 2) mitigates ISO-induced inflammatory response and oxidative stress; and 3) reduces expression levels of fatty acid synthase (FASN)—a target of 424-5p.

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Mitochondria-Related Ferroptosis Drives Cognitive Deficits in Neonatal Mice Following Sevoflurane Administration. Piao Zhang, Yeru Chen, ShuXia Zhang, & Gang Chen. July 2022

Using neonatal mice, investigators explore the mechanism of sevoflurane (SEVO)-induced neurotoxicity in the developing hippocampus. Findings show SEVO-induces 1) cognitive impairment with reductions in dendritic length, density, and nodes; 2) elevations in mitochondrial (MITO) reactive oxygen species production; 3) the opening of MITO permeability transition pores; 4) a decrease in MITO membrane potential; 5) an increase in MITO lipid hydroperoxide production; 6) an increase in hippocampal iron deposition with MITO iron overload; and 7) significant changes in ferroptosis-related protein expression. Protecting MITO function and preventing iron build up can reverse these pathological processes and prevent SEVO-induced cognitive impairment.

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Multiple exposures to sevoflurane across postnatal development may cause cognitive deficits in older age. Yuanping Zhong et al. July 2022

How do multiple neonatal exposures to sevoflurane (SEVO) affect mice in later stages of development? Researchers expose young mice to SEVO on Postnatal Days (PNDs) 7, 14, and 21 with testing at PND 31 (juvenile stage), 91 (adult stage), and 18 months (aged stage). Findings show 1) a significant decrease in performance on water maze tests for the aged group; 2) an increase in Tau expression in CA1 and CA3 hippocampal regions for juveniles; and 3) an increase in phosphorylated Tau (p-Tau) only in the CA3 region for adult mice. The overexpression of Tau, p-Tau, and Aβ proteins in aged mice may be the underlying mechanism of neurotoxicity, particularly in old age.

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Fentanyl induces autism-like behaviours in mice by hypermethylation of the glutamate receptor gene Grin2b. Sheng et al. June 2022

Does fentanyl (FTL), a widely used opioid anesthetic, cause autism-like behaviors? To explore, investigators administer FTL to mice on Postnatal Days 6-10 followed by behavioral and histochemical testing in days 30-32. Findings show FTL induces autism-like behaviors in both male and female mice and, through hypermethylation, downregulates expression of the Grin 2b gene in the anterior cingulate cortex. Naloxone (a mu-opioid receptor antagonist) and over-expression of Grin 2b reduces FTL’s neurotoxic effects. However, injection of DAMGO {[D-Ala,2 N-MePhe,4 Gly-ol]-enkephalin}, a mu opioid agonist, into the anterior cingulate cortex induces autism-like behaviors.

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Sevoflurane Exposure in the Developing Brain Induces Hyperactivity, Anxiety-Free, and Enhancement of Memory Consolidation in Mice. Rui Li et al. June 2022

What are the long term effects of early exposure to sevoflurane (SEVO) on locomotor activity, anxiety, learning, spatial memory, and synapse development? To explore, investigators expose Postnatal Day (PND) 7 mice to SEVO followed by testing in PNDs 60-90. Findings in living adult mice and in brain slices, show that early postnatal SEVO exposure 1) increases motor activity and decreases anxiety; 2) enhances consolidate-space memory; 3) increases dendritic spine density of pyramidal neurons; 4) increases the N-Methyl-D-Aspartate Receptor GluN2A Subunit in the hippocampus; and 5) has no effect on long-term potentiation.

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Propofol and Sevoflurane Anesthesia in Early Childhood Do Not Influence Seizure Threshold in Adult Rats. Paweł Piwowarczyk et al. November 2021

Do anesthesia-induced neuropathological changes during synaptogenesis (SYN) lead to changes in seizure threshold in adulthood? What is the potential influence of commonly used hypnotic agents on co-morbidities that may result from an increase in neurodegeneration during SYN? Using neonatal rat pups treated with propofol (PPF), sevoflurane (SEVO), or saline, investigators find no changes in seizure threshold using three seizure models. Subjects show a significant weight gain after exposure to anesthetics during SYN in the PPF, but not the SEVO group. A single, prolonged exposure to SEVO or PPF during SYN appears to have no undesirable side effects on the progression of epilepsy in adulthood.

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Commentary on Previously Summarized Article

Undiagnosed attention-deficit/hyperactivity disorder may be a risk factor for requiring anaesthesia. Andrew Conway Morris & Anke Conway Morris. March 2022

These comments on the study by Yu Shi et al address the unresolved debate over finding clinically relevant neurotoxic effects from general anesthesia in children. Data from studies using animal models are affected by various factors, including 1) differences in neurogenesis among species; 2) differences in duration of anesthesia exposure in various experiments; and 3) uncertainty in attributing vulnerability to the organism vs neuronal age. Anesthesia exposure is not randomly distributed across all children and this poses a high risk for confounding factors. Therefore, “natural experiments” on the effects of clinically indicated measures of anesthesia in children are more reliable.

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Research News & Updates

Anesthetic Exposure During Childhood and Neurodevelopmental Outcomes – A Systematic Review and Meta-analysis. Reighard et al. June 2022

Is there an association between exposure to general anesthesia and domain-specific neurodevelopmental outcomes in children? For their meta-analysis, investigators look at 31 studies reflecting data on 571 to 63,315 exposed children at < 18 years with an evaluation of long-term neurodevelopmental function after exposure vs. 802 to 311,610 unexposed children. Findings show children with any exposure, single or multiple, have significantly lower behavioral scores, indicating more behavioral problems and worse, but variable, scores in academics, cognition, executive function, general development, language, motor function, and non-verbal reasoning. The association between early anesthesia exposure and neurodevelopmental deficits differs based on the neurodevelopmental domain.

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Early Neurodevelopmental Outcomes Following Exposure to General Anesthesia in Infancy: EGAIN, a Prospective Cohort Study. Choon Looi Bong et al. May 2022

How does a single exposure to general anesthesia (GA) affect healthy infants? To explore, investigators conduct a prospective cohort study using 250 full-term infants exposed to GA for minor surgery at < 15 months. GA-exposed children show differences in experimental measures relating to behavior and neurophysiology at 6 and 18 months. Assessments at 24 months reflect no difference between GA-exposed and non-exposed children in cognitive, language, motor, and socio-emotional domains. However, parents of GA-exposed children report worse scores in behavioral areas, including general adaptability.

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Neonatal Pain, Opioid, and Anesthetic Exposure; What Remains in the Human Brain After the Wheels of Time? van den Bosch et al. May 2022

What are the possible negative long-term effects of neonatal exposure to pain, opioids, and anesthetics? Investigators study 94 older children/adolescents with a history of neonatal exposure to pain, opioids, or anesthetics at different points along a continuum: from no pain to intense pain and from no opioid exposure to very high opioid exposure in the presence or absence of anesthetics. Findings show no major long-term effects from neonatal pain or opioid/anesthetic exposure apart from neuropsychological effects in those with the highest opioid exposure. Future studies with larger sample sizes should test for less pronounced differences between exposed and unexposed children.

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Anaesthesia-Related Pediatric Neurotoxicity: A Survey Study. Yıldız, Kozanhan, Aydoğan, Tire, & Sekmenli. May 2022

A survey among 202 Turkish anesthesiologists and 51 Turkish pediatric surgeons finds they are aware of the risks of anesthesia-related neurotoxicity in children and willing to take action to reduce these risks. Approximately one-half of respondents expect to postpone operations > 3 hours for children < 3 years. One-third of anesthesiologists would seek feasible and more reliable/alternative anesthesia strategies. More than two-thirds of respondents are aware of the US Food and Drug Administration anesthesia safety warnings, but still have unanswered questions about anesthesia-related neurotoxicity. The field needs more results from large-scale pediatric clinical trials on the effects of anesthesia and surgery on cognitive development in young children.

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Current status of nitrous oxide use in pediatric patients. Nishkarsh Gupta, Anju Gupta, & Vishnu Narayanan. March 2022

In their narrative review, the authors address the present status of nitrous oxide (NOx) in pediatric anesthesia practice. The discussion on NOx includes 1) pharmacologic properties; 2) advantages/drawbacks of use; and 3) issues in neurodevelopment. While large clinical trials report no major adverse effects with the use of NOx in children, the literature is insufficient. This shortcoming makes it difficult to advise on whether to routinely use or eliminate NOx. Clinicians should balance the risks and benefits of using NOx on an individual case basis as the field awaits further research.

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Maresin 1 alleviates sevoflurane-induced neuroinflammation in neonatal rats via JAK2/STAT3/IL-6 pathways. Yuanyuan Wu et al. July 2022

What role does maresin 1 (MaR1), an anti-inflammatory agent, play in sevoflurane (SEVO)-induced neuroinflammation and neurotoxicity? Findings in neonatal rats show 1) MaR1 stops SEVO-induced cognitive dysfunction, tau hyper-phosphorylation, and synaptic protein reduction; 2) SEVO upregulates while MaR1 downregulates the protein levels of interleukin-6 (IL-6) and its upstream regulator, called the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. When JAK2 is activated, it blocks the protective effect of MaR1 against SEVO-induced neurotoxicity. The JAK2/STAT3/IL-6 signaling pathway mediates the protective effect of MaR1 against developmental neurotoxicity.

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Nonhuman Primates and Developmental Anesthesia Neurotoxicity Research: Pitfalls of Surrogate Models and Déformation Professionnelle. Vutskits, Laszlo, Soriano, Sulpicio G. June 2022

In follow up to Wang et al, the authors comment on the use of non-human primates (NHPs) in pediatric anesthetic neurotoxicity research. If driven by a defined outcome, research in NHPs may be unjustified and unethical. However, NHPs may be an essential translational link between rodents and humans. NHP brain cell cultures may be useful and in vitro experiments can guide the planning of in vivo approaches. Identifying the most translationally relevant questions and outcome measures is critical. Studies in NHPs, often limited in the number of subjects, may provide translational clues to guide larger clinical studies. Clinical observations in humans, and no other species, should direct guidelines/regulations on safe anesthesia in children.

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Systemic inflammation exacerbates developmental neurotoxicity induced by sevoflurane in neonatal rats. Useinovic et al. June 2022

What is the impact of underlying inflammation on anesthesia-induced neurotoxicity on the developing mammalian brain? Investigators explore this question in neonatal rats receiving sevoflurane (SEVO), or carrier gas after bacterial lipopolysaccharide (LPS), or vehicular injection. Findings show SEVO or LPS treatment activates caspase-3 and caspase-9 expression in the brain. LPS and SEVO-induced neuronal injury results in sex-specific behavioral outcomes: cognitive deficits in males and heightened anxiety in females. LPS and LPS + SEVO regulate hippocampal caspase-1 and NLRP1 (nucleotide-binding domain/leucine-rich repeat containing protein 1), which normally helps to regulate the inflammatory processes in the brain.

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miRNA-384-3p alleviates sevoflurane-induced nerve injury by inhibiting Aak1 kinase in neonatal rats. Yuanyuan Chen, Xuan Gao, & Hao Pei. June 2022

What is the role and mechanism of miRNA (micro ribonucleic acid) 384-3P (mi384), a molecule that helps to control gene expression, in sevoflurane (SEVO)-induced nerve injury? Investigators explore this question in neonatal rats with SEVO-induced nerve injury. Findings show mi384 1) reduces SEVO-induced structural changes and cell death in hippocampal neurons; 2) stops the associated decline in spatial memory and learning ability; and 3) alleviated SEVO-induced nerve injury by inhibiting the expression of Aak1 (adaptor-associated kinase 1).

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PP2A-associated tau hyperphosphorylation was involved in sevoflurane induced neonatal neurotoxicity. Chaoli Huang et al. June 2022

What is the underlying mechanism for hyper-phosphorylation (HP) of the tau protein in sevoflurane (SEVO)-induced brain abnormalities? Does protein phosphatase 2A (PP2A), an enzyme involved in cell regulation, play a role? Investigators explore these questions in neonatal mice exposed, repeatedly, to SEVO. Findings show that early, repeated SEVO exposures associate with 1) cognitive dysfunction in adulthood; 2) HP of the tau protein with decreased levels of PP2A in the mouse hippocampus; and 3) a short-term increase in glycogen synthase kinase-3β activity. PP2A-associated HP may contribute to SEVO-induced developmental neurotoxicity.

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Prolonged sevoflurane exposure causes abnormal synapse development and dysregulates beta-neurexin and neuroligins in the hippocampus in neonatal rats. Wenhua Zhang et al. June 2022

Using neonatal rat pups, researchers study the long-term effects of prolonged sevoflurane (SEVO) exposure during peak synaptogenesis on neurexin-neuroligin molecules (which normally support nerve and synaptic connections), synaptic ultrastructure, and cognition. Findings show SEVO-exposure associates with 1) long-term cognitive deficiency; 2) downregulation of βeta-neurexin, N-methyl-d-aspartate receptor 2 subunits, neuroligin-1, and postsynaptic density protein-95; and 3) upregulation of GABAAα1 (α1-subunit of the γ-aminobutyric acid A receptor), neuroligin-2, and gephyrin. SEVO exposure changes the balance of excitatory and inhibitory synapses in the brain due, possibly, to dysregulated expression of βeta-neurexin and neuroligins.

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Isoflurane and Sevoflurane Induce Cognitive Impairment in Neonatal Rats by Inhibiting Neural Stem Cell Development Through Microglial Activation, Neuroinflammation, and Suppression of VEGFR2 Signaling Pathway. Chunlong Zuo et al. June 2022

What is the molecular mechanism underlying anesthesia-induced neurodevelopmental toxicity vis-à-vis vascular endothelial growth factor receptor-2 (VEGFR2) as it interacts with microglia and neural stem cells (NSCs)? Experiments in neonatal rat pups exposed to isoflurane (ISO) and sevoflurane (SEVO) show immediate deficits in spatial learning and working memory. ISO induces stronger and more prolonged neurotoxicity than SEVO. Both anesthetics induce cognitive impairment by inhibiting NSC development and neurogenesis via microglia activation, neuroinflammation, and suppression of VEGFR2 signaling pathways.

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Notoginsenoside R1 attenuates sevoflurane-induced neurotoxicity. Yibing Zhang et al. June 2022

Using neonatal rats, the authors assess the neuroprotective effects of notoginsenoside R1 (NGR1), a bioactive compound from the Panax notoginseng root, against sevoflurane (SEVO)-induced neurotoxicity. Subjects receive SEVO on postnatal day (PND) 7 and pretreatment with different doses of NGR1 on PNDs 2-7. Findings show NGR1 pretreatment 1) stops SEVO-induced generation of reactive oxygen species (ROS); 2) reduces cell death counts; and 3) upregulates NRf2 (nuclear factor erythroid 2-related factor 2) expression. Investigators also observe 4) lower levels of cleaved caspase 3; 5) lower pro-death protein expression; and 6) enhanced sestrin-2/phosphorylated AMPK (adenosine monophosphate-activated protein kinase) expression.

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Nonapoptotic caspases in neural development and in anesthesia-induced neurotoxicity. Sarić, Hashimoto-Torii, Jevtović-Todorović, & Ishibashi. April 2022

In their review, the authors explore both genetic and environmental factors that regulate apoptotic (part of the cell death process) and sub-lethal caspase responses. Findings show that caspase activity supports normal neuron development in relation to axonal pathfinding, dendritic arborization, and synaptic plasticity. However, some pediatric anesthetic agents can induce non-lethal, excess caspase activation that impairs synaptic transmissions and the tree-like growth of neurons, leading to long-term behavioral deficits. For children undergoing surgery, these factors create an increased risk for anesthesia-induced, non-apoptotic caspase injury. Finding neuroprotective strategies calls for a greater understanding of molecular and cellular differences between apoptotic and non-lethal caspase activity/responses.

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The Role of Epigenetic Modifications in Neurotoxicity Induced by Neonatal General Anesthesia. Lin-Hui Ma, Jing Yan, Xin-Hao Jiao, Cheng-Hua Zhou, & Yu-Qing Wu. April 2022

What are the mechanisms of general anesthesia (GA)-induced cognitive impairment in neonates? What is the role of epigenetics? In their review, the authors describe factors in GA-induced cognitive impairment vis-a-vis 1) DNA methylation; 2) post-translational modifications of histones; 3) non-coding RNA; 4) RNA methylation; and 5) interactions of epigenetic modifications. When compared to mechanisms that have been widely reported, epigenetics remains a novel field in need of greater exploration.

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Neonatal Exposure to Propofol Interferes with the Proliferation and Differentiation of Hippocampal Neural Stem Cells and the Neurocognitive Function of Rats in Adulthood via the Akt/p27 Signaling Pathway. Hui Hui Miao et al. April 2022

What is the underlying mechanism of neurotoxicity and neurocognitive decline following neonatal exposure to propofol (PPF)? Findings in rats show that neonatal exposure to PPF 1) inhibits phosphorylation (p) of AKT, also known as protein kinase B; 2) enhances expression of the p27 gene; 3) inhibits neural stem cell (NSC) proliferation; and 4) decreases NSC differentiation. Two months after PPF exposure, rats display weakened neurocognitive function. Injection of an AKT activator reduces PPF-induced inhibition of p-AKT and increases p27 expression. The activator does not fully reverse PPF-induced neurocognitive deficits, but rescues NSC proliferation and differentiation from PPF’s neurotoxic effects.

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Research News & Updates

Effect of Anesthetics on Functional Connectivity of Developing Brain. Xu Chen et al. March 2022

Investigators study the effects and mechanisms of anesthesia-induced neurotoxicity (AIN) in the developing animal brain using functional magnetic resonance imaging (fMRI) techniques. Findings show that functional connectivity (fC, measurable neural signals between brain regions) differ in the newborn and adult brain. Bold-oxygen-level-dependent (BOLD)-fMRI is useful in detecting cerebral hemodynamics and oxidative metabolism.  Anesthesia-induced neural activation coincides with regional increases in blood flow, blood volume, and oxygen consumption.  fMRI techniques can also detect a decrease in fC—one possible mechanism of AIN and neurodegenerative change in the neonatal brain.

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Anesthetic Neurotoxicity in Children. Irim Salik. March 2022

Are we overly concerned about anesthetic neurotoxicity (NT) in healthy children? To answer, the author conducts a literature review, including human studies between 2009 and 2020. Findings show that clinical evidence for anesthesia-related NT in children is not clear—there are incongruous results based on human trials. However, a number of independent, retrospective studies find no association between anesthesia and maladaptive cognitive outcomes in healthy children <2 years old, even with multiple exposures. This suggests minimal or non-existent long-term neurodevelopmental risk with a single anesthesia exposure in healthy infants and children. Factors other than anesthesia may be more important in determining a child’s cognitive potential.

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Impact of surgery and anesthesia during early brain development: A perfect storm. Keunen, Weiland, de Bakker, de Vries, &  Stevens. March 2022

This review explores the effects of neonatal surgery on neurobiological processes in the rapidly developing brain. The authors 1) provide a structured summary of early brain development; 2) discuss the literature on brain injury and neurodevelopmental outcomes; 3) describe mechanisms of injury after neonatal surgery; and 4) propose a disease model built on the triad of inflammation, vascular immaturity, and neurotoxicity due to prolonged exposure to anesthesia.  This triad creates the “perfect storm” for anesthesia-induced neonatal brain injury.

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Disruption of hippocampal P2RX2/CaMKII/NF-κB signaling contributes to learning and memory impairment in C57BL/6 mice induced by surgery plus anesthesia in neonatal period. Weiming Zhao et al. April 2022

What are the long-term effects of neonatal surgery and anesthesia? Investigators administer sevoflurane (SEVO) alone or abdominal surgery + SEVO to six-day-old C57BL/6 mice, followed by testing in the mouse juvenile phase. Findings show that neonatal surgery + SEVO impairs learning and memory, but SEVO alone does not. Behavioral abnormalities associate with increased levels of P2RX2 (P2), phosphorylated-calcium-calmodulin-dependent protein kinase II (P-CaMKII), and activated nuclear factor kappa B (NF-κB)—elements that normally support brain health. For the surgery + SEVO group, P2 inhibitors reduce cognitive impairments and mitigate surgery-induced signaling enhancement of P2, P-CaMKII, and NF-κB.

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Differential epitranscriptome and proteome modulation in the brain of neonatal mice exposed to isoflurane or sevoflurane. Yanqiong Wu et al. March 2022

What are the underlying molecular mechanisms of neurotoxicity after early exposure to isoflurane (ISO) or sevoflurane (SEVO)? How do these anesthetics affect N6-methyladenosine (m6A) methylation modification, known to play a role in gene regulation and neurodevelopment? To explore, investigators administer ISO or SEVO to neonatal mice, followed by evaluation and testing on Postnatal Days 21 and 30-35. Findings in juveniles show both agents induce abnormal social behaviors, differing social patterns, and numerous m6A modification-related changes in the brain. In drug-specific effects, ISO alters the proteins associated with epilepsy, ataxia, and brain development; SEVO alters proteins related to social behavior. ISO and SEVO-specific alterations in patterns of m6A modification are also evident. 

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Post-operative behavioural disorders in paediatric anaesthesia caused by anaesthetics and sedatives.  Petrikova, Saniova, & Job. April 2022

In their review, which includes retrospective and observational studies in mammals and data on children, the authors address ways to minimize and/or prevent the adverse effects of pediatric anesthesia, including anesthesia-induced maladaptive and behavioral disorders. The discussion covers 1) the influence of anesthetic agents and sedatives from development to maturity; 2) mechanisms of anesthesia-induced neurotoxicity; and 3) consequences of neurotoxicity.  Future research is needed to identify A) absolute and dose-specific anesthetic effects; B) mechanisms of anesthesia-induced brain impairments in the child’s first month; C) specific points in neurogenesis at which anesthesia impairs synaptic development; and D) therapies to protect the young brain from anesthesia-induced neurotoxic effects.

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Does Resveratrol Prevent Sevoflurane Toxicity in Newborn Rats? Ayşenur Sümer Coşkun et al. April 2022

Does pretreatment with resveratrol (RES), a plant-based supplement with antioxidant qualities, protect newborn rats from long-term sevoflurane (SEVO)-induced cognitive damage? Investigators evaluate 4 subject groups: 1) control, 2) SEVO alone, 3) SEVO + RES 25mg, and 4) SEVO + RES 50mg.  SEVO is administered on Postnatal Days (PNDs) 7-9. Findings show RES pretreatment reverses SEVO-induced deficits in target quadrant time during water maze tests on PND 35. Pretreatment with RES 50 mg, but not RES 25 mg, stops the SEVO-induced reduction in brain-derived neurotropic factor (BDNF) and boosts performance in open field tests on PND 41. SEVO can impair long-term cognitive abilities in newborn rats and RES, at certain levels, can reverse this damage.

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Echinacoside alleviates sevoflurane-induced cognitive dysfunction by activating FOXO1-mediated autophagy. Huifang Yang, Li Zhao, & Qin Li. April 2022

What is the effect of echinacoside (ECC), a plant-derived compound with neuroprotective qualities, on sevoflurane (SEVO)-induced cognitive impairment? To explore, researchers inject Forkhead Box Protein O1 (FOXO1), si-FOXO1, and si-con into the mouse brain before SEVO exposure, then compare the NO SEVO control to SEVO only, SEVO + saline, and SEVO + Ech groups. Findings show pretreatment with Ech reduces SEVO-induced cognitive dysfunction, upregulates FOXO1 expression in the hippocampus, and increases expression of select proteins in autophagy, the cell cleansing and renewal process. Silencing FOXO1 aggravates cognitive deficits and reduces expression of autophagy-related markers. Ech reverses the toxic effects of si-FOXO1 on memory and reduces SEVO-induced cognitive impairment.

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The role and mechanism of TLR4-siRNA in the impairment of learning and memory in young mice induced by isoflurane. Lin Lin et al. April 2022

This study examines the role of small interfering ribonucleic acid (siRNA) in isoflurane (ISO)-induced cognitive impairment vis-à-vis toll-like receptor 4 (TLR4), a protein that triggers the brain’s inflammatory response to invading pathogens and threatening molecular patterns. Investigators divide newborn mice into 4 test groups: 1) control, 2) ISO only, 3) TLR4 interference empty vector + ISO (siRNA-NC), and 4) TLR4 interference + ISO (TLR-siRNA). Findings show ISO stimulates over-expression of the inflammatory response factor that plays an important role in cognitive impairment. TLR4, as a mediator of immune inflammation, also plays a key role in the brain cell injury process which can be delayed by blocking the TLR4 signal.

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Sevoflurane-Induced Neurotoxicity in the Developing Hippocampus via HIPK2/AKT/mTOR Signaling.  Lirong Liang et al. April 2022

What is the role of homeodomain interacting protein kinase 2 (HIPK2), which supports neural cell and synaptic health, in sevoflurane (SEVO)-induced neurotoxicity? Investigators discover that 1) neural cell death is higher after exposure to SEVO; 2) SEVO induces upregulation of HIPK2 and Ak strain transforming/mammalian Target of Rapamycin (AKT/mTOR) signaling in hippocampal neurons; 3) the HIPK2 antagonist A64 significantly reduces the increase in SEVO-induced neural cell death and activation of AKT/mTOR signaling; and 4) the AKT antagonist MK2206 reduces neural cell death without affecting HIPK2 expression. HIPK2/ AKT/mTOR signaling plays a key role in SEVO-induced neurotoxicity and has potential as a protective target against anesthesia-induced cytotoxicity.  

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Sevoflurane-Induced Apoptosis in the Mouse Cerebral Cortex Follows Similar Characteristics of Physiological Apoptosis. Qi Wang, Yuan Li, Hong Tan, & Yingwei Wang. April 2022

Does the pattern of SEVO-induced apoptosis (a cell death process) follow the known developmental pattern of physiological apoptosis that eliminates excess and inappropriately integrated neurons?  Using Postnatal Day (PND) 5 and 9 mice, investigators find that SEVO exposure increases levels of brain cell death without interfering with developmental patterns of physiological apoptosis.  By PND 9, mouse brain cells that are more vulnerable to both physiological and SEVO-induced apoptosis shift from one brain layer to another—this reduces the magnitude of both SEVO-induced and physiological apoptosis. The Akt-FoxO1-PUMA (Ak strain transforming/Forkhead Box O1/p53 upregulated modulator of apoptosis) pathway may be responsible for SEVO-induced apoptosis. However, the magnitude, lamination pattern, and cell-type specificity are age-dependent and follow the known physiological apoptosis pattern.

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Repeated neonatal exposure to sevoflurane induces age-dependent impairments in cognition and synaptic plasticity in mice. Xiaoyan Zhao et al. February 2022

What are the mechanisms of sevoflurane (SEVO)-induced neurotoxicity in the developing brain? Researchers expose neonatal mice to SEVO, followed by studies of learning and memory, synaptic plasticity, and neuronal excitability. Findings show repeated exposure to SEVO results in 1) significant cognitive impairment in adolescence, but no effect in adulthood; 2) a reduction in hippocampal long-term potentiation (LTP) in adolescence with normal LTP in adulthood; and 3) no significant difference in LTP between the controls and mice receiving 1- minimum alveolar concentration (MAC) dose.  The authors conclude that sevoflurane may impair cognitive performance and neuronal plasticity when administered repeatedly or in a high MAC during infancy, which is noticeable during adolescence but alleviates during adulthood. 

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Identification of microRNA/target gene in the dentate gyrus of 7-day-old mice following isoflurane exposure. Bing-Nan Yang et al. 2022

This study profiles the network of micro ribonucleic acid (miRNA) molecules and potential target genes in the neonatal mouse dentate gyrus (DG) after isoflurane (ISO) exposure. For their work, investigators integrate two independent data sets: one for miRNA sequencing and the other for messenger RNA (mRNA) sequencing. Findings show a single 4-hour exposure to ISO yields 1059 pairs of differently-expressed miRNAs and target genes in the DG. Using gene ontology (the classification of genes and their molecular functions) and the Kyoto Encyclopedia of Genes and Genomes, the authors conclude that dysregulated miRNAs and target genes have far-reaching effects on pathophysiological cellular events, including brain cell death, axon development, and synaptic transmission. 

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MiRNA-384-5p targets GABRB1 to regulate ketamine-Induced Neurotoxicity in Neurons. Qiange Yang & Feiyu Long. January 2022

What is the function of micro ribonucleic acid (miRNA) 384-5P (384) in ketamine (KT)-induced neurotoxicity (NT)?  The authors isolate neonatal rat hippocampal neurons, treat them with varying doses of KT, and follow with measurements of KT levels in treated neurons. Findings show KT induces NT and 384 upregulation. Downregulation of 384 mitigates KT-induced NT by restraining brain cell death and reactive oxygen species (ROS) activation. Gamma-Aminobutyric Acid Type A Receptor Subunit Beta1 (GABRB1), as the gene target of 384, increases KT-induced NT.  When depleted, GABRB1 reduces the protective effect of 384 inhibition on KT-mediated NT. 

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Downregulation of HOTAIR reduces neuronal pyroptosis by targeting miR-455-3p/NLRP1 axis in propofol-treated neurons in vitro. Haixia Gong, Xianwen Wan, Yang Zhang, & Sisi Liang. May 2021

What is the effect of HOX transcript antisense ribonucleic acid (HOTAIR), a human gene transcript, on propofol (PPF)-induced pyroptosis, a form of programmed cell death involving inflammation? What are the mechanisms of neurotoxicity? Investigators show that PPF significantly reduces neuron viability, promotes inflammation, and induces neuron death while deleting HOTAIR has the opposite effect. HOTAIR and Nod-like receptor protein1 (NLRP1) are the targets of micro ribonucleic acid 455-3p (455). PPF treatment decreases the levels of 455 and increases NLRP1. HOTAIR inhibits PPF-induced neuronal pyroptosis by regulating the 455/ NLRP1 axis, thus making HOTAIR a potential therapeutic target for PPF-induced neurotoxicity.

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LncRNA SNHG12 ameliorates bupivacaine-induced neurotoxicity by sponging miR-497-5p to upregulate NLRX1. Lijie Sun & Ru Yuan. April 2022

What is the role and associated mechanisms of long noncoding ribonucleic acid/small nucleolar RNA host gene 12 (SNHG12) in local anesthetic bupivacaine (BV)-induced neurotoxicity (NT)? Using an in vitro cell model, investigators find 1) SNHG12 overexpression promotes cell viability while inhibiting cell death and oxidative stress in BV-treated human neuroblastoma cells; and 2) miR-497–5p decreases cell viability and induces cell death and oxidative stress. SNHG12 may relieve BV-associated NT in vitro by sponging miR-497–5p to upregulate NLRX1, thus providing novel clues and biomarkers for the treatment and prevention of BV-associated NT.

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Neonatal Anesthesia and Oxidative Stress. Gascoigne, Minhaj, &  Aksenov. April 2022

This literature review explores the relationship between anesthesia and oxidative stress that, in excess, can be damaging to neonatal brain cells. The authors discuss 1) mechanisms of action for common anesthetic agents; 2) the pathways that produce the majority of oxidative stress and  reactive oxygen species (ROS); 3) the main antioxidants; and 4) possible immediate short- and long-term pathways of neonatal-anesthesia-induced oxidative stress. Findings suggest that the short-term pathway has a limited effect on oxidative stress while the long-term pathway can manifest years later due to altered development of neurons and neurovascular interactions. 

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Sevoflurane diminishes neurogenesis and promotes ferroptosis in embryonic prefrontal cortex via inhibiting nuclear factor-erythroid 2-related factor 2 expression. Ruixue Song, Rong Wang, Ziying Shen, & Haichen Chu. April 2022

Does sevoflurane (SEVO) cause ferroptosis (FT), a type of cell death, and neurogenesis abnormalities in the embryonic prefrontal cortex? What role does nuclear factor-erythroid 2-related factor 2 (Nrf2), a protective protein within cells, play in the mechanisms of SEVO-induced neurotoxicity (NT)? Experiments in rodents and primary neural stem cells show that SEVO exposure can induce 1) neurogenesis inhibition and FT with little effect on apoptosis (another unique cell-death process); 2) a significant decrease in Nrf2 expression; and 3) an increase in reactive oxygen species accumulation. Mechanistically, Nrf2-related neurogenesis inhibition and FT are central to SEVO-induced NT in the embryonic brain.

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Panel Session – SmartTots: New Directions in Pediatric Anesthetic Neurotoxicity Research

We hope that you were able to join us for the IARS 2022 Annual Meeting this past weekend. The meeting included a SmartTots sponsored session entitled, “SmartTots: New Directions in Pediatric Anesthetic Neurotoxicity Research,” which highlighted the latest pediatric anesthetic neurotoxicity research.  During this session moderated by Dr. Dean Andropoulos, investigators and experts on this topic, Drs. Vesna Jevtovic-Todorovic, Viola Neudecker and Caleb Ing, presented the major findings of recent studies, and how these results contribute to the literature in the area of anesthesia neurotoxicity. View the session video here.

Commentary on Previously Summarized Articles

Sex hormones and the young brain: are we ready to embrace neuroprotective strategies? Vesna Jevtovic-Todorovic. February 2022

In her editorial, the author questions if the scientific community is ready to consider new and alternative strategies to reduce anesthesia-induced neurotoxicity. She highlights the study by Wali and colleagues on prophylactic progesterone as a protective treatment against anesthesia-induced neuroinflammation. It may be worthwhile to explore “safening” agents, from among currently available drugs, that can modulate brain pathways involved in anesthesia-induced over-activation of programmed brain cell death. As a new class of anesthetics, neuroactive steroids may be neuroprotective and serve as a basis for novel anesthetics.

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Does inflammation mediate behavioural alterations in anaesthesia-induced developmental neurotoxicity? Neudecker, Perez-Zoghbi, & Brambrink. January 2022

In this editorial, the authors comment on research by Wali and colleagues on the neuroprotective role of progesterone (PG) pretreatment and its anti-inflammatory properties in anesthesia-induced neurotoxicity (AIN). “We cannot discard the possibility of PG mediating its neuroprotection via a mechanism independent of its anti-inflammatory properties, such as brain-derived neurotropic factor,” they say. “The potential role of neuroinflammation in AIN is still open to question and the inflammatory process specific to developmental AIN remains undefined.” This calls for additional studies in nonhuman primates to validate Wali’s findings on progesterone in rodents.

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Testosterone: much more for the brain than a sex hormone. Jevtovic-Todorovic. January 2022

In her editorial, this research scientist praises the “well designed” study by Yongyan Yang et al (Yang) for its findings on the role of sex hormones in critical stages of brain development. Yang demonstrates that exogenous (from an external source) testosterone, when delivered at the time of sevoflurane exposure, increases levels of testosterone in the neonatal mouse brain. This increase, in turn, reverses the anesthesia-induced decrease in neuronal activation and cognitive impairment.

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Research News & Updates

Local Anesthetic Injection Before Incision Decreases General Anesthesia Requirements in Pediatric Trigger Thumb Release: A Randomized Controlled Trial. Lin et al. March 2022

This single-center randomized control trial in children ≤ 4 years having unilateral trigger thumb release aims to find which is better at reducing anesthesia exposure: pre-incision local anesthetic injection (PRE) or post release local anesthetic injection (POST). For cumulative anesthesia dose, findings show a significant difference between the PRE and POST groups with a 21% reduction in anesthesia for the PRE group. The results suggest that pre-incision is a low risk, easy method to reduce anesthesia requirements and potentially mitigate risks of neurotoxicity.

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Synthetic neuroactive steroids as new sedatives and anaesthetics: Back to the future. Manzella, Covey, Jevtovic-Todorovic, & Todorovic. February 2022

Should we revisit the use of neuroactive steroids (NSs) as safe anesthetics? The authors review NS history in animal and human models, their diverse mechanisms of action, and their neuroprotective properties. While briefly abandoned for clinical use due to unwanted vehicle side effects, there is renewed interest in NSs given their neuroprotective actions in the developing animal brain. This includes the way NSs 1) help the brain to modulate synaptic receptors and neuronal excitability, 2) support brain cell survival, and 3) prevent anesthesia-induced brain cell death.

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Do We Have Viable Protective Strategies against Anesthesia-Induced Developmental Neurotoxicity? Useinovic, Maksimovic, Near, Quillinan, and Jevtovic-Todorovic. January 2022

This mini review summarizes strategies for protecting the developing human brain from general anesthesia (GA)-induced neurotoxicity. The authors explore 1) mechanisms of neuroprotection and clinical applications; 2) intracellular targets and signal-transduction pathways for a diverse group of chemicals; 3) epigenetic and transgenerational effects of GA, potential remedies, and approaches that delay or reduce anesthesia; and 4) evidence for a novel class of anesthetics with distinct mechanisms of action and promising safety profiles.

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Longitudinal assessment of cognitive function in young children undergoing general anaesthesia. Shi et al December 2021

How does general anesthesia (GA) for elective surgery affect processing speed (PS), working memory (WM), and fine motor skills (FMS) in children ages 2.5-6 years? Investigators assess cognitive function at a pre-operative visit, 1-2 weeks post-operatively (Visit-2), and 3 months post-operatively (Visit-3). Findings show significant improvements in picture memory, cancellation, and PS at Visit-2 along with significant improvement in FMS at Visit-3. This study found no association between exposure to GA and the decline in WM, PS, and FMS in the first 3 months after surgery.

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Moderators of the association between attention-deficit/hyperactivity disorder and exposure to anaesthesia and surgery in children. Shi et al. November 2021

What characteristics influence the association between anesthesia exposure and attention-deficit/hyperactivity disorder (ADHD)? From a sample of 185,002 children <5 years of age, investigators identify and evaluate 9,179 with ADHD. Findings show single and multiple anesthesia exposures, when compared to no exposure, associate with hazard ratios (relative measures of risk) for ADHD of 1.39 and 1.75, respectively. Exposure to anesthesia and surgery associate with an increase in ADHD. Race is the only statistically significant moderating factor for ADHD. Non-white children are at a greater risk for ADHD than whites.

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Risk of Attention Deficit Hyper Activity Disorder After Early Exposure to General Anesthesia; A Case Control Study. Sedighnejad et al. April 2020

This study explores the association between early exposure to general anesthesia (GA) and the development of attention-deficit/hyperactivity disorder (ADHD). From a sample of 210 children, physicians identify and collect data on 105 with ADHD. Findings show 19% of children with ADHD have a history of GA exposure compared to 3.8% in the control group. Significant differences appear for gender, age at exposure, history of exposure, and number of exposures. Early exposure to GA and male gender may be risk factors for ADHD development with boys being potentially more sensitive to the long-term adverse effects of anesthesia.

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Neonatal isoflurane exposure disturbs granule cell migration in the rat dentate gyrus. Uchida, Hashimoto, Saito, Takita, & Morimoto. January 2022

How does early exposure to isoflurane (ISO) affect granule cell (GC) migration in the dentate gyrus (DG) of neonatal rats? Using immunofluorescence to track cell migration, investigators find a significant increase in abnormal migration by Postnatal Day 21 in subjects with ISO exposure on PN Day 7. The concentration of ISO and day of exposure influence the number of hilar (from the hilus region of the hippocampus) GCs with abnormal migration. Neonatal ISO disturbs the migration of GCs in the rat DG–this may be a possible mechanism of ISO-induced neurotoxicity.

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Application of Nonhuman Primate Models in the Studies of Pediatric Anesthesia Neurotoxicity. Cheng Wang et al. February 2022

This review highlights the evolutionary likeness between nonhuman primates (NHPs) and humans, including similarities in reproduction, development, neuroanatomy, and cognition. The authors explore the use of NHPs for modeling pediatric anesthesia exposure, identify gaps in NHP data, and address applications of the NHP model in studies of general anesthesia-induced developmental toxicity. While not as widely used as other animal models, the NHP model can play a unique role in broadening our knowledge of potential neurotoxicity associated with pediatric general anesthetics.

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General Anesthesia and the Young Brain: The Importance of Novel Strategies with Alternate Mechanisms of Action. Maksimovic et al. February 2022

What do we currently know about neuroactive steroids as a promising novel general anesthetic for children? Given the number of preclinical and clinical studies describing and/or suggesting an association between exposure to general anesthesia (GA) and neurocognitive issues, investigators explore alternatives to general anesthesia (GA), focusing on synthetic neuroactive steroid analogues (NSAs). NSAs have emerged as effective hypnotics free of neurotoxic effects and long-term cognitive side effects. Some steroid analogues, with different cellular targets and mechanisms of action than currently used GAs, may be safe alternatives.

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Sevoflurane induced neurotoxicity in neonatal mice links to a GSK3β/Drp1-dependent mitochondrial fission and apoptosis. Jinsheng Liu et al. February 2022

Using neonatal mice and a human cell line, investigators explore the mechanisms of sevoflurane (SEVO)-induced neurotoxicity in mitochondrial fission (MS) and brain cell death. Findings show SEVO 1) upregulates glycogen synthase kinase 3β (GSK3β) stability and activation; 2) promotes phosphorylation of dynamin-related protein-1(Drp1), and its translocation (change in location) to mitochondria; and 3) promotes the interaction between GSK3β and Drp1. SEVO-induced neurotoxicity links to GSK3β/Drp1-dependent MS and brain cell death.

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Anesthesia and neurotoxicity study design, execution, and reporting in the nonhuman primate: A systematic review. Gao, Wahl, & Floyd. January 2022

Why do studies in animals and nonhuman primates (NHPs) raise greater concerns about the role of anesthesia in pediatric neurotoxicity than do progressive clinical trials in children? To answer, investigators evaluate the design, execution, and reporting in 23 published manuscripts in pediatric neurotoxicity using NHPs. Findings show a lack of data analysis in all studies; low sample size in 91%; behavioral outcomes not significantly different from controls in 67-100%; insufficient blinding data in 57%; and supra-therapeutic dosing in 22%. These deficits may account for divergent results in studies with human children vs. NHP neonates.

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Tetraethylammonium chloride reduces anaesthetic-induced neurotoxicity in Caenorhabditis elegans and mice. Sangwook Jung et al. January 2022

Using Caenorhabditis elegans (roundworms), the authors screen for compounds that alleviate anesthesia-induced neurotoxicity (AIN), followed by testing of candidates in neonatal mice. Findings show 1) isoflurane (ISO) increases ER stress; 2) nine compounds reduce induction of ER stress; 3) of these compounds, tetraethylammonium chloride (TC) and trehalose (TH) alleviate ISO-induced defects in chemotaxis (cell migration); and 4) TC reduces ISO-induced caspase staining in the anterior cortical and hippocampal regions of the mouse brain. TC reduces ISO-induced neurotoxicity in divergent species, raising its therapeutic potential. In roundworms, ER stress predicts, but does not cause, ISO-induced neurotoxicity.

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Neonatal exposure to sevoflurane impairs preference for social novelty in C57BL/6 female mice at early-adulthood. Huayue Liu et al. January 2022

Using both male and female neonatal mice, investigators study the effect of sevoflurane (SEVO) on social behaviors and brain cells. Subjects receive 3% SEVO or 60% oxygen on Postnatal Day 6, followed by behavioral tests at 1-2 months and brain cell studies. In early adulthood, males show normal results for social novelty preference, an indicator of social memory development, while females are impaired and weak. The mechanism behind this disturbance may be the observed SEVO-induced decrease in levels of postsynaptic density protein 95, normally supportive of synaptic function, in the hippocampus.

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Hippocampal SIRT1-Mediated Synaptic Plasticity and Glutamatergic Neuronal Excitability Are Involved in Prolonged Cognitive Dysfunction of Neonatal Rats Exposed to Propofol. Lin-Hui Ma et al. January 2022

Using neonatal rats, researchers study the effects of early and repeated exposure to propofol (PPF) on the brain’s hippocampus. In particular, what are PPF-induced changes on the SIRT1 (silent mating type information regulation 2 homolog), a protein that regulates many cellular functions? Findings show PPF reduces SIRT1 expression, suppresses synaptic plasticity, decreases glutamatergic neuron excitability, and impairs learning and memory. Overexpression of SIRT1 reduces PPF-induced cognitive dysfunction, excitation-inhibition imbalance, and damage to synaptic plasticity. SIRT1 plays an important role in PPF-induced cognitive dysfunction.

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Repeated exposure to sevoflurane in neonatal rats impairs cognition in adulthood via the PKA-CREB-BDNF signaling pathway. Jili Zhao et al. December 2021

Using neonatal rats, investigators observe the effects of neonatal sevoflurane (SEVO) for 2 hours daily over 3 consecutive days on adult cognition. Findings show SEVO induces 1) a reduction in neurons and brain-derived neurotropic factor (BDNF) in the brain; 2) significantly lower expression of protein kinase A (PKA), p-CREB [phosphorylated c-camp (cyclic adenosine monophosphate response) element binding protein], BDNF, and the p-CREB/CREB ratio; and 3) significant cognitive impairment by Day 56. The PKA-CREB-BDNF signaling pathway plays a key role in SEVO-induced cognitive decline after early exposure to SEVO.

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Exposure to Sevoflurane, But Not Ketamine, During Early-life Brain Development has Long-Lasting Effects on GABA_A Receptor Mediated Inhibitory Neurotransmission. Lin et al. September 2021

Using neonatal mice, investigators study changes in Gamma-Amino Butyric Acid-A (GABA_A)-mediated neurotransmission following early exposure to sevoflurane (SEVO) and ketamine (KT). Findings show that SEVO targets GABA_A receptors while KT targets N-methyl-D-aspartate (NMDA) receptors. Early exposure to KT results in anxiety and depression-like behavior later in life. Early exposure to SEVO, but not KT, reduces hippocampal GABAergic inhibition and enhances induced seizure activity later in life. The anesthetic receptor targets of different anesthetics may predict their long-term effects.

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Research News & Updates

Anesthesia and Developing Brains: Unanswered Questions and Proposed Paths Forward. Ing et al. January 2022

In their report, SmartTots investigators provide consensus and address areas of disagreement on burning issues in pediatric anesthesia safety and neurotoxicity in children. Topics include: 1) preclinical data from animal models and translation to humans; 2) the state of clinical evidence; 3) perioperative factors that affect outcomes; 4) consensus and differences of opinion; 5) evidence required to show that exposure to general anesthesia causes long-term neurodevelopmental deficits in children; 6) children who are most vulnerable; and 7) experience from environmental neurotoxin studies. New research approaches are needed to determine whether a recognized phenotype is caused by anesthetic medications or other factors. Clinical evidence is mixed and key questions on anesthesia-induced neurotoxicity in children are still under debate. Pediatric neurotoxicity research is in the middle of its evolution when compared to research of other potentially toxic chemicals. Further research on the long-term neurodevelopmental effects of anesthesia is necessary.

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Assessing the Safety of a Novel Neonatal Anesthesia Protocol: A Review of 101 Patients With Early Cleft Lip Repair. Wlodarczyk  et al. November-December 2021

This retrospective review of neonatal patients with early cleft lip repair evaluates the short-term safety and efficacy of a novel anesthetic protocol that excludes volatile anesthetic agents against a standard anesthetic protocol. The patient sample includes two cohorts of neonates: one with a gas-based regimen and one with a dexmedetomidine-based protocol; 65 neonates use the novel protocol and 36 use the standard. Findings show no significant differences between cohorts in anesthetic or emergence time, complication rates, and medication side effects. The authors conclude that the novel (non-volatile) protocol is perioperatively the same as the (volatile) anesthetic standard of care.

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Early Development of the GABAergic System and the Associated Risks of Neonatal Anesthesia. Gascoigne, Serdyukova, & Aksenov. November 2021

How does neonatal anesthesia impact the gamma aminobutyric acid-ergic (GABA) system, one that normally supports neuron development, in ways that lead to deficits in learning and behavior in children? Findings show that, because the GABA systems of children develop over a long period of time, it is not possible to identify the entirety of negative anesthesia-induced effects on learning and behavior–they are not immediately evident and take years to develop. Alternatively, the authors offer a variety of in vivo methods for measuring the GABA-related effects of neonatal anesthesia on learning and behavior over time.

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Glial cell-derived neurotrophic factor decrease may mediate learning, memory and behavior impairments in rats after neonatal surgery. Ying Xie, Weixing Zhao, & Zhiyi Zuo. January 2022

Does neonatal surgery under sevoflurane induce hyperactive behavior in addition to impairments in learning and memory? What role does the glial cell-derived neurotrophic factor, GDNF, (a gene that supports neuron development) play? Findings in PN Day 7 rats, tested 23 days after surgery, show surgery 1) reduces GDNF expression in the brain, 2) impairs learning and memory, 3) induces hyperactive behavior, and 4) reduces spine density and tree-like growth of dendrites. GDNF, injected at the end of surgery, stops these neurotoxic effects.

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Prophylactic progesterone prevents adverse behavioural and neurocognitive effects of neonatal anaesthesia exposure in rat. Wali, Sayeed, Stein, & Raper. December 2021

Does pretreatment with a subcutaneous injection of progesterone (PG) prior to  sevoflurane (SEVO) exposure prevent long-term anesthesia-induced neurocognitive and behavioral changes? Findings in neonatal rat pups show that PG pretreatment reduces chemokine C-X-C motif ligand 1 (CXCL1) (a gene that plays a role in inflammation) response to SEVO exposure. Subjects with no PG pretreatment display increased anxiety on elevated plus maze tests along with learning and memory impairments on water maze tests. The authors conclude that PG pretreatment is neuroprotective—it can stop anesthesia-induced, acute peripheral inflammatory response and prevent cognitive and behavioral impairments.

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Testosterone attenuates sevoflurane-induced tau phosphorylation and cognitive impairment in neonatal male mice. Yongyan Yang et al. December 2021

Using male neonatal and adult mice, investigators explore the protective effects of testosterone (T) against anesthesia-induced neurotoxicity. Both PN Day 6 and Day 60 mice receive 3% sevoflurane (SEVO) for 2 hours/3 days; neonates also receive testosterone treatments. When compared to adult mice, neonates inherently show lower T concentrations with higher SEVO-induced tau phosphorylation and cognitive impairment. T treatments in neonates increase T concentrations, reduce SEVO-induced tau phosphorylation, and reduce cognitive impairment. Testosterone acts by inhibiting the interaction between tau and glycogen synthase kinase-3β that, in turn, blocks SEVO-induced inhibition of excitatory post-synaptic currents in the brain.

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Epitranscriptomic Analysis of N6-methyladenosine in Infant Rhesus Macaques after Multiple Sevoflurane Anesthesia. Xiao Chen et al. November 2021

The authors search for mechanisms of anesthesia-induced neuropathological brain changes and long term cognitive deficits by profiling RNA N6-methyladenosine (m6A), involved in almost all aspects of RNA metabolism, in the prefrontal cortex of infant rhesus macaques after sevoflurane (SEVO) exposure. Findings show SEVO induces 1) more peaks in m6A; 2) enrichment of hyper-methylated genes in certain biological processes, including regulation of synaptic plasticity; 3) decreases in mRNA levels of RNA binding proteins (YT521-B homology domain family 1 and 3); and 4) 18 and 35 hyper-methylated genes in female and male infant macaques, respectively.

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LncRNA Riken Attenuated Sevoflurane-Induced Neuroinflammation by Regulating the MicroRNA-101a/MKP-1/JNK Pathway. Qi Hou et al. November 2021

Using mice and neural 2A (N2A) cells, a mouse neural crest-derived cell line, investigators explore the roles of long non-coding RNA Riken (Riken), inflammatory cytokine interleukin-6 (IL-6), and the MicroRNA-101a/MKP-1/JNK signaling pathway in sevoflurane (SEVO)-induced neurotoxicity. Findings show SEVO exposure increases the level of IL-6 in the rat brain and in N2A cells while Riken decreases SEVO-induced neurotoxicity and the level of IL-6. In related actions, miR-101a binds to Riken to block its neuroprotective effects and Riken regulates the expression of Mitogen-activated protein kinase phosphatase 1 (MAPK-1). These interactions play an important role in anesthesia-induced neurocognitive disorders.

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Evaluation of neurotoxicity and long-term function and behavior following intrathecal 1 % 2-chloroprocaine in juvenile rats. Walker et al. November 2021

Researchers study the efficacy and safety of an intrathecal 1% injection of 2-chloroprocaine (2-CP), a short-acting spinal anesthesia. Rodents receive injections of 2-CP on PN Day 7, and days 14 or 21, followed by behavioral and cognitive tests between PN Days 30 and 72. Tissue analysis shows neither significant pathology in, nor differences between, subjects receiving 2-CP and the control groups. Adult behavioral measures reflect expected sex-dependent differences across all groups. The maximum tolerated dose of 2-CP can vary by age and produce short-lived, reversible motor and sensory changes, but has no detectable neurotoxicity in juveniles.

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Pachypodol protects newborn rats from anaesthesia-induced apoptosis in the developing brain by regulating the JNK/ERK pathway. Jingxiong Zhang, Mingsheng Zhu, & Jie Zhang. November 2021

What are the beneficial effects of pachypodol (PPL), a substance used to treat malaria from leaves of the Calycopteris shrub, against isoflurane (ISF)-induced neuronal injury? Investigators treat PN Day 7 rats with intravenous PPL before exposure to ISF and follow with assessments of oxidative stress, neuronal cell death, other biochemical parameters, and cognition. Findings show PPL pretreatment lowers cytokine levels and oxidative stress. It also reverses ISF-induced cognitive deterioration, neuronal cell death, and neurotoxic changes in the JNK/ERK/Akt (C-Jun N terminal kinase/extra-cellular-signal-regulated kinase/protein kinase B) signaling pathway.

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Neonatal Isoflurane Does Not Affect Sleep Architecture and Minimally Alters Neuronal Beta Oscillations in Adolescent Rats. Manzella et al. November 2021

How does neonatal exposure to isoflurane (ISO) affect sleep-wake behaviors and brain wave oscillations–electrical activity in neural tissues that plays an important role in cortical development and cognitive processing? In this study, rat pups are studied for neurotoxic insult 2 hours after ISO exposure or, at weaning age, are implanted with cortical electroencephalogram (EEG) electrodes, followed by measurements in adolescence of sleep architecture and EEG power spectra. Findings show neonatal ISO causes extensive neurotoxic damage, but does not disrupt sleep architecture. Investigators observe a small, but significant reduction in beta oscillations, leading them to conclude dysregulated beta oscillations may be implicated in cognitive and socio-affective outcomes.

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Fetal surgery has no additional effect to general anesthesia on brain development in neonatal rabbits. Van der Veeken et al. October 2021

These authors study the effects of fetal surgery on the developing brain using offspring of pregnant rabbits at 28 days gestation—a time of peak fetal brain development. Neonatal subjects divide into 4 exposure groups: 1) no surgery, 2) general anesthesia, 3) general anesthesia + hysterotomy (abdominal incision to excise uterine contents), and 4) general anesthesia + fetal surgery. Findings are comparable for all 4 groups in survival rates, brain to body weight ratios, and neurobehavioral outcomes. Pups in the no surgery group have significantly higher neuron density than those having maternal surgery, and higher proliferation rates and synaptic values. Fetal surgery under hysterotomy with general anesthesia does not affect fetal brain development.

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Mechanisms underlying neonate-specific metabolic effects of volatile anesthetics. Stokes et al. July 2021

What explains the damaging effects of volatile anesthetics (VAs) on young mice? While studying unexpected metabolic effects of VAs, investigators observe that neonatal blood β-hydroxybutarate, β-HB, (an organic compound made in the liver that carries energy to peripheral tissues, such as muscles, bones, and nerves) is rapidly depleted by VAs at concentrations well below those necessary for anesthesia.  Citrate accumulations, malonyl-CoA production by acetyl-CoA carboxylase, and inhibition of fatty acid oxidation mediate β-HB depletion. The authors urge caution as even brief exposure at low dose can have striking metabolic consequences.

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Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1. Patricia Soriano Roque et al. July 2021

Using juvenile mice, researchers explore the neuroprotective effects of daily intranasal insulin (INI) for 7 days as a pretreatment to repeated doses of isoflurane (ISO). Findings show INI prevents anesthesia-induced death of hippocampal brain cells and deficits in synaptic plasticity and memory. The mTORC1/4E-BP2 (mechanistic target of rapamycin complex 1/4E Binding Protein 2) signaling pathway mediates this rescue. Mice without the mTORC1 downstream translational repressor or 4E-BP2 show no repeated anesthesia-induced brain cell death.

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Research News & Updates

Does Anesthesia and Surgery During Pregnancy Really Affect Learning and Behavior in the Offspring: The Holy Grail in Anesthesiology Research.  Fardelmann & Gaiser. Sept 2021

In their editorial, the authors comment on a recent publication by Dr. Caleb Ing et al entitled, “Prenatal Exposure to General Anesthesia and Childhood Behavioral Deficit.” The authors express concern with a few of the conclusions, including, is the utilization of the CBCL test the correct screening tool from which to draw conclusions? Or is it not sensitive enough? Are findings of a 7-point difference in externalizing behavior clinically significant? Were confounding variables adjusted for adequately? While the authors of this editorial found the results of the investigation by Ing et al thought provoking, they feel that we are a long way from changing current practice with regard to medically necessary anesthesia and surgery for the pregnant patient. 

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Parental Decision-Making for Surgery and Anesthesia in Young Children. Rosenblatt et al. June 2021

How does information on neurotoxicity influence a mother’s anesthesia-related decisions for her child? The authors create a theoretical framework and model using qualitative grounded theory analysis, based on interviews with 24 mothers. Findings show moms use a non-linear, iterative decision-making process that reflects five themes: 1) emotional processing, 2) cognitive processing, 3) relationships as resources, 4) the mother-child dyad, and 5) the health care context. A sub-theme includes the role of the medical translator, a person who provides information and context.

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Longitudinal associations between exposure to anesthesia and neurocognitive functioning in pediatric medulloblastoma. Partanen et al. May 2021

What is the association between long-duration anesthesia exposure and neurocognitive deficits in children with medulloblastoma? Investigators administer neurocognitive tests at different points: right after surgery; at < 2 weeks into radiation; and annually for 5 years to 107 children in a multisite pediatric medulloblastoma clinical trial. The average age at diagnosis is 10.2 years and the mean cumulative anesthesia duration is 20.4 hours with a range of .7 to 55.6 hours. Findings show that longer anesthesia exposure associates with a greater decline in IQ, attention, and processing speed. Children <7 years at diagnosis show similar, but lower scores for IQ and attention.

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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. Sepúlveda, Epulef, & Campos.  May 2021

The authors describe data on pharmacologic, electroencephalogic, and neurologic responses in the developing brain that, with clinicians, are not well known. They also address new data in neuroscience, pharmacology, and intraoperative neuromonitoring that can advance pediatric anesthesia practice, but are often overlooked. Investigators offer their perspectives on updated knowledge in neurodevelopment, electroencephalography, and clinical pharmacology. The article’s key sections include 1) the core of current debates; 2) neural development, electroencephalograms, and the emergence of consciousness; and 3) pharmacology.

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NPAS4 suppresses propofol-induced neurotoxicity by inhibiting autophagy in hippocampal neuronal cells. Tongyin Zhang et al. October 2021

Using a mouse hippocampal cell line, researchers study the neuroprotective effect of neuronal PAS (per-ARNT-sim) domain protein 4 (NPAS4), a neuron-specific transcription factor, on propofol (PPF)-induced neurotoxicity in brain neurons. Findings show PPF reduces NPAS4 expression; inhibits cell viability; increases lactate dehydrogenase release and caspase-3 activity; and induces brain cell death and autophagy–a natural process for cleaning out damaged cells. NPAS4 overexpression protects hippocampal neuronal cells from PPF-induced neurotoxicity by reducing autophagy.

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Astrogliosis in juvenile non-human primates 2 years after infant anaesthesia exposure. Neudecker et al. September 2021

This study hypothesizes that glial fibrillary acidic protein (GFAP), a protein in astrocytes that increases during astrogliosis (chronic astrocyte activation), increases in specific brain areas 2 years after anesthesia exposure. To test their hypothesis, investigators treat 6-day-old non-human primates with 5 hours of isoflurane (ISO) one time (1x group); three times (3x group); or expose them to room air (control group). Brain assessments after exposure show GFAP densities 1) increase in the visual cortex in subjects exposed to ISO with no change in the density of activated microglia; 2) increase in the pirirhinal cortex and the subiculum for the 3x group; and 3) increase in the amygdala for both 1x and 3x groups with no increase in the orbitofrontal cortex. There are no differences in hippocampal neurogenesis among groups.

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Repeated neonatal sevoflurane induced neurocognitive impairment through NF-κB-mediated pyroptosis. Jing Dai et al. August 2021

What is the role of pyroptosis (PYR), a type of programmed cell death, in anesthesia-induced neurocognitive inflammation and impairment? To answer, investigators expose both neonatal rats and primary hippocampal neurons to sevoflurane (SEVO) for 2 hours/day for 3 days. Findings show SEVO exposure activates NF-κB (nuclear factor-kappa B)-mediated PYR and neuroinflammation in neonatal rat brains; damages neuronal structure and synaptic integrity; and induces neurocognitive impairments in rats. An NF-κB inhibitor (BAY 11-7082) deactivates PYR, reduces neuronal and synaptic damage, and stops SEVO-induced cognitive impairment. PYR may have potential as a therapeutic target in general anesthesia-induced neuroflammation.

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The Increased Channel Activity of N-Methyl-D-Aspartate Receptors at Extrasynaptic Sites in the Anterior Cingulate Cortex of Neonatal Rats Following Prolonged Ketamine Exposure. Jianhui Jin, Ruirui Wang, & Qing Lin. August 2021

Using rat forebrain slices in vitro, investigators explore the mechanisms of ketamine (KT)-induced neurotoxicity in neonatal neurons vis-à-vis N-methyl-D-aspartate receptors (NMDARs).  More specifically, this study examines the role of GLuN2B (GB), a ionotropic glutamate receptor and subunit of NMDAR in embryonic and early stages of brain development. Findings show GB subunits mediate KT-induced blockage of NMDAR-mediated currents in neonatal neurons. At extrasynaptic neuronal sites, GB-containing NMDARs 1) play a major role in compensatory enhancement of NMDAR-mediated currents in the cortex after repeated KT exposures, and 2) contribute to the high vulnerability of the neonatal brain to KT-induced neurotoxicity.

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Dexmedetomidine does not compromise neuronal viability, synaptic connectivity, learning and memory in a rodent model. Jimenez-Tellez et al. August 2021

Investigators explore the effect of dexmedetomidine (DEX) on neuronal growth, synapse formation, and learning/memory. In rat cortical neurons, a dose below DEX 10 µM does not affect neural viability, but there is significant cell death at higher concentrations. In neonatal rats, a dose of DEX 25 µg/kg for two days does not affect hippocampal-dependent memory. The non-toxic nature of DEX, in both in vitro and in vivo studies, shows that it is a safer anesthetic agent and one that, in vitro, does not alter the total number of synaptic connections between cortical neurons.

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Inhibiting PDE7A Enhances the Protective Effects of Neural Stem Cells on Neurodegeneration and Memory Deficits in Sevoflurane-Exposed Mice. Yanfang Huang, Yingle Chen, Zhenming Kang, & Shunyuan Li. July-August 2021

Using infant mice, investigators study what happens to neural stem cells (NSCs) when they are injected with a knock-down (a suppressed version) of phosphodiesterase 7A (PDE7A), a protein coding gene, following sevoflurane (SEVO) exposure. Findings show that suppressing PDE7A promotes the activation of CREB (cAMP-response element binding) protein signaling, cell proliferation, and neuronal differentiation while profoundly  improving long-term memory and learning. The knock-down of PDE7A improves neuron growth in utero and in vivo, and may help reduce SEVO-induced brain damage in young mice.

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Neonatal Anesthesia and dysregulation of the Epigenome. Cabrera, Useinovic, Jevtovic-Todorovic. July 2021

Mechanistically, what explains why the young pliable brain does not fully recover from a brief exposure to anesthesia? In their review, the authors present evidence for anesthesia-induced genetic and epigenetic dysregulation in the developing brain—changes that can be transmitted from one generation to the next, and to “anesthesia-naive” offspring. Accumulated evidence shows that neonatal anesthesia can dysregulate the genetic tags that influence gene transcription, including histone acetylation and DNA methylation.

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Effects of sevoflurane exposure during different stages of pregnancy on the brain development of rat offspring. Feng-He Cui, Jie Li, Ke-Zhong Li, Yong-Gang Xie, &  Xiao-Ling Zhao. July 2021

In their animal study, research scientists explore the neurotoxic effects of maternal sevoflurane (SEVO) exposure during pregnancy on the brains of offspring. Pregnant rats divide into 4 groups: a control and mothers with SEVO exposure in early (S1), middle (S2), and late (S3) pregnancy. Findings show neurotoxic effects in offspring are greater when mothers are exposed to SEVO in early pregnancy rather than later. The mechanism of neurotoxicity may involve the NR4A1/NF-κB brain-signaling pathway and the increase in secretion of inflammatory cytokines. S1 and S2 offspring show significantly lower memory and learning capacity when compared to offspring of mothers in the S3 and control groups. 

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Long-term evidence of neonatal anaesthesia neurotoxicity linked to behavioural phenotypes in monkeys: where do we go from here? Raper, Simon, & Kamat. July 2021

This editorial praises Neudecker, et al, Astrogliosis in Juvenile Non-human Primates 2 Years after Infant Anaestheia Exposure (tinyurl.com/386yf4u6) for filling a critical gap between pediatric anesthesia neurotoxicity research in animals and humans with a “highly translational non-human primate model.” The editors 1) call for clinical trials to clarify how anesthetic agents impact the human brain and development; 2) describe parallels between Neudecker’s experimental design and prolonged periods of anesthesia exposure in children in sedation suites, imaging centers, and pediatric/neonatal ICUs; 3) encourage scientists to look for biomarkers that reflect structural damage to the brain; and 4) underscore the importance of basic science and translational research into neuroprotective agents and long-term neurodevelopmental outcomes.

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Neuroprotective Effects of Dexmedetomidine on the Ketamine-Induced Disruption of the Proliferation and Differentiation of Developing Neural Stem Cells in the Subventricular Zone. Huanhuan Sha et al. July 2021

Is dexmedetomidine (DEX) neuroprotective of neural stem cell (NSC) proliferation in the subventricular zone (SVZ) of the brain after neonatal ketamine (KT) exposure? To explore, investigators study neonatal rats in five exposure groups: 1) control; 2) KT only; 3) 1 μg/kg DEX + KT; 4) 5 μg/kg DEX + KT; and 5) 10 μg/kg DEX + KT. Findings show KT exposure significantly inhibits the proliferation of NSCs and astrocyte differentiation in the SVZ at 24 hours post exposure. Pretreatment with moderate (5 μg/kg) to high (10 μg/kg) doses of DEX reverse KT-induced disturbances in NSC proliferation, NSC differentiation, and KT-induced olfactory cognitive dysfunction in adulthood.

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Research Progress of Pharmacological Intervention of Sevoflurane-induced Nerve Injury in the Developing Brain. Xiang-Kun Zhao & Yi Tian. June 2021

What are possible mechanisms for sevoflurane (SEVO)-induced neurotoxicity in the developing fetal and infant brain? What mechanisms are neuroprotective? Using animal studies and to answer the first question, investigators explore myelin formation damage; nerve inflammation; brain cell death; oxidative stress; inhibition of histone acetylation; and synapsis and receptor changes. To answer the second question, the authors discuss anti-anemia medicine, plant-based drugs, and alpha 2 adrenoceptor agonists. 

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Gut microbiota mediates cognitive impairment in young mice after multiple neonatal exposures to sevoflurane. Meiyu Liu et al. June 2021

Is there an association between changes in gut microbiota (GM) and cognitive impairment following multiple exposures to sevoflurane (SEVO)? In experiments with young mice, investigators observe GM changes after multiple SEVO exposures. Fecal transplantation confirms that altered GM are responsible for cognitive disorders. GM analysis identifies microbial taxa that is differentially abundant and associated with memory and health of the host, including species of streptococcus. Abnormal composition of GM, following multiple exposures to SEVO, is a risk factor for cognitive impairment. GM may be a target in therapies aimed at reducing anesthesia-induced cognitive disorders.

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

Investigators study changes in interkinetic nuclear migration (INM) of radial glial progenitors (RGPs) in the fetal brain following maternal sevoflurane exposure. Pregnant mice at gestational day 14.5 receive 2.5 % SEVO for 6 hours. Findings show maternal SEVO induces temporary abnormalities in INM and disturbs the cell cycle progression of RGPs in both rodents and cerebral organoids. RNA sequencing and other tests identify the Notch signalling pathway as a potential downstream target of SEVO-induced neurotoxicity. Reactivation of Notch by overexpression of the Jag1 gene and NICD (Notch Intracellular Domain) reverses defects in INM. In young adulthood, offspring show no cognitive impairments.

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Effect of operative trauma and multiple propofol anesthesia on neurodevelopment and cognitive function in developmental rats. Yang Li et al. June 2021

Using neonatal rats and their brain tissue, investigators study the effects of multiple propofol (PPF) treatments with and without abdominal surgery on neuroinflammation and cognitive function. Subjects divide into 4 groups: 1) saline control, 2) PPF only, 3) abdominal surgery + local anesthetic; 4) abdominal surgery + PPF + ropivacaine on day 1 + PPF on day 2. Findings show all but the control with similar and significant increases in TNF-α (tumor necrosis factor- α) concentration, caspase-3, c-fos gene expression, and cell death in the hippocampus. There is no difference among groups in swimming speed, escape latency, target quadrant residence time and crossing times. Abdominal surgery + multiple PPF treatments induce neuroinflammation and brain cell death, but may not associate with long-term neurodevelopmental and cognitive deficits.

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FOXO3 Regulates Sevoflurane-Induced Neural Stem Cell Differentiation in Fetal Rats.  Xingyue Li, Xi Jiang, Qiushi Gao, Ping Zhao. February 2021

What are the effects of maternal sevoflurane (SEVO) on fetal neural stem cell (NSC) differentiation? What are possible mechanisms? What role does autophagy, a natural process for cleaning out damaged cells, play? To answer, investigators expose pregnant rats on gestational day 14 to 2% or 3.5% SEVO followed by measurements of the fetal brain at 48 hours post exposure. Findings show that maternal exposure to 3.5% SEVO in mid-trimester induces NSC differentiation in the fetal brain by activating FOXO3 (Forkhead Box 03, a protein coding gene) expression. Lithium chloride inhibits FOXO3, autophagy activation and NSC differentiation. The inhibition of autophagy reverses improper differentiation of NSCs.

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Research News & Updates

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. Warner et al. July 2021

Does a single exposure to anesthesia before the age of 3 years associate with attention deficit hyperactivity disorder (ADHD) and learning disabilities (LD) later in life? This secondary analysis of data from earlier, retrospective population-based cohort studies involves 5339 Minnesota children at < 3 years with no exposure to anesthesia and 1054 with a single exposure. Investigators find no evidence that a single exposure before the age of 3 years associates with an increased risk of ADHD, LD, or the need for an individualized education plan.

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A decade later, there are still major issues to be addressed in paediatric anaesthesia. Habre & Disma. June 2021

This review explores unanswered questions in pediatric anesthesia practice relating to 1) standardization and harmonization of airway management, 2) analgesia techniques, and 3) outcome measures. The authors highlight ways to improve anesthesia management and the integration of evidence-based findings into clinical practice. They also discuss the importance of age-related and patient-centered perioperative outcomes when interpreting the safety and efficacy of anesthesia and analgesia in children.

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Accounting for General Anesthesia: A Pre-Op Primer and Post-Op Factor. Kornfeld & Wild. May 2021

The authors provide tips to pediatric generalists on counseling families on anesthesia risks to young children, including associated risks of neurocognitive issues later in life. The article touches on the 2016 FDA safety warning, findings from the 2018 Mayo Anesthesia Safety in Kids clinical trial, and conclusions from other retrospective clinical pediatric studies. In light of limited clinical research in this area, clinicians are encouraged to 1) be compassionate and open in discussions with families; 2) validate parental concerns and allow questions on anesthesia risk, duration, and agents; and to 3) individualize each plan of care, ensuring follow up on any long-term, anesthesia-related neurocognitive issues.

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Recent advances in understanding cognitive and behavioural alterations after early-in-life anaesthesia exposure and new mitigation/alternative strategies in preclinical studies. Neudecker, Perez-Zoghbi, & Brambrink. May 2021

In their review of recent preclinical studies, the investigators find growing evidence for the association of early anesthesia exposure with long-term behavioral alterations in non-human primates (NHPs), but the association with cognitive deficits remains controversial. Promising strategies for mitigating anesthesia-induced developmental neurotoxicity include co-administration of anesthesia agents with dexmedetomidine or the alternative use of hypnotic neurosteroids. Carefully designed translational studies are critical to advancing the field.

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Testosterone is Sufficient to Impart Susceptibility to Isoflurane Neurotoxicity in Female Neonatal Rats. Chinn et al. June 2021

Do androgens, hormones responsible for male traits, modulate the expression of the chloride transporters NKCC1 and KCC2 and, in the process, change susceptibility to anesthesia-induced neurotoxicity? Investigators inject female neonatal rats with exogenous testosterone (ET) or vehicle followed by exposure to isoflurane (ISO) or sham. Findings show that ET exposure modulates anesthetic neurotoxicity and alters protein levels of NKCC1 and KCC2. In turn, increasing and decreasing protein levels cause behavioral changes that correspond with ISO-induced cognitive deficits.

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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. Luofang Peng, Xian Liu, Yong Yang, Qulian Guo, Tao Zhong. June 2021

Using neonatal mice, investigators study the neuropsychiatric effects of exposures to isoflurane (ISO) and chronic variable stress (CVS). Testing of mice in adulthood shows repeated ISO exposures facilitate a CVS-induced anxiety-like behavioral phenotype. The ISO-induced increase in histone deacetylase 2 (HDAC2, a protein-coding gene) expression associates with repression of brain-derived neurotropic factor (BDNF) expression. Early anesthesia exposure induces chronic stress-induced neuropsychiatric outcomes. HDAC2-related epigenetic dysregulation of BDNF gene expression plays a role in this mechanism.

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Repeated Neonatal Isoflurane Exposure is Associated with Higher Susceptibility to Chronic Variable Stress-induced Behavioural and Neuro-inflammatory Alterations. Luofang Peng et al. June 2021

Researchers explore the neuropsychiatric effects of early and repeated exposures to isoflurane (ISO) in neonatal mice. Testing of mice in adulthood shows that repeated ISO exposures 1) enhance susceptibility to chronic variable stress-induced anxiety-like behaviors, 2) alter neuronal activity in the basolateral amygdaloid nuclei and hippocampal dentate gyrus regions, and 3) facilitate stress-induced neuroinflammation in these same brain regions.

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Neonatal administration of a subanaesthetic dose of JM-1232(-) in mice results in no behavioural deficits in adulthood. Koji Iwanaga et al. June 2021

Using neonatal mice, the authors explore the effects of JM-1232(-), (“JM”) a novel intravenous anesthetic, on the developing brain relative to propofol (PPF) and midazolam (MDZ). Findings show JM associates with slight but measurable brain cell death 6 hours after injection, but less than with PPF and MDZ. In adulthood, there are PPF and MDZ-induced impairments in social and cognitive function, but no JM-induced behavioral deficits. JM may hold promise for use in pediatric and obstetric practice.

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lncRNA Xist regulates sevoflurane-induced social and emotional impairment by modulating miR-98-5p/EDEM1 signaling axis in neonatal mice. Lili Xu et al. June 2021

Using neonatal mice and neuron cells, investigators explore the role of long non-coding RNA X-inactive specific transcript (LncRNA Xist) in sevoflurane (SEVO)-induced neurotoxicity. Findings show SEVO increases LncRNA Xist, decreases microRNA-98-5p (gene) expression levels, and impairs social and emotional performance. Suppression of LncRNA Xist 1) ameliorates SEVO-induced social/emotional impairments and 2) inhibits neuronal cell death and endoplasmic reticulum (ER) stress by targeting the microRNA-98-5p/EDEM1 (ER degradation-enhancing α-mannosidase-like protein 1) axis.

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The effect of xenon on fetal neurodevelopment following maternal sevoflurane anesthesia and laparotomy in rabbits. Devroe et al. May 2021

Using rabbits, researchers compare the neurobehavioral effects on offspring of maternal exposure to 1) sevoflurane (SEVO) alone vs. 2) SEVO + xenon vs. 3) monitoring alone (SHAM group) for laparotomy in pregnancy. Findings indicate fetal survival is significantly higher in the sham-group vs. the SEVO group. Neonates with antenatal exposure to anesthesia show significantly lower motor and sensory neurobehavioral scores along with lower neuron density, neuronal proliferation and synaptic density. Xenon, when combined with SEVO, offers no measurable neuroprotection.

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Maternal anesthesia with sevoflurane during the mid-gestation induces social interaction deficits in offspring C57BL/6 mice. Qingcai Chen et al. May 2021

Using mouse offspring, the authors study the effects of in-utero exposure to sevoflurane (SEVO) on social interaction behaviors. Testing of pups in juvenile stages reveals abnormal sociability and impaired preferences for social novelty. By early adulthood, mice show normal sociability, but a continuation of impaired preference for social novelty. While deficits in sociability are reversible, impairments in preference for social novelty can be long lasting.

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Evaluation of the Neuroprotective Effect of Pycnogenol in a Hypoxic-Ischemic Brain Injury Model in Newborn Rats. Ruya Çolak et al. May 2021

Using an experimental hypoxic-ischemic (HI) rat model with sevoflurane (SEVO), investigators explore the efficacy, and antioxidant and neuroprotective effects of pycnogenol (PYC), a product of natural chemicals from European pine tree bark. Neonatal mice test in three groups: A-with PYC 40 mg; B-with saline; and C-the SHAM. Findings show neuronal injury is statistically lower in Group A. PYC reduces cell death and neuronal injury in the brain and may protect against HI encephalopathy.

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RIPK1/RIPK3-Mediated Necroptosis is Involved in Sevoflurane-Induced Neonatal Neurotoxicity in the Rat Hippocampus. Rui Xu et al. May 2021

Using neonatal mice, investigators clarify the role/existence of necroptosis (NCT), a newly discovered pathway for neuronal cell death and cognitive impairments, in sevoflurane (SEVO)-induced neurotoxicity (SIN). Study variables include Z-VAD, a caspase-specific inhibitor; RIPK1/RIPK3, receptor interacting protein kinases; and NEC-1, a RIPK1 inhibitor. Findings show SEVO exposure enhances the binding of RIPK1 and RIPK3, significantly. RIPK1 and RIPK3 mediate NCT and NCT is involved in SIN in the hippocampal neurons. Blocking NCT can alleviate SEVO-induced cognitive impairments.

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Sevoflurane impairs m6A-mediated mRNA translation and leads to fine motor and cognitive deficits. Lei Zhang et al. April 2021

How does the mechanism of sevoflurane (SEVO)-induced neurotoxicity in the mouse brain involve YT521-B homology domain family 1 (YTHDF1), a critical reader protein for N6-methyladenosine-modified RNA (m6A)? SEVO 1) induces significant downregulation of YTHDF1 in the prefrontal cortex; 2) induces a decrease in protein synthesis in mouse cortical neurons; 3) reduces m6A methylation of synaptophysin; and 4) impairs fine motor control skills and cognition. Findings indicate that YTHDF1 rescued sevoflurane-induced protein synthesis inhibition and fine motor deficits in young mice.

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Long Noncoding RNA SPRY4-IT1 Modulates Ketamine-Induced Neurotoxicity in Human Embryonic Stem Cell-Derived Neurons through EZH2. Jingyuan Huang et al. April 2021

Investigators inject ketamine (KT) into human embryonic stem cell (hESC)-induced neurons to identify the role of S-1 (long non-coding RNA sprouty receptor tyrosine kinase signaling antagonist 4-intronic transcript 1) in KT-induced neurotoxicity. Findings show KT induces dose-dependent brain cell death, neurite degeneration, and upregulates S-1. Lentivirus mediates S-1 downregulation to protect KT neurotoxicity. Overexpression of the enhancer of zeste homolog 2 (EZH2) gene reverses the protective effects of S-1 knockdown. The role of S-1 in anesthesia-induced neurotoxicity may be in regulating the EZH2 gene.

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Ferroptosis contributes to isoflurane-induced neurotoxicity and learning and memory impairment. Pengfei Liu et al. April 2021

Using an in vivo mouse model, researchers explore the interactions between a new type of programmed cell death called ferroptosis (FT), isoflurane (ISO)-induced neurotoxicity, and learning/memory impairments. Findings show ISO 1) induces FT in a dose and time-dependent way in brain, 2) increases the activity of cytochrome C oxidase/Complex IV in the mitochondrial electron transport chain, and 3) may contribute to cysteine deprivation-induced FT. Ferrostatin-1, a FT inhibitor, can reverse ISO-induced FT. Dimethyl fumarate, a mitochondrial activator, is an effective therapeutic action against ISO-induced learning and memory impairments.

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Ketamine-induced neurotoxicity in neurodevelopment: A synopsis of main pathways based on recent in vivo experimental findings. Konstantina Kalopita et al. January-March 2021

This review describes the cellular and molecular mechanisms that mediate ketamine (KT)-induced developmental neurotoxicity based on recent in vivo experimental studies. Topics include 1) main pathways of KT-induced neurotoxicity, 2) mitochondrial dysfunction and oxidative stress under KT exposure, 3) deregulation of neurogenesis through premature neuronal differentiation, 4) other findings of interest, and 5) translational perspectives. The authors conclude that the “pathways they describe form a bigger picture in which the extent and nature of neuronal susceptibility to KT in neurodevelopment is strongly dependent on experimental conditions used.”

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Hypermethylation of EFEMP1 in the Hippocampus May Be Related to the Deficit in Spatial Memory of Rat Neonates Triggered by Repeated Administration of Propofol. Nu Zhang, Zhiyi Liao, Pinwen Wu, Hao Fang, & Guoping Cai. December 2020

What are the neurotoxic effects of repeated exposures to propofol in neonatal rat pups? Findings show multiple exposures cause 1) significant growth retardation, 2) impairments in spatial learning and memory, 3) hypermethylation of CpG sites (regions of DNA), 4) hypermethylation of the promoter regions of epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1), and 5) lower expression of EFEMP1 and tissue inhibitor of metalloproteinase 3 (TIMP-3), and enhanced expression of matrix metalloproteinase-9 (MMP-9). Taken together, these anesthesia-induced changes can impair development of the central nervous system and lead to cognitive deficits.

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Research News & Updates

Pediatric Anesthetic Neurotoxicity related items from the 2021 IARS Annual Meeting

Pediatric Anesthetic Neurotoxicity Poster Sessions

Anesthetic activation of GABA_A receptors in astrocytes trigger a persistent increase in cell-surface expression of α5GABA_A receptors in neurons via IL-1β in mice

Arsène Pinguelo, Ph.D. candidate
University of Toronto

Using cortical astrocytes and hippocampal neurons from fetal mice, investigators explore mechanisms that raise inhibitory tonic current (surface expression) linked to post-anesthetic cognitive deficits generated by the α5 subunit-containing GABA_A Receptors (α5GABA_ARs) in mouse hippocampal neurons.

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Anesthesia and Neurotoxicity Study Design, Execution, and Reporting in the Non-Human Primate: A Deep Dive

Feng Gao, MD, Investigator
Baylor College of Medicine

What is the quality of non-human primate (NHP) studies used to support the concern for anesthesia-related neurodevelopmental delays in children?  This poster session describes a systematic review of 18 manuscripts from studies in NHPs at postnatal ages 0 to 40 day with early anesthesia exposure.

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SmartTots Panel on Pediatric Anesthesia Neurotoxicity Research

Moderated by SmartTots Medical Officer, Dean Andropoulos, MD
Pre-Clinical Research: What are the priorities?  Laszlo Vutskits, MD, PhD
Challenges with Clinical Studies and Update on the T-REX Trial -Andrew Davidson, MBBS, MD, FANZCA
Clinical Anesthetic Neurotoxicity:  Is there a phenotype? – Caleb Ing, MD, MS

The 2021 SmartTots Panel, held virtually on May 15, addresses timely issues in pediatric anesthesia neurotoxicity research with three dynamic presentations.  Dr. Laszlo Vutskits discusses priorities in pre-clinical research, Dr. Andrew Davidson describes challenges in clinical studies with an update on the SmartTots-sponsored TREX clinical trial, and Dr. Caleb Ing explores the challenges of finding a clinical phenotype in anesthetic neurotoxicity.  Dr. Dean Andropoulos moderates the program with a brief, live question and answer period at the end.

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

In their review and discussion of recent data from preclinical and clinical literature on anesthetic neurotoxicity in children, the authors bring in the perspectives of preclinical researchers, neuropsychologists, and pediatric anesthesiologists. What is true about neurotoxic effects in children? What is false? The debate continues and findings from clinical literature remain controversial. Stronger translational research from preclinical scientists can help resolve the disconnect between preclinical and clinical findings and provide concrete answers.

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Anesthetic Exposure in Staged Versus Single-Stage Cleft Lip and Palate Repair: Can We Reduce Risk of Anesthesia-Induced Developmental Neurotoxicity? Davila, Holzmer, Kubiak, & Martin.  April 2021

Is single-staged (SS) cleft lip and palate repair (CLPR) better than staged (S) CLPR at reducing anesthesia exposure (AE) time? Using a retrospective review of 86 SS-CLPR and 28 S-CLPR operations, investigators find a significant decrease in AE with SS-CLPR compared to S-CLPR despite similar lengths in procedure times. There is a near two-fold increase in minutes of AE for the S group, suggesting that SS operations can eliminate some wasted time under general anesthesia and, potentially, reduce the neurotoxic risk for this vulnerable pediatric population.

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Intrapartum opioid analgesia and childhood neurodevelopmental outcomes among infants born preterm. Robbins et al. April 2021

Through secondary analysis of clinical trial data, investigators clarify the effects of maternal parenteral opioid (PO) use during labor on their pre-term offspring, when assessed up to the age of 2 years.  Findings show no significant differences in psychomotor and cognitive delays between infants born to mothers who receive POs and those who do not.  Intrapartum exposure of infants to POs does not associate with an increase in the risk of neurodevelopmental delays or worse perinatal outcomes.

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The effect of sevoflurane anesthesia for dental procedure on neurocognition in children: a prospective, equivalence, controlled trial. Pinping Zhou et al. April 2021

Does dental general anesthesia (DGA) have an adverse effect on neurocognition in children? In their prospective equivalence trial, investigators compare two groups of children <7 years having dental caries treatment: 129 subjects with sevoflurane only  v. 144 subjects with awake-local anesthesia. Testing at 6 months after treatment shows the two groups to be equivalent in IQ scores, the primary outcome measure, with no significant difference in anesthesia duration.  Within this 6-month window, prolonged DGA in children does not adversely affect neurocognition.

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Effects of general anaesthesia during pregnancy on neurocognitive development of the fetus: a systematic review and meta-analysis. Bleeser et al. April 2021

What is the scientific evidence underlying the U.S. Food and Drug Administration’s warning that exposure of pregnant women to general anesthesia may impair fetal brain development? In a systematic literature review up to April 2020, researchers include 65 preclinical studies, but are unable to identify acceptable clinical studies. Results show anesthesia in pregnancy impairs learning and memory and induces neuronal injury in all experimental models. A number of factors contribute to bias in preclinical studies and their poor translation to clinical situations, including 1) lack of similarity between rodent and human brain development, 2) sub-standard monitoring of physiological homeostasis, and 3) long duration and frequency of anesthesia exposure.

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Anesthesia and the Developing Brain: A Review of Sevoflurane-induced Neurotoxicity in Pediatric Populations. Carol Apai, Rohan Shah, Khoa Tran, & Shridevi Pandya Shah. March 2021

In their literature review of published studies between 1969 and 2020, the authors investigate the tolerability of sevoflurane (SEVO) in the pediatric population. What pharmacokinetic properties make SEVO a good option for children? What are the related mechanisms in anesthesia-induced neurotoxicity? What are the considerations for short and long procedures? Findings support concerns about SEVO’s neurotoxic effects, particularly in regard to memory loss and developmental deficits. Clinicians may need to adapt the duration and dose of SEVO, where possible, especially in longer pediatric procedures.

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Prediction of levobupivacaine concentrations in neonates and infants following neuraxial rescue blocks. Frawley, Cortinez, & Anderson. March 2021

The authors conduct a pharmacokinetic simulation to measure total concentrations of levobupivacaine (LBC), a local anesthetic, and its neurotoxic potential in neonates after regional anesthesia rescue for failed spinal anesthesia. Predictions show total bupivacaine, the more toxic form of LBC, concentrations after a repeat spinal or a caudal rescue dose of LBC 1.5 mg kg^-1, one hour after spinal LBC, at below the neurotoxic threshold.

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Changes in Plasma Glial Fibrillary Acidic Protein in Children Receiving Sevoflurane Anesthesia: A Preliminary Randomized Trial. Eun-Hee Kim et al. February 2021

A randomized control trial with 55 children at < 3 years explores the effects of sevoflurane (SEVO) only v. SEVO + dexmedetomidine (DEX) on glial fibrillary acidic protein (GFAP) concentrations, a blood biomarker for neuronal injury.  Findings show no neuronal injury based on GFAP levels after 3 hours of SEVO. The addition of DEX does increase GFAP levels at 180 minutes of infusion, but has limited neuroprotective effects.

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Epidural analgesia, intrapartum hyperthermia, and neonatal brain injury: a systematic review and meta-analysis. Morton, Kua, & Mullington. February 2021

In their systematic review and meta-analysis of 79 studies, the authors explore the link between epidural analgesia (EA), intrapartum hyperthermia (IH), and neonatal brain injury (NBI). When the mode of analgesia is randomized, EA associates with IH and IH associates with an increase in the risk of NBI.  However, it is not possible to quantify the association between epidural-induced hyperthermia and NBI—the link is not clear.

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Effects of sevoflurane general anesthesia during early pregnancy on AIM2 expression in the hippocampus and parietal cortex of Sprague-Dawley offspring rats. Yulin Zhu, Chao Lv, Jingying Liu, Shujun Shang, & Wei Jing. May 2021

How does maternal sevoflurane (SEVO) exposure in early rat pregnancy affect interferon-inducible protein AIM2 (AIM2) in the brains of offspring 30 days after birth? Investigators look for changes in structural morphology of neurons in the hippocampus and parietal cortex where, findings show, maternal SEVO promotes AIM2 expression and inflammatory response. Rat babies have poor long-term learning and memory ability with different degrees of damage in both the hippocampus and cortex. There are SEVO-induced increases in expression levels of glial fibrillary acidic protein, AIM2, protein CD 45, interleukin 1-beta, pro-caspase-1, and the caspase-1-p10 antibody.

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MicroRNA-1297 suppressed the Akt/GSK3 β signaling pathway and stimulated neural apoptosis in an in vivo sevoflurane exposure model.  Quan Wang, Jingcong Luo, Ruiqiang Sun, & Jia Liu. April 2021

“Children are an important group for sevoflurane (SEVO) application,” these investigators assert, as they study and describe the function of microRNA-1297(miR-1297) in SEVO-induced neurotoxicity. Findings in mice show that SEVO exposure upregulates expression of miR-1297. In vitro, upregulation of miR-1297 leads to neuronal brain cell death, inhibition of cell proliferation, an increase in lactate dehydrogenase activity, and suppression of the Akt/GSK3β signaling pathway. Upregulation also induces PTEN protein expression. miR-1297 stimulates SEVO-induced neurotoxicity via the Akt/GSK3β signaling pathway by regulating PTEN expression.

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Intranasal levosimendan prevents cognitive dysfunction and apoptotic response induced by repeated isoflurane exposure in newborn rats. Serdar Demirgan et al. March 2021

Using neonatal rat pups, investigators study the neuroprotective effects of pretreatment with .08 mg of intranasal levosimenden (LVS), a medicinal agent used with patients suffering from heart failure, before isoflurane (ISO).  Findings show LVS significantly prevents ISO-induced deficits in spatial learning/memory and brain cell death. Pretreatment with intranasal LVS may be a simple strategy in clinical anesthesia practice for protecting infants and children from the risk of general anesthesia and associated cognitive deficits.

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Effect of dexmedetomidine on sevoflurane-induced neurodegeneration in neonatal rats. Jeong-Rim Lee et al. March 2021

Can dexmedetomidine (DEX) be combined with sevoflurane (SEVO) in a dose-dependent strategy that reduces the dose of SEVO and mitigates neurotoxic effects? Baby rats receive SEVO 2.5% v. SEVO 1% with or without injections of DEX every few hours. Researchers conclude that a sub-anesthetic dose of SEVO combined with DEX can provide a level of anesthesia comparable to SEVO at 2.5%.  Findings also show that SEVO 2.5 % is more neurotoxic than SEVO 1%, that SEVO 1% + DEX does not reliably reduce brain cell death, and SEVO 1% does not provide complete anesthesia.

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Edaravone Alleviated Propofol-Induced Neurotoxicity in Developing Hippocampus by mBDNF/TrkB/PI3K Pathway. Yangliang Yang, Jing Yi, Mengzhi Pan, Baoji Hu, & Hongwei Duan. March 2021

Using newborn rats, their brain cells, and HT22 cells (a mouse hippocampal cell line), investigators study the neuroprotective effects of edaravone, EDV, (a therapy for amyotropic lateral sclerosis) on excessive-dose propofol (ED-PPF).  Findings show 1) EDV increases cell proliferation and decreases brain cell death after ED-PPF in neonates and HT22 cells; 2) reduces levels of proinflammatory interleukin 6 and tumor necrosis factor-α; and 3) mitigates ED-PPF neurotoxicity through the mature brain-derived neurotropic factor (mBDNF)/TrkB/phosphoinositide 3-kinase (PI3K) pathway. At the PPF test dose, there is no significant long-term effect on learning and memory in rats.

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Singular and short-term anesthesia exposure in the developing brain induces persistent neuronal changes consistent with chronic neurodegenerative disease. Kaley Hogarth, Ramesh Babu Vanama, Greg Stratmann & Jason T. Maynes. March 2021

The authors study the long-term effects of early exposure to sevoflurane (SEVO) on the neonatal rat brain vis-à-vis cortical tissue structure, mitochondria biogenesis, oxidative stress, and inflammation. They conclude that early exposure to SEVO may produce lasting cellular dysfunction by inducing an energy deficient state with persistent neuroinflammation and changes in proteostasis/toxicity.  These findings support the idea that therapeutic agents aimed to reduce energetic dysfunction at the time of surgery may represent viable options to mitigate developmental toxicity, and that markers of neuroinflammation may be useful to acutely determine anesthetic effects.

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Protective Effect of GM1 Attenuates Hippocampus and Cortex Apoptosis After Ketamine Exposure in Neonatal Rat via PI3K/AKT/GSK3β Pathway. Zhiheng Zhang et al. March 2021

How is monosialotetrahexosylganglioside (GM1), a part of the membrane in nerve cells, neuroprotective against ketamine (KT)-induced brain cell death? To answer, investigators divide neonatal rats into four groups for testing: 1) saline control, 2) KT only, 3) GM1 + saline, and 4) GM1 before continuous KT.  Findings show GM1 protects the hippocampus and cortex by reducing expression of the Bcl-2 and caspase-3 proteins; increases expression of the Bax gene; and increases expression of phosphorylated-AKT and phosphorylated-GSK3β. Inhibiting phosphorylation blocks the anti-cell death effect of GM1. GM1 reduces KT-induced brain cell death by regulating the PI3K/AKT/GSK3β signaling pathway.

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Behavioural impairments after exposure of neonatal mice to propofol are accompanied by reductions in neuronal activity in cortical circuitry. Hang Zhou, Zhongcong Xie, Ansgar Brambrink, & Guang Yang. February 2021

Researchers study neuronal circuit mechanisms underlying behavioral impairments in the adult brains of mice who receive 1 or 3 doses of propofol (PPF) in postnatal days 7-11. Findings show repeated, but not single, exposures to PPF cause cortical circuit dysfunction with long-term behavioral and motor learning impairments. PPF induces a drop in the number of pyramidal nerve cells and alters activity in motor cortex and inhibitory interneurone (nerve cells that communicate with each other) networks. Potentiation of neuronal activity during recovery from anaesthesia reduces these adverse effects of early-life anaesthesia.

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Anaesthesia, neural activity, and brain development: interneurones in the spotlight. Laszlo Vutskits. April 2021

The editor praises the study by Zhou and colleagues, on the long-term impact of early-life anesthesia exposure on developing neural networks. “This is a sophisticated animal study that puts interneurones in the spotlight,” he says. It is “an important experimental study that strengthens the growing body of evidence that exposure to general anesthesia can induce lasting changes in neuronal circuitry, extending the effects of drugs far beyond the duration of the anesthetic state…provides us with new and fascinating mechanistic insights…may guide us in the hunt for the human clinical phenotype that supports the biological plausibility of developmental anesthesia neurotoxicity.”

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Research News & Updates

Detrimental effects of general anaesthesia on young primates: are we closer to understanding the link? Jevtovic-Todorovic, Vesna. January 2021

“Early exposure (of children) to general anesthesia during critical periods of brain development is not innocuous…even a single exposure of common duration could pose a risk.” The editor reaches this conclusion while praising two current studies. Neudecker et al, in monkeys, reminds us that few neonatal procedures require 5 hours of anesthesia and multiple episodes; that alterations in social behavior in children exposed to anesthesia mimic observed impairments in non-human primates. Ing et al, in children, cites the key vulnerability as timing of exposure and whether it occurs during critical stages of brain development. Further, a single exposure to general anesthesia increases the risk of deficits in internalizing behavior and executive function.

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Predictors of Anesthetic Exposure in Pediatric MRI. Machado-Rivas et al. March 2021

In their retrospective record review, investigators explore the association of propofol (PPF) exposure with MRI scan times and other variables. Subjects include children with a single MRI brain scan vs. a multiple organ scan. Findings show a single organ scan generally requires less PPF, but scan times and PPF exposure increase when there is a higher ASA classification and/or oncologic diagnosis, more IV contrast medium administration (IV-cma), and use of the 1.5-T magnet. In multivariable analysis, greater propofol exposure was predicted by MRI scan time, multiple body parts, and IV-cma, but lower exposure is predictable with the 3-T magnet.

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Developmental exposure to general anaesthesia: missed connections? Mark G. Baxter. February 2021

The author, in his editorial, discusses problems in translating findings from preclinical to clinical research due to differences in anesthesia duration and frequency of exposure for animals and humans. Concurrently, he praises Young et al, a study in rhesus monkeys, for describing the effects of anesthesia on white matter microstructure under more clinically relevant anesthetic conditions. Investigators detect oligodendrocyte loss in infant monkeys in vivo via diffusion imaging. The neurotoxic changes that appear after longer, single exposures to general anesthesia may also occur with shorter exposures throughout development.

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Prenatal Exposure to General Anesthesia and Childhood Behavioral Deficit. Caleb Ing et al. January 2021

This clinical study evaluates the association between prenatal exposure to general anesthesia (GA) during maternal procedures in pregnancy and neuropsychological/behavioral outcome scores in offspring at age 10. Findings associate maternal exposure to GA with an increase in externalizing behavioral problems in offspring during childhood. The authors call for more research before clinicians make changes in practice due to study limitations and the detrimental effects of avoiding necessary surgery during pregnancy.

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Fundamentals and innovations in regional anaesthesia for infants and children. Heydinger, Tobias , & Veneziano. January 2021

The authors discuss progress in recent years in pediatric regional anesthesia that reduces invasive techniques, use of general anesthesia, and the risk of long-term neurotoxicity while safely extending anesthesia duration. Advances appear in peripheral nerve blocks, infant spinal anesthesia, the combination of spinal and epidural techniques, and use of continuous 2-chloroprocaine infusions. There is, however, ongoing debate over certain practices, including direct thoracic epidural or caudal placement in infants.

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The effects of early anesthesia on neurodevelopment: A systematic review. Grabowski et al. January 2021

The authors delve into 100 journal articles as they search for an association between general anesthesia (GA) and long-term neurodevelopmental deficits in infants. Findings show no conclusive evidence that a single short episode of GA has detectable neuro-developmental effects. However, longer and multiple exposures may affect developmental domains at different ages. Dexmedetomidine and certain intravenous agents can be neuroprotective when combined with regional anesthesia for select short procedures. The data do not support delaying a single short procedure under GA.

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Neurodevelopmental Outcomes after Premedication with Atropine/Propofol vs Atropine/Atracurium/Sufentanil for Neonatal Intubation: 2-Year Follow-Up of a Randomized Clinical Trial. Tauzin et al. December 2020

A multicenter double-blind randomized control trial in 173 two-year-old infants compares atropine-propofol to atropine-atracurium-sufentanil for premedication before non-emergency intubation. Does one reduce the frequency of severe hypoxemia more than the other? The primary outcome measure is a pulse oximetry value of <80% for more than 60 seconds. Secondary outcomes include short and long-term neurodevelopmental issues and changes in physiologic parameters. Findings show no significant difference between the two drug combinations in death rates and/or risk of neurodevelopmental delays.

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Dexmedetomidine and Clonidine Attenuate Sevoflurane-Induced Tau Phosphorylation and Cognitive Impairment in Young Mice via α-2 Adrenergic Receptor. Mingyang Sun et al. March 2021

Using neonatal mice and their harvested brain cells, investigators discover that dexmedetomidine (DEX) and clonidine (CL) mitigate the sevoflurane (SEVO)-induced increase in phosphorylated tau (Phos-t), reduction of post-synaptic density protein-95 (PSD-95), and cognitive impairment (CI). Yohimbine, an α-2 adrenergic receptor antagonist, reverses the neuroprotective effects of both DEX, an α-2 adrenergic receptor agonist, and CL. Findings suggest DEX and CL play their neuroprotective role via activation of the α-2 adrenergic receptor.

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Regulation of CRMP2 by Cdk5 and GSK-3β participates in sevoflurane-induced dendritic development abnormalities and cognitive dysfunction in developing rats. Zhaoxia Liao et al. February 2021

How are these brain pathways involved in sevoflurane (SEVO)-induced developmental toxicity? They are pathway A: cycline dependent kinase-5/collapsin response mediator protein 2 (Cdk5/CRMP2) and pathway B: glycogen synthase kinase-3β (GSK-3β)/ CRMP2. Findings in neonatal rats and their brain slices show SEVO 1) activates the A and B pathways, 2) reduces dendritic length and density of dendritic spines; 3) reduces drebrin expression and synaptophysin; 4) impairs memory, and 5) inhibits long term potentiation. Pretreatment with Cdk5 or GSK-3β inhibitors reduces these impairments. Both A and B pathways participate in the development of SEVO-induced dendritic abnormalities and cognitive dysfunction.

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A synthetic peptide rescues rat cortical neurons from anesthetic-induced cell death, perturbation of growth and synaptic assembly. Iqbal et al. February 2021

Can the non-toxic, short-life synthetic peptide-P110 help preserve mitochondrial networks by protecting cortical neurons against inhalational and intravenous anesthetic neurotoxicity? Investigators find answers while observing the impact of desflurane, propofol, and ketamine on neonatal rat cortical neuronal viability, neurite outgrowth, and synaptic assembly. Results show that inhibition of mitochondrial fission-1 protein – mediated mitochondrial fission reverses anesthesia-induced damage in a drug-specific way.

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General anaesthesia during infancy reduces white matter micro-organisation in developing rhesus monkeys. Jeffrey T. Young, et al. February 2021

Using MRI scans on developing monkeys, the authors examine the cumulative effects of exposure to ketamine (KT), Telazol® and inhaled isoflurane (ISO) on early brain development. Diffusion MRI scans show significant, widespread reductions in fractional anisotropy (up to 40% in some brain regions) with increases in axial, mean, and radical diffusivity across the brain due to repeated anesthesia exposure. These effects are dose dependent and remain after accounting for age and sex at time of exposure. Multiple exposures to commonly used anesthetics associate with marked changes in white matter microstructure; it is unknown if the maturing brain can recover from these changes.

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The Role of the lncRNA-LRCF in Propofol-Induced Oligodendrocyte Damage in Neonatal Mouse. Zhen Zeng et al. January 2021

What is the role of LRCF, a cognition-related long noncoding RNA and regulator of gene expression, in propofol (PPF)-induced damage to the oligodendrocytes (OLGs)? Findings in neonatal mice associate high levels of LRCF with more injury to PPF-exposed OLGs. Up-regulation of the hypoxia-inducible transcription factor-1α (HIF-1α) in PPF-treated OLGs promotes and prevents brain cell death through two critical signaling pathways. The effect of HIF-1α on capase-3 expression depends on LRCF expression. High LRCF expression may be a marker for a high risk of PPF-induced OLG injury in animals and children.

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Repeated exposure to propofol in the neonatal period impairs hippocampal synaptic plasticity and the recognition function of rats in adulthood. Jie Wan et al. January 2021

How does early propofol (PPF) exposure alter synaptic plasticity and neurocognitive function? Investigators expose PN Day 7 rats to propofol followed by tests in neonatal to adult stages. Finding show PPF exposure 1) significantly inhibits expression of brain-derived neurotropic factor, tropomyosin-receptor kinase B, and postsynaptic density protein-95; 2) reduces the number of dendritic branches, total dendritic length, and dendritic spine density of neurons; 3) significantly diminishes long-term potentiation in hippocampus; 4) prolongs escape latency; and 5) decreases time in target quadrants.

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Dexmedetomidine attenuates sevoflurane‑induced neurocognitive impairment through α2‑adrenoceptors. Yufeng Zhang et al. January 2021

Using neonatal male mice, investigators study the neuroprotective effects of dexmedetomidine (DEX) as a pretreatment to sevoflurane (SEVO). Findings show DEX counters SEVO-induced neurotoxicity by 1) decreasing the expression of activated caspase-3; 2) decreasing levels of tumor necrosis factor‑α, interleukin‑1β, and interleukin‑6; 3) increasing superoxide dismutase activity; and 4) reversing impairments in learning and memory. DEX protects neurons in the brain from cell death, inflammation, oxidative stress, and cognitive-related deficits.

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Ketamine inhibits neuronal differentiation by regulating brain-derived neurotrophic factor (BDNF) signaling. Sheng Liu et al. January 2021

Using mouse embryonic stem cells (mESCs), investigators study the effect of ketamine (KT) on neuronal differentiation (ND). Findings show KT significantly inhibits ND and, in the process, may interfere with brain-derived-neurotropic factor (BDNF) expression. When downregulated by shRNA, BDNF also inhibits ND. Overexpression of BDNF, as a rescue effort, mitigates KT-induced inhibition of ND.

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Expression Signature of lncRNAs and mRNAs in Sevoflurane-Induced Mouse Brain Injury: Implication of Involvement of Wide Molecular Networks and Pathways. Congshan Jiang, Thiago Arzua, Yasheng Yan , & Xiaowen Bai. January 2021

Using neonatal mice, investigators profile thousands of long noncoding RNAs (lncRNAs) and messenger RNAs (mRNAs) to discover the role they play in sevoflurane (SEVO)-induced neurotoxicity. Findings show SEVO exposure induces significant neurotoxicity and neuronal death, along with abnormal expression of 148 mRNAs and 301 lncRNAs. By PN Day 60, mice display impaired memory. Dysregulated mRNAs and lncRNAs may play a role in 34 neurodegenerative signaling pathways; they may form a wide molecular network that contributes to various functional neurological disease pathways.

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Sevoflurane Exposure Induces Neuronal Cell Parthanatos Initiated by DNA Damage in the Developing Brain via an Increase of Intracellular Reactive Oxygen Species. Meihua Piao et al. December 2020

What leads up to Parthanatos, a type of cell death, after sevoflurane-(SEVO)-induced damage to DNA? Investigators explore this question in neuronal cells and neonatal mice exposed to SEVO. Findings show SEVO induces neuronal cell death with Poly ADP-ribose polymerase1 (PARP-1) hyperactivation, cytoplasmic polymerized ADP-ribose (PAR) accumulation, mitochondrial depolarization, and apoptosis-inducing factor (AIF) nuclear translocation in neuronal cells and the hippocampus. SEVO exposure damages DNA and stimulates the overproduction of intracellular reactive oxygen species (ROS) followed by the start of neuronal cell Parthanatos.

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Resveratrol ameliorates sevoflurane-induced cognitive impairment by activating the SIRT1/NF-κB pathway in neonatal mice. Xiao le Tang et al. December 2020

Can pretreatment with resveratrol (RVT), a natural antioxidant in grapes and seeds, reduce sevoflurane (SEVO)-induced cognitive impairment in neonatal mice? Findings show SEVO exposure suppresses Sirtuin1 gene expression and activates microglia cells, which normally fight infection and inflammation, in the brain. Pretreatment with RVT stops these neurotoxic changes and provides neuroprotection by reversing the SEVO-induced imbalance in microglia ratios—as evidenced by increasing and decreasing mRNA levels in clusters of differentiation 206 and 86, respectively, and suppression of cytokine signaling 3.

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Sevoflurane-induced neuronal apoptosis in neonatal mice is prevented with intranasal administration of insulin. Hengchang Li et al. December 2020

Using neonatal mice, researchers explore the neuroprotective effects of intranasal insulin when administered prior to a single, 6-hour exposure to sevoflurane (SEVO). Findings show that a single dose of SEVO induces over-activation of the neuron-cell-death process (apoptosis). Pretreatment with intranasal insulin protects against these toxic, anesthesia-induced changes in the brain.

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Yes‑associated protein protects and rescues SH‑SY5Y cells from ketamine‑induced apoptosis. Yanni Chen et al. September 2020

Using an in vitro model, the authors explore the role of yes-associated protein (YAP) in ketamine (KT)-induced brain cell death (apoptosis). Findings show YAP, which normally regulates brain signaling, controls KT-induced apoptosis in a dose-dependent way. When YAP is overexpressed, KT-treated SH-SY5Y cells (a human cell line) are more active and viable while expression levels in cell-death markers diminish. In contrast, KT-induced markers for apoptosis strengthen after YAP knockdown. YAP plays an important role in KT-induced neurotoxicity.

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The Effects of Hesperidin on Neuronal Apoptosis and Cognitive Impairment in the Sevoflurane Anesthetized Rat are Mediated Through the PI3/Akt/PTEN and Nuclear Factor-κB (NF-κB) Signaling Pathways. Haijin Huang et al. April 2020

Can hesperidin (HPD), a bioflavonoid in citrus fruits, reduce sevoflurane (SEVO)-induced neurotoxicity in neonatal rats? To answer, the authors explore the role of HPD on cerebral morphology and cognitive behavior in subjects exposed to different doses of SEVO with and without HPD. Findings show HPD is neuroprotective. It reduces SEVO-induced neuronal degeneration, hippocampal inflammation, and oxidative stress while improving memory and cognition by modulating the PI3/Akt/PTEN and NF-kappa B signaling pathways.

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Look for us during 2020 at the following events:

• SPA/AAP Pediatric Anesthesiology 2021, February 25-28. The meeting and exhibit hall will occur virtually.

Research News & Updates

Emerging Role of Long Noncoding RNAs in Perioperative Neurocognitive Disorders and Anesthetic-Induced Developmental Neurotoxicity. Pant, DiStefano, Logan, Zeljko, & Bosnjak. December 2020

In their review, the authors explore advances in perioperative neurocognitive disorders (PDN) and anesthesia-induced developmental neurotoxicity (AIDN) research. Investigators also examine the role of long noncoding RNAs (lncRNAs) – biologically active transcripts, that find expression in the brain under normal and pathological conditions. Evidence shows that changes in lncRNAs can be neurotoxic with aberrant expression in PDN and AIDN. LncRNAs may have clinical potential as diagnostic and therapeutic targets for the prevention of neurocognitive disorders.

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Hypotension and Adverse Neurodevelopmental Outcomes among Children with Multiple Exposures to General Anesthesia: Sub-analysis of the Mayo Anesthesia Safety in Kids (MASK) Study. Gleich et al. December 2020

Is there a greater incidence of learning disabilities (LD) and attention deficit hyperactivity disorder (ADHD) in children < 3 years with multiple exposures to general anesthesia and intraoperative hypotension? Using cohorts from retrospective (n=116) and prospective (n=206) MASK studies, investigators calculate z scores for lowest consecutive systolic blood pressure (BP) and intraoperative hypotension. Findings show no overall association of the lowest z-scores or hypotension with LD or ADHD in the retrospective cohort and no overall association of the lowest scores z scores or hypotension with factor scores or cluster membership in the prospective cohort.

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Prenatal sevoflurane exposure: Effects of iron metabolic dysfunction on offspring cognition and potential mechanism. Yong Zuo, Yanzhong Chang, Anand Thirupathi, Changhao Zhou, & Zhenhua Shi. December 2020

In their review, the authors explore the association of maternal exposure to sevoflurane (SEVO) with cognitive and neurogenic problems in the fetus and offspring. Findings in mice show SEVO exposure during pregnancy induces cognitive impairment in offspring due to iron deficiency and inhibition of brain and spinal cord formation/development. Pregnant women receive SEVO for many non-obstetric reasons, but the exact mechanisms of SEVO-induced neurotoxicity in human offspring are unclear. The answer is complex, may involve multiple developmental processes, and current studies do not clarify the direct target of SEVO injury to nerve cells.

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Analysis of 1478 Cases of Hypospadias Repair: The Incidence of Requiring Repeated Anesthetic Exposure as Well as Exploration of the Involvement of Trainees on Case Duration. Adler, et al. November 2020

This study explores anesthesia exposure (AE), duration, and use of surgical trainees for hypospadias (HP) repair in children <3 years. Investigators analyze 1326/1478 HP-related procedures including 1105/1241 HP repairs (89%) with < 3 hours of AE. Findings show no difference in anesthesia time in cases performed solely by the attending vs. with trainees, but surgery time is longer with trainees (85.5 vs. 98.3 minutes). Surgeries performed by the attending alone have a lower total AE in minimal alveolar concentration hours. A majority of HP repairs in children <3 years involve a single AE. Case complexity separate from use of trainees may increase AE, but is not likely to be clinically significant.

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Hot Topics in Safety for Pediatric Anesthesia. Lorinc, Walters, Lovejoy, Crockett, & Reddy. November 2020

With a section on neurotoxicity, this literature review describes progress in the field of pediatric anesthesia vis-à-vis patient safety and efforts to reduce anesthesia risk. Discussion includes the contribution of SmartTots, the 2016 FDA safety warning, and conclusions of the GAS, PANDA, and MASK clinical studies. Based on current findings, the authors present recommendations for pediatric anesthesia practice: do not delay surgery for life-threatening pediatric conditions and, in terms of anesthetic agents, make no specific changes in anesthesia practice at this time.

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Prospectively assessed neurodevelopmental outcomes in studies of anaesthetic neurotoxicity in children: a systematic review and meta-analysis. Ing et al. October 2020

Combining results of studies utilizing prospectively collected outcomes, the authors compare neurodevelopmental outcomes in children with a single exposure vs. no exposure to general anesthesia. Findings show children with a single exposure with higher mean (worse) score differences on the parent-reported Child Behavior Checklist and Behavior Rating Inventory of Executive Function; subjects have a 47% greater risk for internalizing behavioral deficits and a 68% greater risk for impaired executive function. There are no significant differences in intelligence scores between subject groups.

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Attention deficit hyperactivity disorder and educational level in adolescent and adult individuals after anesthesia and abdominal surgery during infancy. Håkanson, Fredriksson, & Lilja. October 2020

Using 485 subjects and 4835 controls, the authors explore the association of income and education with attention deficit hyperactivity disorder (ADHD) and early exposure to anesthesia for abdominal surgery in children. The median gestational age at exposure is 38 weeks, median age at surgery is 7 days, median operating time is 80 minutes, and median age at follow up is 28 years. Findings show exposure to anesthesia and abdominal surgery during infancy has no association with cognitive dysfunction when comparing education levels, disposable income, and the diagnosis of ADHD in adolescence/early adulthood.

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Neonatal exposure to ketamine disrupts developmental synapse unsilencing and predisposes adult mice for stressor-evoked anxiety. Xiaoyun Zhang, Yue Kong, Guiqin He, & Zikai Zhou. December 2020

How does early exposure to ketamine (KT) affect neuron development and adult behavior? Investigators expose neonatal rats to KT and apply mild stressors one day before behavioral tests in adulthood. Findings show KT significantly disrupts synapse unsilencing (the normal inhibition of synapse transmission) and impairs expression of unsilencing-mediated long-term potentiation. The AMPAkine drug, CX546, reverses this damage and prevents stressor-evoked anxiety in adulthood.

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The differential effects of isoflurane and sevoflurane on neonatal mice. Shuai Zhao et al. November 2020

What are the comparative effects of isoflurane (ISO) and sevoflurane (SEVO) on the developing brain? Investigators expose neonatal mice to equivalent doses of ISO and SEVO and test/observe for brain cell death, inflammation, synaptic function, and memory. Findings show both agents induce acute neuronal cell death. Unlike SEVO, ISO induces significant levels of neuro-inflammation along with changes in protein expression levels affecting synaptic transmission and memory.

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Infant isoflurane exposure affects social behaviours, but does not impair specific cognitive domains in juvenile non-human primates. Neudecker et al. November 2020

Using monkeys, investigators explore the effects of neonatal exposure to isoflurane (ISO) on cognition and behavior, when measured in adolescence. Subject group 1X receives ISO once; subject group 3X receives ISO 3 times; and a third group is the control. These exposures are followed by cognitive/ behavioral assessments and provoked response testing in the first 2 years of life. Findings reveal no difference in cognitive scores between groups. However, Group 1X exhibits increased anxiety and more inhibition around novel objects. Group 3X shows less close social behavior.

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Effects of early postnatal sevoflurane exposure on oligodendrocyte maturation and myelination in cerebral white matter of the rat. Ziyi Wu, Hang Xue, Qiushi Gao, & Ping Zhao. November 2020

What are the effects of 4.9% vs. 3.3% sevoflurane (SEVO) exposure on neuron development, behavior, and cognition in PN Day 2 rats? Findings show the higher, not lower, dose induces 1) oligodendrocyte (Oligo) proliferation with a widespread increase in abnormal astrocytes 12 hours post exposure, 2) disruptions in Oligo maturation at PN Day 14, 3) hypomyelination and axonal damage at PN Day 28, and 4) less exploratory behavior, more anxiety, and impaired learning and memory. These results underscore the need for careful dosing.

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Interval-dependent neurotoxicity after multiple ketamine injections in late post-natal mice. Yulim Lee and Ann Misun Youn et al. November 2020

The authors compare the neurotoxic effects of short (2-hour) vs. long (24-hour) intervals between three ketamine (KT) injections in PN Day 17 mice. Findings for short intervals show enhanced excitatory synaptic transmission, as evidenced by an increase in the frequency of miniature excitatory post-synaptic currents. With long intervals, there is no similar increase. Instead, there is a decrease in the amplitude of miniature inhibitory postsynaptic currents plus greater anxiety behavior in open field tests. The length of the interval between exposures to anesthesia can be a factor in anesthesia-induced synaptic and behavioral dysfunction.

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General anesthesia activates the mitochondrial unfolded protein response and induces age-dependent, long-lasting changes in mitochondrial function in the developing brain. Yulim Lee et al. November 2020

How does a single, early exposure to sevoflurane (SEVO) affect mitochondria (MT) and the MT unfolded protein response (UPRmt), which normally helps maintain protein-unfolding stability and function? Neonatal mice receive SEVO followed by an injection of rotenone, an MT inhibitor. Six hours after SEVO exposure there is an increase in the expression UPRmt. Rotenone blocks the SEVO-induced increase in MT function and prevents changes in excitatory synaptic transmission at PN Day 17, but not at PN Day 7.

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Neuroprotection of the Developing Brain by Dexmedetomidine Is Mediated by Attenuating Single Propofol-induced Hippocampal Apoptosis and Synaptic Plasticity Deficits. Wenchong Sun, Jian Wang, Dasheng Cai, & Ling Pei. October 2020

How does pretreatment with dexmedetomidine (DEX) followed by one exposure to propofol (PPF) affect brain cell death and gene expression in neonatal mice? Findings show DEX saves hippocampal neurocytes from cell death, enhances synaptic plasticity, and reverses aberrant expression levels of the BCL2L1 gene, matrix metallopeptidase 9 (inflammation marker), and cleaved caspase 3 (a mediator of cell death). At P30 and P60, mice show no impairments in long-term learning and memory.

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Androgenic Modulation of the Chloride Transporter NKCC1 Contributes to Age-dependent Isoflurane Neurotoxicity in Male Rats. Chinn et al. October 2020

Researchers explore the role of androgen receptors/chloride transporters, NKCC1 and KCC2, in isoflurane (ISO) – induced neurotoxicity in neonatal male rats. Subjects receive pretreatment with 1) flutamide (FL), an androgen receptor antagonist + ISO, or 2) ISO alone (control), or 3) ISO with a NKCC1 blocker, or 4) ISO alone, two weeks later, when rats are slightly older. On tests in adulthood, the FL + ISO group performs well on spatial and recognition memory tasks, but the ISO control group does not. FL changes expression patterns of NKCC1 and KCC2. Disrupting NKCC1 and delaying ISO exposure stops ISO-induced neurotoxicity and protects spatial memory.

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Behavior and Regional Cortical BOLD Signal Fluctuations Are Altered in Adult Rabbits After Neonatal Volatile Anesthetic Exposure. Drobyshevsky et al. October 2020

Using MRI connectivity and eyeblink classical conditioning (ECC), investigators study functional changes in the brain that associate with anesthesia-induced long-term cognitive and behavioral deficits. Neonatal rabbits receive isoflurane (ISO) or no ISO (control) and testing in adolescence. For ISO-exposed rabbits, 1) the trace ECC learning rate is significantly lower and 2) there are no changes in long-range connectivity, Fractional Amplitude of Low-Frequency Fluctuation (f-ALFF), or regional homogeneity between brain regions. ALFF is also significantly higher in the primary and secondary somato-sensory cortices, where disruption of neuronal circuits may find its start.

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Sevoflurane Post-Conditioning Ameliorates Neuronal Deficits and Axon Demyelination After Neonatal Hypoxic Ischemic Brain Injury: Role of Microglia/Macrophage. Hang Xue et al. September 2020

In neonatal rats, what are the effects and mechanisms of sevoflurane (SEVO) post-conditioning (SPC) on microglia/macrophage polarization after hypoxic-ischemic brain injury (HIPI)? Findings show SPC significantly reduces the HIPI-induced increase in neuronal cell death, improves cognitive function, slows the hypoxic-ischemic-induced decrease in Nissl-positive cells within neurons and myelin basic protein expression. After HIBI, SPC stops microglia polarization and axon demyelination by regulating microglia autophagy and expression of the brain enzyme cathepsin B. These actions provide long-term cognitive, learning, and memory protection.

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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. Yunan Lin et al. September 2020

Does decitabine (DC), a DNA methyltransferase (DNMT) inhibitor, reduce anesthesia-induced neurotoxicity? Investigators expose PN Day 5 rats to pretreatment with DC + sevoflurane (SEVO) vs. vehicle + SEVO (control). At PN Days 19-21, the control group has 1) seizures, 2) stress-related secretions, 3) altered dendrite development, and 4) aberrant changes in gene expression and DNMT regulation in the cortex and thalamus, and (at and beyond PN Day 120) the hippocampus. Pretreatment with DC diminishes these effects.

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Tau Contributes to Sevoflurane-induced Neurocognitive Impairment in Neonatal Mice. Yang Yu et al. September 2020

Why does sevoflurane (SEVO) exposure induce tau phosphorylation and cognitive impairment in neonatal but not adult mice? The authors expose PN Day 6 and PN Day 60 mice to SEVO followed by biochemical and cognitive testing. Findings show neonates have higher amounts of Tau—a brain protein, Tau oligomer–small Tau molecules, and the Nuak1 gene, but less adenosine triphosphate (ATP) and lower mitochondrial metabolism in the cerebral cortex. Therefore, for neonates, and not adults, SEVO contributes to developmental stage-dependent cognitive dysfunction.

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Increasing the interval between repeated anesthetic exposures reduces long-lasting synaptic changes in late post-natal mice. Xianshu Ju et al. July 2020

With multiple exposures to sevoflurane (SEVO), how does the length of time (interval) between exposures affect neurotoxicity? The authors expose PN Day 16-17 mice to SEVO three times in short intervals (2 hours) vs. long intervals (24 hours), then test. Short intervals induce 1) a miniature inhibitory post-synaptic current (mIPSC) frequency after the last exposure (in females) and 2) long-term behavioral deficits for both sexes, consistent with changes in mIPSC, but more robust in females. Long intervals have no long-lasting neurotoxic effects.

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Upcoming sessions at ASA’s Anesthesiology 2020 that relate to pediatric anesthetic neurotoxicity:

RCL – Regional Anesthesia in Children
Speaker: Santhanam Suresh, M.D., M.B.A., FASA
October 2, 2020, 11:00am – 12:00pm

Anesthesia Exposure And Neurocognitive Outcomes In Infants With Congenital Heart Disease
Speakers: Isabel Randazzo, B.A., et al.
October 3, 2020, 10:00am – 11:00am

Clinical Trials in Pediatric Anesthesia: Specific Challenges and Solutions
Speaker: Mary Ellen McCann, M.D., M.P.H.
October 5, 2020, 9:00am – 11:00am

A Structure for Collaborative Clinical Trials: The International Perspective
Speaker: Andrew J. Davidson, M.D.
October 5, 2020, 9:00am – 11:00am

To learn more and to register, go to: https://www.asahq.org/annualmeeting
Note: The ASA is generously offering 12 months of access to their annual meeting recordings.

Research News & Updates

SmartTots Partner Study ~ Regions of the basal ganglia and primary olfactory system are most sensitive to neurodegeneration after extended sevoflurane anesthesia in the perinatal rat. Burks, Bowyer, Walters, & Talpos, FDA National Center for Toxicological Research. July-August 2020.

Are there markers for neurodegeneration in the forebrain and basal ganglia of neonatal rats following sevoflurane (SEVO) exposure? Findings show a prolonged period of neurodegeneration in certain brain regions and a distinct second wave of neurodegeneration that is region specific. There is minimal to no neurodegeneration in select areas of the midbrain, most of the hypothalamus, and frontal cortex. By 24 hours post exposure, neurodegeneration doubles in some areas of grey matter, the hippocampus, basal ganglia, hypothalamus, and amygdala.

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Research progress and treatment strategies for anesthetic neurotoxicity. Fan Yang, Hai Zhao, Kaiyuan Zhang, Xiuying Wu, & Hongtao Liu. August 2020.

Investigators discuss progress in finding the molecular mechanisms for pediatric anesthesia neurotoxicity (PAN) and therapeutic interventions. Animal studies show that early exposure to general anesthesia causes nerve damage, changes in synaptic plasticity, induces brain cell death, and affects long-term learning and memory. Yet, the association between general anesthesia and long-term cognitive deficits in children remains controversial. Drugs with anti-oxidant qualities, like dexmedetomidine, can reduce anesthesia-induced neurotoxicity.

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Is Anesthesia Bad for the Brain? Current Knowledge on the Impact of Anesthetics on the Developing Brain. Soriano & McCann. July 2020.

The authors discuss current findings in pediatric anesthesia neurotoxicity research. Retrospective studies in children with early exposure to anesthesia show difficulties in school later on. However, these findings may be due to multiple factors, not all of which are anesthesia related. For best surgical results, the pediatric surgical patient should stay at a normal body temperature, at a normal blood sugar level, and in a neutral position. Clinicians should control for too much or too little carbon dioxide in the child’s blood; too much or too little oxygen in their tissues and organs; and avoid unnecessary procedures. Anesthesiologists, surgeons, pediatricians, and neonatologists are encouraged to foster better outcomes by working together.

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Association between surgical procedures under general anesthesia in infancy and developmental outcomes at 1 year: the Japan Environment and Children’s Study. Kobayashi et al. July 2020.

A Japanese birth cohort study describes the risk of developmental delays (DD) in 64,141 infants at age 1 year with one, two, and three or more early procedures under general anesthesia. Findings show the percent of DD significantly increases with the number of surgical procedures. This is particularly true with three or more surgeries where the adjusted odds ratios in the five domains of gross motor, communications, fine motor, personal social, and problem solving are 4.69, 3.32, 2.99, 2.55, and 2.47, respectively.

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Anesthetic Drugs in Children and Pregnant Women – Implications of the Recent FDA Warning. Amit Lehavi & Aeyal Raz. June 2020

Anesthesiologists from Israel describe the rationale of the European Society of Anesthesiology and Israeli Society of Anesthesiologists for not adopting the 2016 FDA policy recommendations about general anesthesia in young children. Israelis will not change their informed consent forms and consent processes at this time, citing promising findings on single exposures of limited duration in young children. Such a change would delay necessary procedures based on inconclusive evidence on human risk along with selection bias and contradicting results in retrospective studies.

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General anesthesia affecting on developing brain: evidence from animal to clinical research. Xinyue Liu, Jing Ji, & Guo-Qing Zhao. June 2020

Pre-clinical evidence associates general anesthesia with neurotoxicity and long-term cognitive deficits in the developing brain–but these findings do not translate to human children and clinical practice. Recent clinical studies show no association between general anesthesia and long-term neurodevelopmental deficits for a single exposure to anesthesia—but the association between general anesthetics and neurotoxicity in human children is inconclusive. Investigators call for robust clinical studies with longer duration of anesthesia exposure, more sensitive outcome measures, and stricter controls on confounding factors.

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Sevoflurane Induces Hippocampal Neuronal Apoptosis by Altering the Level of Neuropeptide Y in Neonatal Rats. Wenbin Kang et al. September 2020

What effect does neuropeptide Y (NPY), an abundant brain molecule that supports communication between neurons, have on anesthesia-induced neurotoxicity? To answer, investigators study NPY in the neonatal rat brain and in cultured brain cells following sevoflurane (SEVO) exposure. Findings show SEVO causes a significant reduction in NPY expression, but external NPY supplementation reverses SEVO’s deadly effect both in vivo and in vitro.

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Regions of the basal ganglia and primary olfactory system are most sensitive to neurodegeneration after extended sevoflurane anesthesia in the perinatal rat. Burks, Bowyer, Walters, & Talpos. July-August 2020

Are there markers for neurodegeneration in the forebrain and basal ganglia of neonatal rats following sevoflurane (SEVO) exposure? Findings show a prolonged period of neurodegeneration in certain brain regions and a distinct second wave of neurodegeneration that is region specific. There is minimal to no neurodegeneration in select areas of the midbrain, most of the hypothalamus, and frontal cortex. By 24 hours post exposure, neurodegeneration doubles in some areas of grey matter, the hippocampus, basal ganglia, hypothalamus, and amygdala.

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Anesthesia plus surgery in neonatal period impairs preference for social novelty in mice at the juvenile age. Xin Jin et al. July 2020

How does exposure to sevoflurane (SEVO) alone v. exposure to sevoflurane + surgery affect sociability in neonatal mice? Investigators find SEVO alone does not disrupt social interaction in mice. SEVO + surgery impairs preference for social novelty, but not sociability. Anesthesia + surgery associate with a decrease in levels of hippocampal and cortical OXTR, the oxytocin brain receptor affecting social and emotional behaviors; and a decrease in levels of hippocampal NMDAR1, a brain receptor that supports neuronal cell development and plasticity.

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Maternal Treadmill Exercise Reduces the Neurotoxicity of Prenatal Sevoflurane Exposure in Rats via Activation of p300 Histone Acetyltransferase. Ziyi Wu, Yinong Zhang, Xu Yang, & Ping Zhao. July 2020

Does maternal exercise–running on a treadmill–during pregnancy, after sevoflurane (SEVO) exposure, improve brain plasticity and function in rat pups? Findings show maternal exercise helps offspring by 1) reducing the SEVO-induced decrease in P300 histone acetyltransferase expression and inhibition of brain-derived-neurotropic-factor (BDNF) signaling; 2) improving performance on water maze tasks; and 3) reducing SEVO-induced cognitive dysfunction. The P300 inhibitor can reverse these neuroprotective effects.

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Sevoflurane leads to learning and memory dysfunction via breaking the balance of tPA/PAI-1. Yunxia Dong et al. July 2020

What role do elements of the brain’s blood flow-support system, including tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1), play in sevoflurane (SEVO)-induced cognitive dysfunction? The authors expose developing rats to SEVO followed by testing at 28 days. Findings show SEVO downregulates expression of synaptic-related proteins; decreases dendritic spine density; creates an imbalance in tPA/PAI-1 expression; inhibits maturity in brain-derived-neurotropic-factor (BDNF); and activates tropomyosin-related kinase B (TrkB).

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LncRNA Rik-203 Contributes to Sevoflurane Induced Neurotoxicity? Lei Zhang, Zhenyu Xue, Jia Yan, & Hong Jiang. July 2020

How does sevoflurane (SEVO) affect neural differentiation in embryonic stem cells and mice? SEVO decreases the amount of long non-coding RNA Riken-203 (LncRNA Rik-203) in the mouse brain which then represses neural differentiation. SEVO also downregulates brain derived neurotrophic factor (BDNF), a direct target of miR-466l-3p (4661). Investigators suggest that SEVO related LncRNA Rik-203 facilitate neural differentiation by inhibiting 4661’s ability to reduce BDNF levels.

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Neonatal Isoflurane Anesthesia or Disruption of Postsynaptic Density-95 Protein Interactions Change Dendritic Spine Densities and Cognitive Function in Juvenile Mice. Schaefer et al. July 2020.

How does early postnatal disruption of the postsynaptic density-95 PDZ2 domain affect dendritic spine formation and cognitive function? Investigators expose PN Day 7 mice to isoflurane or inject them with active PSD-95 PDZ2 peptide, then observe at 6-8 weeks. Findings show either exposure causes 1) a long-term decrease in mushroom spikes; 2) deficits in object recognition; and 3) deficits in fear learning and memory. The addition of a nitric oxide donor mitigates these effects, suggesting the neuronal nitric oxide synthase pathway mediates neurotoxic cellular changes associated with cognitive impairment.

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An appropriate level of autophagy reduces emulsified isoflurane-induced apoptosis in fetal neural stem cells. Ze-Yong Yang, Lei Zhou, Qiong Meng, Hong Shi, & Yuan-Hai Li. June 2020

A study in rat fetal neural stems cells explores the role of autophagy, the body’s cell cleaning and repair system, in isoflurane (ISO)-induced neurotoxicity. Investigators pretreat stem cells with autophagy inhibitors and transfect with small interfering RNA against ATG5. Findings show ISO induces toxicity and autophagy while pretreatment increases cell death. Transfection decreases Atg5 expression and inhibits cell proliferation. Results confirm that the Atg5 protein pathway can support autophagy and inhibit ISO-induced neurotoxicity.

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LncRNA LINC00641 Sponges miR-497-5p to Ameliorate Neural Injury Induced by Anesthesia via Up-Regulating BDNF. Qingxia Chen et al. June 2020

What roles do long non-coding RNA LINC00641 (641), miR-497-5p (497), and brain-derived-neurotropic-factor (BDNF) play in ketamine (KT)-induced neural injury? Investigators use an in vivo model with rat cells of embryonic origin and PN Day 7 rats. Findings show the 641/497/BDNF axis as a critical signaling pathway in modulating KT-induced neural injury. KT induces cell death; down regulates 641 and BDNF, and upregulates 497. 641 binds to and reduces expression of 497 while indirectly increasing BDNF expression, which is neuroprotective.

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Neonatal sevoflurane exposure induces impulsive behavioral deficit through disrupting excitatory neurons in the medial prefrontal cortex in mice.
Linghua Xie et al. June 2020

Researchers explore the effects of multiple early exposures to sevoflurane (SEVO) on attention deficit hyperactivity disorder (ADHD)-like impulsivity in adult mice. Findings show an increase in the number of jumps and shorter jumping latency after multiple SEVO exposures. Excitatory neurons in the prefrontal cortex (mPFC) are highly activated, and these relate to impulsive behavior. Inhibitory viruses, injected to reduce impulsivity, produce a partial rescue of overactive mPFC excitatory neurons.

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Autophagic Network Analysis of the Dual Effect of Sevoflurane on Neurons Associated with GABARAPL1 and 2. Guolin Lu et al. June 2020

How does sevoflurane (SEVO) induce the dual effect of protecting excitatory neurons and inducing neurotoxicity early or late in life? The authors discover SEVO has 23 essential direct protein targets (DPTs) that interact with 77 proteins, found in the STRING database of protein-protein interactions. Two autophagy-associated proteins, GABARAPL1 & 2, are significantly expressed in the brain and enriched in GABAergic synapses. This network of SEVO-DPTs-GABARAPL1 & 2 relates to SEVO’s dual effect on neurons.

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Upregulation of miR-215 attenuates propofol-induced apoptosis and oxidative stress in developing neurons by targeting LATS2. Fang Tang et al. May 2020

How does the miRNA 215 (mi215) gene regulate propofol (PPF)-mediated neurotoxicity? A study in neonatal rat hippocampal neurons finds mi215 reduces PPF-induced brain cell death and oxidative stress while targeting large tumor suppressor kinase 2 (LATSA2). When overexpressed, LATSA2 can suppress mi215’s neurotoxic effects. A gene that mimics mi215 also inhibits oxidative stress in neurons, reflected in the suppression of reactive oxygen species, midbrain dopaminergic neurons, and lactate dehydrogenase LDH levels, along with an increase in superoxide dismutase.

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Compound Porcine Cerebroside and Ganglioside Injection (CPCGI) Attenuates Sevoflurane-Induced Nerve Cell Injury by Regulating the Phosphorylation of p38 MAP Kinase (p38MAPK)/Nuclear Factor kappa B (NF-κB) Pathway. Haigang Song, Shining Xun, Huali He, Chongzhen Duan, & Qiang Li. March 2020

Is compound porcine cerebroside and ganglioside injection (CPCGI), a drug used to treat brain disorders, neuroprotective against sevoflurane (SEVO)-induced nerve damage? Using SEVO-exposed neurons from embryonic rats, investigators find CPCGI plays a neuroprotective role by regulating the MAPK/NF-kappaB signaling pathway. When used as a pretreatment, CPCGI reverses the effects of SEVO, enhances cell viability, and reduces neural cell death.

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Research News & Updates

Standards for preclinical research and publications in developmental anaesthetic neurotoxicity: expert opinion statement from the SmartTots preclinical working group. Chinn et al. March 2020

The authors summarize the 2019 SmartTots/IARS/FDA meeting on the importance of preclinical research and reporting standards in the field of anesthetic perinatal neurotoxicity. Leading researchers, anesthesia journal editors, and government representatives describe the advantages/disadvantages of common preclinical models (in vitro, in vivo, non-mammalian, mammalian, small rodent, guinea pigs, pigs, sheep, non-human primates). Participants formulate best practice guidelines, including general considerations and 14 elements of study design and reporting standards, as a road map for novel, rigorous and replicable experimental research.

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Use of Dexmedetomidine and Opioids as the Primary Anesthetic in Infants and Young Children: A Retrospective Cohort Study. Efune et al. June 2020

What are the comparative pediatric complications of dexmedetomidine (DEX) and opioids without sevoflurane (SEVO) or in combination with a low concentration of SEVO? To answer, investigators conduct a chart review on 244 children ≤ 2 years of age receiving DEX and remifentanil with or without SEVO. Findings show complications between SEVO and non-SEVO groups as comparable and both have sufficient hypnosis based on bispectral index values. DEX and opioids may be an alternative to total IV anesthesia with or without 1 minimum alveolar concentration of SEVO.

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Effect of Xenon and Dexmedetomidine as adjuncts for general anesthesia on postoperative emergence delirium after elective cardiac catheterization in children: study protocol for a randomized, controlled, pilot trial. Devroe et al. April 2020

Does the combination of xenon and dexmedetomidine offer a balanced anesthesia technique in young children? How does this combination compare to sevoflurane in reducing the incidence of emergence delirium? The authors, citing issues of neurotoxicity and the 2016 FDA safety warning, seek answers in their Phase II prospective, randomized pilot trial in 80 children ages 0-3 years with congenital heart disease. This article describes the study design, inclusion/exclusion criteria, outcome parameters, sample size, investigational plan, study flow, statistical methodology, and safety issues.

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How Should Trainees’ Influences on Postoperative Outcomes Be Disclosed? Ekeoduru R. April 2020

Drawing on two pediatric cases, the authors illustrate communication issues between anesthesiologists and surgeons that affect length of surgery, anesthetic risk, and informed consent practices. This discussion includes 1) barriers to anesthesiologist-surgeon communication, 2) ethical questions about consent, 3) practice modifications that reduce risk, 4) shared responsibility and decision-making, and 5) the influence of new technologies and physician trainees on length of surgery and risk.

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Optimization of Ultrasound Backscatter Spectroscopy to Assess Neurotoxic Effects of Anesthesia in the Newborn Non-human Primate Brain. Castañeda-Martinez et al. August 2020

Investigators test the feasibility of using ultrasound backscatter spectroscopy (UBS) to monitor and measure death of brain cells in neonatal macaques exposed to sevoflurane (SEVO). Testing of brain cells in vivo involves ultrasound scanning of radiofrequency echo signals; finding the effective scatter size (ESS) and the scattering form factor when measuring echo signals; and analyzing diffuse scattering. Findings show the UBS parameter of ESS has the potential to detect changes in brain microstructure related to anesthesia-induced brain cell death in a non-human primate model.

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Coenzyme Q10 Alleviates sevofluraneinduced Neuroinflammation by Regulating the Levels of Apolipoprotein E and Phosphorylated Tau Protein in Mouse Hippocampal Neurons. Man Yang et al. July 2020

How does Coenzyme Q10 (CoQ10), an antioxidant, protect against sevoflurane (SEVO)-induced neuroinflammation? Findings in cultured mouse neurons show SEVO increased Apolipoprotein E (ApoE) mRNA, total ApoE protein, full-length ApoE, ApoE fragments, phosphorylated Tau protein, and other neuroinflammatory factors. CoQ10 reverses the expression of these factors, replenishes energy, and inhibits oxidative stress—possibly increasing ApoE and phosphorylated Tau protein expression to mitigate SEVO-induced neuroinflammation.

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Propofol Attenuates Isoflurane-Induced Neurotoxicity and Cognitive Impairment in Fetal and Offspring Mice. Yangyang Nie et al. June 2020

Investigators explore the effects of isoflurane (ISO) on embryos and offspring of pregnant mice, and the ability of propofol (PPF) to reduce ISO-induced neurotoxicity. Findings show that maternal ISO at gestational day 15 induces neuroinflammation and brain cell death in fetal embryos, leading to cognitive impairment in offspring at PN Day 31. ISO impairs brain function by increasing interleukin (IL)-6 and poly-ADP ribose polymerase (PARP) fragment levels in the fetus and reducing postsynaptic density (PSD)-95 and synaptophysin levels in offspring. PPF stops these deleterious effects.

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Upregulation of miR-496 Rescues Propofol-Induced Neurotoxicity by Targeting Rho Associated Coiled-Coil Containing Protein Kinase 2 (ROCK2) in Prefrontal Cortical Neurons. Zemei Mao et al. May 2020

What is the role of miR-496 (496), which normally supports healthy gene expression, in propofol (PPF)-induced neurotoxicity? Using primary prefrontal cortical neurons from neonatal rats, investigators study cell viability, cell death, and the relationship of 496 and Rho Associated Coiled-Coil Containing Protein Kinase 2 (ROCK2), a factor in healthy cellular activity. Findings show PPF decreases cell viability, promotes cell death, and increases expression of ROCK2 by inhibiting 496. Overexpression of 496 reduces neurotoxicity by targeting ROCK2.

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Acetyl-l-carnitine Does Not Prevent Neurodegeneration in a Rodent Model of Prolonged Neonatal Anesthesia. Walters et al. May 2020

Researchers explore the neuroprotective effects of acetyl-l-carnitine (ALC), an amino acid and health supplement that may support brain function, in neonatal rats exposed to sevoflurane (SEVO). Findings show SEVO-induced neurodegeneration and elevated levels of Fluoro-Jade C staining in the rat brain, but no signs of SEVO-induced behavioral changes. ALC does not protect against SEVO-induced neurotoxicity and has little effect on Fluoro-Jade C staining.

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Neurotoxicity of Sub-Anesthetic Doses of Sevoflurane and Dexmedetomidine Co-Administration in Neonatal Rats. Perez-Zoghbi et al. May 2020

Does dexmedetomidine (DEX) when co-administered with 1.1% sevoflurane (SEVO), considered a sub-anesthetic dose, reduce responsiveness to external stimuli and protect against SEVO-induced brain cell death? Findings in neonatal rats show SEVO-induced brain cell death increases as the dose of SEVO increases. DEX at 1 ug/kg has no effect on responsiveness to neither stimuli nor SEVO-induced brain cell death. DEX at 5 ug/kg or higher reduces responsiveness to stimuli, but makes brain cell death more likely. DEX at 5-25 ug/kg increases the likelihood of brain cell death when paired with SEVO at 1.1%.

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Neonatal Exposure to Anesthesia Leads to Cognitive Deficits in Old Age: Prevention With Intranasal Administration of Insulin in Mice. Chun-Ling Dai et al. May 2020

Does early and repeated exposure to anesthesia increase the risk of cognitive impairment in old age? Can intranasal insulin reverse anesthesia-induced neurotoxicity? Researchers study these questions by exposing neonatal rats to sevoflurane on PN Days 7-9 followed by measurements in adulthood. At 18-19 months, subjects show cognitive impairment, but no detectable changes in neurobehavioral development, tau phosphorylation, or levels of synaptic protein. Intranasal insulin, given before anesthesia, prevents the increased risk of anesthesia-induced cognitive impairment.

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Iron Overload Contributes to General Anaesthesia-Induced Neurotoxicity and Cognitive Deficits. Jing Wu et al. April 2020

The authors find that ketamine (KT) and sevoflurane (SEVO) exposure disrupts iron metabolism in cultured neurons from young and old mice. This disruption, in turn, creates iron overload, activated by N-methyl-D-aspartate Receptor – Dexamethasone-induced Ras-related protein 1 (NMDAR-RASD1) signaling via Divalent metal transporter 1 (DMT1) action in the brain. Deferiprone, a drug that removes excess iron from the body, stops KT and SEVO-induced mitochondrial dysfunction, iron-dependent brain cell death, and further cognitive deficits.

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Sevoflurane Inhibits Neuronal Migration and Axon Growth in the Developing Mouse Cerebral Cortex. Dongdong Chai, Jia Yan, Chunzhu Li, Yu Sun, Hong Jiang. April 2020

Using pregnant mice in mid-gestation and cultured neurons from the brains of their offspring, investigators study the effects of maternal exposure to sevoflurane (SEVO) on fetal cortical neuron migration, axon length, and spatial memory. Findings show two maternal exposures to SEVO induce a decrease in neuro-oncological ventral antigen (Nova2) expression resulting in neural migration deficits in the fetal brain—these can lead to learning and behavioral deficits. The resulting data also suggested that Netrin-1/Dcc might be an effective target for drugs designed to decrease anesthetic absorption and protect fetal development when anesthesia is necessary during pregnancy.

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Potential Neurodevelopmental Effects of Pediatric Intensive Care Sedation and Analgesia: Repetitive Benzodiazepine and Opioid Exposure Alters Expression of Glial and Synaptic Proteins in Juvenile Rats. O’Meara et al. April 2020

How does repeated treatment with benzodiazepines and opioids affect the developing brain? To explore, investigators inject juvenile rats with morphine and midazolam (MDZ) followed by screening for neurodevelopmental effects. When compared to controls, morphine + midazolam subjects show that repetitive morphine and midazolam administration effected synaptic, astrocytic, microglial, and myelin proteins.

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Evaluation of the Toxicity of Sugammadex in Zebrafish Larvae. Woon Young Kim, Yeon Hwa Kim, Ji Yoon Lee, Jae Hwan Kim, & Too Jae Min. March 2020

Is Sugammadex (SX), a neuromuscular blockade reversal agent, toxic to the fetus and to children <3 years of age? To answer, investigators study the viability of SH-SY5Y neuronal cells, a human-derived cell line, and zebrafish larvae treated with SX. Findings show no adverse effects on neuronal cells or larvae from SX. Survival rates for neuronal cells and heart formation are the same in all concentrations. The authors conclude that SX may be feasible in pregnancy, but call for clinical studies to validate preclinical findings and demonstrate SX safety in humans.

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Cyclophilin D Contributes to Anesthesia Neurotoxicity in the Developing Brain. Yiying Zhang et al. February 2020

What is the role of Cyclophilin D (CypD), a protein in mitochondria, in sevoflurane (SEVO)-induced neurotoxicity? This study explores the question using young wild type (WT) and CypD knock out (KO) mice at PN Days 6-8, and neural progenitor cells (NPCs). Findings show SEVO induces a build-up of CypD, mitochondrial dysfunction, impaired neurogenesis, and cognitive deficits in WT mice and NPCs from WT mice, but not in CypD KO mice or NPCs from KO mice. SEVO reduces the binding of CypD with adenine nucleotide translocator, a second component to mitochondrial permeability transition pore (mPTP), normally modulated by CypD.

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Research News & Updates

Pediatric anesthesiologists’ attitudes about neurotoxicity and the FDA drug safety communication. Gentry, Feldman, & Opel. April 2020

The authors report survey findings from 270/3315 members of the Society of Pediatric Anesthesia on the impact of the 2016 FDA drug safety communication regarding general anesthetics/sedation drugs in young children/pregnant women. 59% agree with the recommendation to discuss risks, benefits, and timing of procedures. 65% agree that parents/caregivers should be aware that unnecessary surgery should be delayed regardless of the authenticity of the FDA warning. 51% discuss neurotoxicity more frequently following the FDA communication. There is considerable variation among anesthesiologists’ agreement with and informed consent practices, suggesting that many are not following the FDA recommendations.

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GAS, PANDA, and MASK: No Evidence of Clinical Anesthetic Neurotoxicity! Editorial Views. Vutskits & Culley. October 2019

The authors conclude that primary and secondary outcomes of the GAS study, which are consistent with results of PANDA and MASK studies, show no association between 1 hour of sevoflurane and low cognitive scores at 2 years or low IQ tests at 5 years. There is strong evidence that short exposure to general anesthesia does not alter neurodevelopmental outcomes, a factor relevant to many short, elective procedures in infants. Is it therefore time to eliminate the 2016 FDA warning? Is there now sufficient evidence to support a general anesthetic over an awake regional procedure with no sedation?

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GAS, PANDA, and MASK: Comment – Williams & Sartorelli. March 2020

Williams & Sartorelli agree that short exposure to general anesthesia is unlikely to cause clinically significant neurocognitive deficits in young children. However, choosing a form of awake regional anesthesia is not about theoretical neurotoxicity risk. This is a conscious choice to use a technique with lower risk of hypotension, apnea, and laryngospasm, along with lower pain scores and shorter anesthesia control times.

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GAS, PANDA, and MASK: Comment – Ing, et al. March 2020

This comment takes issue with “No Evidence of Clinical Anesthetic Neurotoxicity!” (above). The authors say it is untrue that GAS finds no difference in primary and secondary outcomes; and untrue that PANDA and MASK provide strong evidence for lack of detectable alterations in neurodevelopmental outcomes. In children with a single exposure to anesthesia for inguinal herniorraphy, PANDA finds a higher proportion with abnormal scores on scales measuring depression and anxiety. MASK finds similar on scales measuring aggression and rule breaking. Parent reports also show differences in tests of behavior/emotions and executive function./p>

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GAS, PANDA, and MASK: Reply. Vutskits & Culley. March 2020

The authors respond to comments on their editorial (shown above). Interpretation of data can vary among experts. Differences of opinion stem from unsolvable limitations in experimental and clinical studies. On secondary outcomes, a statistical association does not imply a causal relationship; they do not provide evidence of clinical anesthetic neurotoxicity. On multiple exposures leading to worse outcomes—many questions remain and there are confounding factors. Awake regional block is an option for some surgeries in small infants; hypothetical risks should not dictate regional vs. general anesthesia; a combination may be optimal. The skill of the anesthesiologist may be more important than choice of anesthetic.

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“Pediatric Anesthetic Neurotoxicity” Time to Stop! Barnes, Richard K. November 2019.

The author cites select animal and clinical studies, since 1981, to underscore the lack of evidence for anesthesia-induced neurotoxicity in children. He points to statements from leading organizations in the field and editorials in major journals as embracing the assumption that anesthesia associates with brain cell death, developmental and behavioral impairments, and disorders like autism and ADHD. Proving this assumption wrong fuels extensive research into a “phenomenon unlikely to exist,” while known risks in pediatric anesthesia go unaddressed.

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General anesthesia in infants: neurobiological and neuropsychological concerns. Jáuregui-Huerta, Redolar-Ripoll, Cupul-García, Trillo-Gómez, & Ruvalcaba-Delgadillo. March 2020

In their review, the authors explore the effects of general anesthesia on brain development in children. Findings, primarily from uncontrolled retrospective cohort studies and a few controlled studies, “partially support” the 2016 FDA drug safety warning. Cumulative evidence supports the safety of general anesthesia in children with no “massive effects” on cognitive development. However, there is evidence to suggest alterations in cognitive function with long-term anesthesia exposure.

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Anesthesia for Major Surgery in the Neonate. Kuan & Shaw. March 2020

The authors urge anesthesiologists to recognize, and be highly vigilant about, the unique needs of neonates, defined as pre and full-term babies up to 28 days, throughout any course of major surgery. There is no consensus on the safest anesthetic regimen for them. They face a higher perioperative risk for death and illness than older children and adults. Premature neonates and neonates with major or severe congenital heart disease and pulmonary hypertension need specialized care.

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Neurotoxicity of Drugs in Children During Antenatal and Postnatal Development Periods. Postnikov et al. February 2020

When pregnant women take drugs, including anticonvulsants, antidepressants, antipsychotics, and anesthetic agents, what are the neurotoxic effects on offspring at ages 0 to 3 years? The authors find a high incidence of central nervous system complications that are transient (seizures, impaired consciousness) and persistent (developmental brain malformations and impaired cognitive function). Population-based risks of neurotoxicity are associated with ethnic and genetic factors, renal and hepatic failure, and incidence of neuropsychic disease.

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General anesthesia risk across pediatric surgical specialties: Low in otolaryngology. Kolb, Tinley-Strong, Rangarajan, Uejimac, & Shah. February 2020

This retrospective review analyzes data on 11,757 children having pediatric surgery at a tertiary-care center. Of these children, 430 (3.7%) are <3 years old with surgery > 3 hours–nearly half of which (47%) are cardiothoracic surgeries. 36% of the 430 are in neuro, cardiology, plastic, and general surgery; 9% are in urology, ophthalmology, and orthopedic surgery; and .5% in otolaryngology. Investigators urge clinicians to weigh the risks of surgery against the known functional and neurodevelopmental consequences of not doing surgery.

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Playing with dexmedetomidine pharmacokinetics! Hammer & Shafer. December 2019

The authors comment on results of a phase 1 clinical trial on dexmedetomidine (DEX) bolus and infusion in corrective infant cardiac surgery (Zuppa et al, December 2019). DEX is a promising agent for pediatric procedural sedation and surgical anesthesia, where its use is on the rise. There is no FDA approval for the use of DEX in infants and children, but it has a favorable hemodynamic and ventilator profile. Animal studies also show that DEX does not increase risk during periods of synaptogenesis.

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Neurotoxicity effects of anesthetic exposure on the developing brain of non-human primates. Weiwei Yu, Ziyi Wu, & Ping Zhao. July 2020

In their overview, the authors discuss findings on anesthetic neurotoxicity in non-human primates. Results show varying degrees of neurodegeneration by anesthesia type, duration/dose of exposure, timing of exposure, and brain region. Significant advances in minimally and non-invasive neuroimaging techniques hold great promise for pediatric neurotoxicity research into brain structure and function.

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HSP90 inhibitor 17AAG attenuates sevoflurane-induced neurotoxicity in rats and human neuroglioma cells via induction of HSP70. Min Liu, Moyun Li, Yu Zhou, Qian Zhou, & Yugang Jiang. April 2020

Investigators explore the neuroprotective effects of 17 AAG (17), an antibiotic with neuroprotective effects, on sevoflurane-induced neurotoxicity in rat neurons and H4 human brain tumor cells. Findings show 1) 17 reduces sevoflurane (SEVO)-induced cell death and oxidative stress, 2) suppresses SEVO-induced upregulation of interleukin-6 (IL-6) and activation of the nuclear factor-κB (NF-κB) signaling, and 3) protects against sevoflurane-induced neurotoxicity via heat shock protein, HSP70.

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The Role of Histone Acetylation in the Sevoflurane-induced Inhibition of Neurogenesis in the Hippocampi of Young Mice. Junke Jia et al. April 2020

The authors explore mechanisms of sevoflurane (SEVO)-induced neurodegeneration and the associated role of histone acetylation, which normally supports gene function. Neonatal mice receive a mixture of SEVO + oxygen for 3 days plus sodium butyrate (NaB) before, during, and through testing. Findings show SEVO-induced deficits in learning and memory at 4 weeks post exposure. NaB reverses these deficits by increasing the number and proliferation of neural stem cells; restoring histone acetylation and BDNF/TrkB protein expression; and improving performance on tests for learning and memory.

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PDE-7 Inhibitor BRL-50481 Reduces Neurodegeneration and Long-Term Memory Deficits in Mice Following Sevoflurane Exposure. Chen, Li, Zhong, Kang, and Chen. April 2020

Can the phosphodiesterase PDE-7 inhibitor BRL-50481 (BRL) protect against sevoflurane (SEVO)-induced neurodegeneration in young mice? Findings show BRL has positive effects when co-administered with SEVO. BRL 1) reduces SEVO-induced deficits in learning and memory, 2) protects recognition memory and mitigates neuron cell death, 3) restores cAMP (a messenger in cell-to-cell communications), and 4) activates the cAMP/CREB signaling pathway.

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Inhibition of the electron transport chain in propofol induced neurotoxicity in zebrafish embryos. Lin Hea, Xuan Wang, & Shan Zheng. March-April 2020

The authors explore the mechanisms of propofol (PPF)-induced neurotoxicity in the developing brain using a new model with zebrafish embryos. Findings show PPF significantly affects processes essential to brain cell life by reducing 1) electron transport chain complex IV activity, 2) expression of cytochrome c oxidase subunit IV and transcription level cox 4i1, 3) mitochondrial membrane potential, and 4) adenosine triphosphate (ATP) content.

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Ketamine promotes the neural differentiation of mouse embryonic stem cells by activating mTOR. Xuhui Zhou et al. March 2020

Using mouse embryonic stem cells (mESCs), investigators explore the effects of low-dose ketamine (KT) on neural cell differentiation. Findings show KT promotes differentiation of mESCs into neural stem cells and activates mTOR, a signaling pathway that supports cell survival, by upregulating the expression of phosphorylated mTOR. Rapamycin, a naturally derived drug compound with immunosuppressant properties, or a knockdown of mTOR, can inhibit mTOR and suppress neural differentiation.

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Effects of propofol on hippocampal neuron viability. Xu, Wu, Liu & Zhang. March 2020.

The authors use hippocampal neurons in vitro to discover the effects of propofol (PPF) at different concentrations on neuron cell viability and death. Findings show low concentrations of PPF (.5 μM and 1 μM) improve the neuron cell survival rate while high concentrations of PPF (10, 50, 100, 200 μM) reduce cell viability and promote cell death. The P38MAPK signaling pathway in the brain plays a role, reversible with inhibitor SB203580, in PPF effects at high concentrations.

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Resveratrol Mitigates Sevoflurane-Induced Neurotoxicity by the SIRT1-Dependent Regulation of BDNF Expression in Developing Mice. Xiaole Tang et al. February 2020

What is the mechanism of sevoflurane (SEVO)-induced neurotoxicity in neonatal mice? Findings show SEVO inhibits the protein levels of Sirtuin1 (SIRT1), which normally supports synaptic function and cognition. Inhibition of SIRT1 associates with downregulation of BDNF, modulated by MeCP2 and CREB—three brain proteins. Pretreatment with resveratrol, an antioxidant-like compound found in grape skins, reverses SIRT1 inhibition and increases BDNF expression. Resveratrol rescues CREB and MeCP2 levels and improves long-term cognitive performance in adult mice with early exposure to SEVO.

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Exogenous GM1 Ganglioside Attenuates Ketamine-Induced Neurocognitive Impairment in the Developing Rat Brain. Meng et al. February 2020

Can pretreatment with Monosialotetrahexosylganglioside (GM1), a type of lipid, prevent ketamine (KT)-induced developmental neurotoxicity in mice? To answer, investigators pretreat PN Day 7 rat pups with GM1, expose them to KT, then follow with tests in adulthood for cognitive function, brain cell death, protein expression, and protein phosphorylation. Findings show positive potential for the clinical use of GM1 to prevent the cognitive deficits induced by ketamine in the young per se.

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L-theanine attenuates Isoflurane-induced Injury in Neural Stem Cells and Cognitive Impairment in Neonatal Mice. Yong Chen et al. February 2020

Can L-theanine (L-t), an amino acid found in green and black tea, reduce isoflurane-induced damage in neural stem cells (NSCs) and cognitive impairment in young mice? To answer, investigators pretreat NSCs and young mice with a gas mixture, isoflurane or L-t, followed by exposure to isoflurane and testing. In NSCs, ISO exposure inhibits cell viability and cell proliferation, promotes cell death, increases caspase-3 activation, and downregulates the Akt/GSK-3β signaling pathway. Pretreatment with L-t eliminates NSC damage and late cognitive deficits in mice.

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Neuroprotective effects of dexmedetomidine against the ketamine-induced disturbance of proliferation and differentiation of developing neural stem cells in the subventricular zone. Huang h et al. February 2020

This in vivo study in neonatal mice explores the neuroprotective role of dexmedetomidine (DEX) in neural stem cells (NSCs) exposed to ketamine (KT). The authors create five test groups: control, KT only, and KT with 1kg DEX or 5kg DEX or 10 kg DEX. Findings show KT significantly inhibits neural stem cell proliferation and astrocytic differentiation in the subventricular zone of the brain. Pretreatment with DEX at moderate (5kg + KT) and high (10kg + KT) doses reverses KT-induced disturbances in proliferation and differentiation of NSCs.

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Conflicting Actions of Inhalational Anesthetics, Neurotoxicity and Neuroprotection, Mediated by the Unfolded Protein Response. Hiroshi Kokubun, Hisayo Jin, Mari Komita, & Tomohiko Aoe. January 2020

Investigators explore the neurotoxic and neuroprotective effects of sevoflurane, (SEVO) in neuroblastoma cells of developing and adult mice. Findings show pre-exposure to SEVO reduces expression of C/EBP homologous protein (CHOP) in neuroblastoma cells and significantly improves cognitive function in adult-wild type mice, but not in adult mice with the binding immunoglobin protein (BiP) mutation. SEVO causes endoplasmic reticulum (ER) stress that stimulates the unfolded protein response (UPR); this may help cells adapt to injury and improve neuronal function—in adults but not developing mice.

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The mTOR Inhibitor Rapamycin Prevents General Anesthesia-Induced Changes in Synaptic Transmission and Mitochondrial Respiration in Late Postnatal Mice. Xianshu Ju et al. January 2020

Investigators evaluate the role of mTOR signaling in anesthesia-induced neurotoxicity (AIN) in PN Day 16-17 mice exposed to sevoflurane (SEVO). Findings show SEVO induces widespread mTOR phosphorylation in male and female mice. Pretreatment with rapamycin, a widely used pediatric inhalation agent and mTOR inhibitor, prevents mitochondrial respiration and male dependent excitatory synaptic transmission, but does not affect inhibitory synaptic transmission in females. mTOR inhibitors may prove to be effective therapeutic agents for AIN.

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Dexmedetomidine Alleviates Neurogenesis Damage Following Neonatal Midazolam Exposure in Rats through JNK and P38 MAPK Pathways. Shan Lei et al. January 2020

The authors explore the neuroprotective effects of dexmedetomidine (DEX) on midazolam (MDZ)-induced neurogenic damage in neonatal mice and neural stem cells (NSCs). Findings show MDZ decreases cell proliferation and increases cell death in the subventricular and subgranular zones of the brain, and in cultured NSCs. MDZ decreases cell viability and increases expression of protein levels in critical signaling pathways. Co-treatment with DEX reduces MDZ-induced damage to cell proliferation, cell death, cell viability, and protein expression of p-JNK and p-P38 in cultured NSCs.

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NR2B receptor- and calpain-mediated KCC2 cleavage resulted in cognitive deficiency exposure to isoflurane. Tang et al. January 2020

Researchers explore the effects of isoflurane (ISO) on dendritic development via mediation of KCC2 cleavage (brain protein division or split) in developing mice. Findings show that ISO induces a significant increase in NR2B nerve receptor levels; excessive activation of calpain-2 (a brain protein), and increases in KCC2 cleavage. Pretreatment with ifenprodil, a known inhibitor, helps to alleviate many of these ISO-induced neurotoxic changes. KCC2 cleavage is a major determinant of ISO-induced long-term cognitive deficiency.

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Effects of embryonic propofol exposure on axonal growth and locomotor activity in zebrafish. Lin He, Xuan Wang, & Shan Zheng. January 2020.

The authors explore the effects of propofol (PPF) on long-term learning and memory in a new model using zebrafish embryos. Findings show 1, 2, and 4 ml of PPF have no effect on spontaneous movement in larvae. Two and 4 ml significantly impair learning and memory function. PPF significantly restricts axonal growth of motor neurons in their embryonic phase. Neuronal growth correlates with learning and memory function.

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Best Pharmaceuticals for Children Act (BPCA) Priority Releases 2020-2021 List of Needs in Pediatric Therapeutics

The National Institutes of Health (NIH) recently announced an updated BPCA Priority List of Needs in Pediatric Therapeutics. In an ongoing effort to improve the level of information on the safe and effective use of pharmaceuticals used to treat children, the BPCA requires that the NIH poll pediatric experts annually to identify the latest, highest priority needs. This year, anesthetics have been added and prioritized for study to the BPCA list.

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Research News & Updates

Definition of Clinical Outcomes in Pediatric Anesthesia Research: It Is Like the Tower of Babel! Nafiu, Tobias, & DiNardo. February 2020.

Problems persist in pediatric anesthesia research due to a lack of standardization in definitions for outcome variables, including wide variability in diagnostic criteria for anesthesia-related long-term neurobehavioral deficits. There are too many different terms or definitions for the same ideas and concepts. This leads to problems in translating research to clinical practice, in replicating studies, and in conducting meta-analyses. Many studies use a variety of diagnostic instruments and comparing them is difficult. What should we be measuring in a battery of neurobehavioral tests? Which variables are most important? These questions need answers.

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Exposure to Surgery and Anesthesia in Early Childhood and Subsequent Use of Attention Deficit Hyperactivity Disorder Medications. Ing et al. January 2020

Investigators identify the risk of using attention deficit/hyperactivity disorder (ADHD), nonpsychotropic, and psychotropic medications after a single exposure to surgery and anesthesia in children <5 years. Findings show a significant/37% higher risk for persistent use of ADHD medications and a significant risk for use of psychotropic medications (sedatives, antidepressants, antipsychotics, mood stabilizers). There is less risk for use of nonpsychotropic medications (amoxicillin, azithromycin, diphenhydramine).

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Paediatric Anaesthesia Neurotoxicity: Bring Back the Papoose Board? Gino Gizzarelli, BScPhm, DDS, MSc (Dental Anaesthesia). January 2020

Does anesthesia exposure increase the risk of learning disabilities (LDs)? The author highlights findings from several seminal studies, including a 2009 landmark study of children <4 years born 1976-1982. Results show no increased risk for LPs with a single exposure (N=449); an increased risk with two exposures (N=100); and an increased risk with three+ exposures (N=44). This particular study does not address unknown confounding factors, but the author includes a long list of potential indirect, confounding factors. The author also highlights several, more recent studies whose results and conclusions differ from those of Wilder in 2009.

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General Anesthetic-Induced Neurotoxicity in the Immature Brain: Reevaluating the Confounding Factors in the Preclinical Studies. Ailin Luo et al. January 2020

What factors in experimental research may lead investigators to overestimate the adverse effects of general anesthesia on the developing brain? The authors summarize advances in experimental research while providing suggestions for increasing the strength of preclinical data and findings.

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Exposure to General Anesthesia May Contribute to the Association between Cesarean Delivery and Autism Spectrum Disorder. August 2019

Does cesarean section (CS) increase the risk of autism spectrum disorder (ASD)? The authors explore this question in 347 children with ASD, including 117 with other developmental delays (DD). There are 2226 matched controls. Findings show a significant association of CS with an increased risk for ASD, but not DD. General anesthesia for CS increases the risk of ASD with no significant difference in risk between indicated and not indicated surgeries.

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False Interpretation of Scientific Data Leads to Biased Conclusions About the Association Between Cesarean Deliveries Under General Anesthesia and Risk of Autism Spectrum Disorder. February 2020

In Response to Exposure to General Anesthesia May Contribute to the Association between Cesarean Delivery and Autism Spectrum Disorder.

Authors of the study “Exposure to General Anesthesia May Contribute to the Association Between Cesarean Delivery and Autism Spectrum Disorder” respond point-by-point to a letter to the editor criticizing their research. The authors clarify several false statements and interpretations, and explain the importance and validity of their study.

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MicroRNA-582-5p reduces propofol-induced apoptosis in developing neurons by targeting ROCK1. Zhang, Xu, Chi, & Cui. February 2020

Using newborn rat neurons, investigators explore the role of microRNA-582-5p (582) in propofol (PPF) – induced neurotoxicity. Findings show 582 reduces brain cell death by inhibiting Rho-associated serine-threonine protein kinase1 (ROCK1), a regulatory gene. Overexpression of 582 reverses the expression of proteins involved in brain cell death and reduces PPF toxicity in neuronal cells, with no effect on normal nerve cells.

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Desflurane and Surgery Exposure During Pregnancy Decrease Synaptic Integrity and Induce Functional Deficits in Juvenile Offspring Mice. Zou et al. February 2020

Using mice, investigators explore the effects of maternal desflurane (DES) exposure in pregnancy on cognition and memory functions in offspring. Findings in fetal tissues and juvenile offspring show significantly reduced expression of PSD-95 in hippocampal neurons; and impaired memory function with higher sensitivity to fear conditioning. Neurotoxic effects including cell death and disruption in synaptic integrity appear in offspring.

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Vitexin improves neuron apoptosis and memory impairment induced by isoflurane via regulation of miR-409 expression. Qi, Chen, Shan, Nie, & Wang. January 2020

How does vitexin (VT), a plant-based compound used in Chinese medicine, reduce isoflurane (ISO) – induced neurotoxicity in rat neurons? Investigators find VT mitigates ISO-induced damage to cell viability, reduces PC-12 cell death, and reduces expression of inflammatory cytokines. VT significantly increases miR-409 expression, an effect that further stimulates VT’s neuroprotective qualities and expression of the p-AMPK/t-AMPK and p-GSK3β/t-GSK3β pathways.

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Distinct, sex-dependent miRNA signatures in piglet hippocampus induced by a clinically relevant isoflurane exposure: a pilot study. Whitaker et al. January 2020

The authors explore the effect of sex on miRNA (mRNA) expression in neonatal piglets exposed to isoflurane (ISO). Findings show distinct sex-dependent differences in the effects of ISO on mRNAs in the hippocampus. In males, 17/326 mRNAs show changes: 10 mRNAs are highly expressed and seven males have lower expression than females. In females, 14/326 mRNAs change with no overlap between sexes in the mRNAs that change.

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Sex differences in neurodevelopmental abnormalities caused by early-life anaesthesia exposure: a review. Cabrera et al. January 2020

A review of 11 animal studies explores sex differences, an understudied biological variable, in the field of anesthesia-induced developmental neurotoxicity. The authors present an emerging pattern of potentially sex-dependent neurodevelopmental abnormalities in cognitive, behavioral, molecular, cellular, and genetic domains that may be relevant to human infant exposure.

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Ketamine exerts neurotoxic effects on the offspring of pregnant rats via the Wnt/β-catenin pathway. Zhang et al. January 2020

In their animal study, the authors explore the effects on offspring of maternal ketamine exposure in the second trimester. Findings show cognitive memory impairment and neurotoxicity in babies due to nerve injury, and changes in hippocampal nerve density and dendritic spines. There is down regulation (loss of cell response) in some genes relating to the Wnt/β-catenin pathway and TCF/LEF transcription factors—both important to healthy brain cell function.

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Downregulation of CDK5 Restores Sevoflurane-Induced Cognitive Dysfunction by Promoting SIRT1-Mediated Autophagy. Yang et al. January 2020

What is the role of autophagy, a process of cell clean up and renewal, in anesthesia-induced neurotoxicity? To answer, investigators perform both in vivo and in vitro experiments, including exposing PN Day 6 mice to sevoflurane (SEVO) followed by treatment with CDK5 and autophagy inhibitors. Findings show the CDK5 inhibitor reverses SEVO-induced nerve cell death and cognitive dysfunction by activating Sirtuin1 expression. Suppressing Sirtuin1 expression blocks the protective effects of CDK5 inhibition by blocking autophagy.

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Effects of Xenon-Based Anesthetic Exposure on the Expression Levels of Polysialic Acid Neural Cell Adhesion Molecule (PSA-NCAM) on Human Neural Stem Cell-Derived Neurons. Liu et al. January 2020

Investigators explore the neuroprotective effects of xenon (XEN) against propofol (PPF) – induced neurotoxicity in a human neural stem cell model. Findings show neuronal cell surface polysialic acid (PSA) cleaves off from the neural cell adhesion molecule (NCAM) by endoneuraminidase N (Endo-N, an enzyme). With XEN, there is intense PSA staining on the neuronal cell surface 16 hours after Endo-N washout. Prolonged exposure to PPF significantly decreases the positive rate of PSA-labeled neurons. XEN attenuates the adverse effects of PPF on neurons.

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Look for us during 2020 at the following events:

• SPA/AAP Pediatric Anesthesiology 2020, February 28 – March 1, Paradise Island, Bahamas
• 2020 Midwest Anesthesia Resident’s Conference, April 24 – 26, Milwaukee, Wisconsin
• 2020 Society for Pediatric Sedation Conference, May 18 – 20, Baltimore, Maryland

Research News & Updates

Dexmedetomidine improves neurodevelopment and cognitive impairment in infants with congenital heart disease. Huang, Gou, Rong, & Wang. December 2019

The authors explore the effects of dexmedetomidine, DEX, on 256 infants < 2 years old with congenital heart disease undergoing thoracic surgery. Findings show higher IQ and neurodevelopmental evaluation scores in babies receiving DEX. There are no significant differences between subjects and controls in mortality, duration of mechanical ventilation, and length of stay. DEX shows promise for improving neural development and reducing the adverse effects of general anesthesia in this population.

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Does general anesthesia affect neurodevelopment in infants and children? McCann & Soriano. December 2019

There is clear evidence of anesthesia-induced neurotoxicity in laboratory models, within in vitro and in vivo studies, and with neuronal transmission systems in rats, mice, and non-human primates. In contrast, most studies in children are retrospective. Specifics about medications and monitoring are unavailable. The authors assert that, while the potential for general anesthesia-induced neurotoxicity exists, very little clinical evidence currently supports this in children.

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Neurodevelopmental Effect of General Anesthesia on the Pediatric Patient. Cavuoto, Javitt, & Chang. November 2019

Investigators explore evidence of anesthesia-induced neurotoxicty in children based on recent animal and clinical studies. Research in rodents and non-human primates clearly demonstrates anesthesia-induced neurotoxicity. However, prospective clinical studies show no significant difference in IQ scores in children < 3 years with isolated and/or short exposures. These findings are particularly important for children experiencing trauma and other conditions requiring urgent and early surgery under anesthesia.

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Paeonol attenuates isoflurane anesthesia-induced hippocampal neurotoxicity via modulation of JNK/ERK/P38MAPK pathway and regulates histone acetylation in neonatal rat. Jin et al. January 2020

Using neonatal rats, investigators explore the neuroprotective qualities of paeonal, a plant-derived compound used in Chinese medicine, against isoflurane (ISO)-induced neurotoxicity. Findings show paeonol 1) reduces brain cell death; 2) downregulates ISO-induced elevations in cleaved caspase-3, Bad and BAX expression; 3) enhances expression of cell-protective proteins; 4) improves acetylation of HK39 and HK412; 5) regulates ISO-induced changes in brain signaling; and 6) improves general behavior and freezing responses.

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MicroRNA-665 mediates propofol-induced cell apoptosis in human stem cell-derived neurons. Jiang, Yang, Zhao, & Pan. December 2019

What’s behind propofol (PPF)-induced cell death and neurotoxicity in human embryonic stem cell (hESC)-derived neuron cells? Using TUNEL staining and assessments of chain reactions, investigators find: 1) PPF induces dose-dependent brain cell death followed by upregulation of microRNA-665 (665) expression; 2) overexpression of 665 increases PPF-induced cell death; 3) targeting 665 decreases PPF-induced cell death; and 4) the 665 mechanism plays a key role in PPF-induced cell death.

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Ketamine Regulates Phosphorylation of CRMP2 To Mediate Dendritic Spine Plasticity. Zhang et al. December 2019

This study reveals a new mechanism by which ketamine promotes the growth and development of dendritic spines in developing cortical neurons Using in vitro and in vivo brain cells from rats, investigators discover that KT exposure significantly increases CRMP2 protein expression in the cerebral cortex, stimulating cortical neuron processes and growth of dendritic spines. KT exposure also significantly reduces phosphorylation levels of CRMP2 at Thr514 and Ser 522.

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Hemin treatment protects neonatal rats from sevoflurane-induced neurotoxicity via the phosphoinositide 3-kinase/Akt pathway. Yang et al. December 2019

The authors explore the neuroprotective effects of hemin, a fraction of red blood cells used to treat disease, against sevoflurane (SEVO)- induced neurotoxicity in rat brain cells. Findings show SEVO inhalation increases cleaved-caspase-3 levels, a sign of brain cell death. Through the P13K/Akt signaling pathway, which supports basic cell survival and growth, hemin inhibits brain cell death, increases expression of antioxidant enzymes, and reduces oxidative damage.

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microRNA-124 attenuates isoflurane-induced neurological deficits in neonatal rats via binding to EGR1. Yang et al. December 2019

Investigators study the effects of micro R-124 (124), a molecule that regulates gene expression, on neurons in the brains of neonatal rats after exposure to isoflurane (ISO). Findings show ISO reduces 124 expression; increases EGR1 (a nerve growth factor-induced protein), and damages spatial learning and memory. 124 targets and negatively regulates EGR1 while improving memory. By inhibiting cleaved-caspase-3 and boosting Bcl-2 expression, 124 fights neuronal cell death and supports cell viability.

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Using animal models to evaluate the functional consequences of anesthesia during early neurodevelopment. Maloney et al. November 2019

This literature review describes neurotoxic effects of certain anesthetic and sedative agents (ASAs) in developing rodents and non-human primates. Animal models repeatedly show that anesthesia exposure induces brain cell death and long-term functional impairments, but reporting of behavioral deficits is inconsistent. To improve test sensitivity and translation potential, the authors propose a rodent model for assessing functional deficits after neonatal ASA exposure, with special reference to experimental design, replicability, and procedural issues.

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Voluntary Exercise Rescues the Spatial Memory Deficit Associated With Early Life Isoflurane Exposure in Male Rats. Chinn et al. November 2019

Can exercise alone rescue the cognitive deficits associated with early anesthesia exposure? Investigators answer in the affirmative after exposing neonatal rats to isoflurane (ISO) and 3 weeks of wheel exercise followed by behavioral tests and brain studies. In an otherwise rich environment, exercise restores cell proliferation in the hippocampus and rescues long-term spatial memory deficits. Findings show no ISO-induced deficits in recognition memory tasks. BDNF mRNA levels in the brain are unaffected by ISO exposure and exercise.

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Sirtuin 2 Inhibition Attenuates Sevoflurane-Induced Learning and Memory Deficits in Developing Rats via Modulating Microglial Activation. Wu, Zhang, Zhang, & Zhao. November 2019

Can inhibition of sirtuin 2 (SIRT2), a protein deacetylase, protect the developing brain against anesthesia-induced cognitive deficits? In neonatal rats exposed to sevoflurane (SEVO), investigators find pretreatment with the SIRT2 inhibitor AK7 reverses, mitigates, inhibits, and increases—respectively– SEVO-induced 1) hippocampal-dependent cognitive impairments; 2) neuroinflammation and microglial activation; 3) pro-inflammatory/M1-related markers; and 4) anti-inflammatory/M2-related markers in microglia.

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Dexmedetomidine pretreatment attenuates isoflurane-induced neurotoxicity via inhibiting the TLR2/NF-κB signaling pathway in neonatal rats. Pang, Zhang, Zhou, Zhao, & Liu. November 2019

This animal study explores the protective effects of pretreatment with dexmedetomidine, DEX, against isoflurane (ISO)-induced neurotoxicity. What happens to the TLR2/NF-kB (TLR) signaling pathway along the way? Findings show DEX decreases anesthesia-induced inflammation, improves neuronal structure and viability, enhances spatial learning and memory, and helps reverse ISO-induced activation of the TLR pathway. Injection of Pam3CSK4, a TLR agonist, reverses the protective effects of DEX and reactivates the TLR pathway.

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Early Postnatal Exposure to Isoflurane Disrupts Oligodendrocyte Development and Myelin Formation in the Mouse Hippocampus. Li et al. November 2019

Using neonatal mice, researchers find that early exposure to 4 hours of isoflurane (ISO) disrupts oligodendrocyte (OL) development in the hippocampus by activating the mammalian target of rapamycin pathway (mTOR)—an enzyme that normally supports healthy brain cell growth and function. ISO exposure impairs spatial learning; reduces nerve-protective myelin thickness; and inhibits DNA methylation, proliferation, and differentiation in OL precursor (stem) cells.

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Cognitive impairment and transcriptomic profile in hippocampus of young mice after multiple neonatal exposures to sevoflurane. Song et al. October 2019

Investigators explore the effects of multiple sevoflurane exposures on the genes in the hippocampus of neonatal mice. RNA sequencing after exposure shows 314 differentially expressed genes, highlighting biological processes and signaling pathways. Further analysis clarifies hub-protein involvement: Pten in nervous system development, synapse assembly, learning, memory, and behavior; Nos3 and Pik3cd in oxytocin signaling; and Cdk16 in exocytosis and phosphorylation.

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Hypoxia, hypercarbia, and mortality reporting in studies of anaesthesia-related neonatal neurodevelopmental delay in rodent models: A systematic review. Floyd, Khmara, Lamm R, & Seidman P. October 2019

A review of 103 studies explores hypoxia (HPX, lack of oxygen in tissues), hypercarbia (HPC, too much carbon dioxide in our bloodstream), and mortality in neonatal rodent models of anesthesia neurotoxicity. Spontaneous ventilation appears in 98% of the studies. Of these, only 33% show arterial blood gas monitoring reflecting modest to severe HPC. The median mortality rate of 11% indicates severe HPC. Overall, investigators find inadequate controls for HPC and HPX, which have a known link to brain cell death.

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Maternal surgery during pregnancy has a transient adverse effect on the developing fetal rabbit brain. Van der Veeken et al. October 2019

Investigators study the effect of anesthesia in pregnancy on the fetal brain. Rabbit moms, at the equivalent of the 2nd trimester in humans, receive propofol in sevoflurane for 2 hours, laparotomy, and C-section at term under ketamine-medetomidine/local anesthesia. Offspring show lower motor and sensory scores, brain to body weight ratios, neuron density, cell proliferation rates, and less expression of synaptophysin–a protein that supports nerve connections. By 7 weeks, most impairments resolve with no detectable differences in neuron density or synaptophysin.

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Mild hypothermia ameliorates anesthesia toxicity in the neonatal macaque brain. Ikonomidou et al. October 2019

Can lower body temperatures protect the brain from anesthesia-induced neurotoxicity? Investigators expose neonatal monkeys to > 5 hours of sevoflurane (SEVO), lower body temperatures, and test to quantify death of neuronal cells and oligodendrocytes. Findings show the very narrow protective window of mild hypothermia at 35-36.5 °C offers significant protection from SEVO-induced brain cell death; hypothermia at <35 °C does not.

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Neonatal general anesthesia causes lasting alterations in excitatory and inhibitory synaptic transmission in the ventrobasal thalamus of adolescent female rats. Woodward, Timic Stamenic, & Todorovic. July 2019

Using patch-clamp recordings, investigators discover the effects of anesthesia exposure on synaptic activity and neuron excitability in the thalamus of baby rats. Findings show general anesthesia increases excitatory postsynaptic currents, at a two-fold rate, via AMPA-mediated mechanisms. After a single exposure to isoflurane and nitrous oxide, female rats show an increase in evoked inhibitory postsynaptic AMPA and GABA currents, but males do not. T-type calcium channel and NMDA currents are minimally affected.

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